本期KOL100，我们采访了加拿大皇家科学院院士、加拿大健康科学院院士Moshe Syzf，他为我们讲述了DNA甲基化在多种疾病诊疗中的潜力和优势，也对癌症早筛的未来提出了自己的见解。

访谈中文版

早筛网：您是何时开始研究DNA甲基化的？当时是什么机会让您专注于这个研究方向？

Moshe Syzf院士：

我大约在1974年开始研究，当时我是一名牙科学生，需要写一篇论文。偶然间，我找到了一位刚开始研究DNA甲基化的教授，于是我开始从事这项研究。从一开始，我就对此感到兴奋。我们一直以为DNA只有四种碱基，但现在又多了一种---第五种“碱基”，而且这种碱基的形成方式与其他不同。这表明DNA具有两层信息，一层是遗传信息，另一层是其他信息。当我们开始研究时，对DNA甲基化的作用一无所知，但我们猜测它一定很重要。

早筛网：DNA甲基化与哪些健康或疾病状态相关？未来它可以应用于哪些疾病？

Moshe Syzf院士：

实际上，我认为它与任何疾病都相关，因为任何疾病都涉及基因表达的改变，而基因表达的改变通常也涉及到表观遗传学的变化，而DNA甲基化就是其中的一部分，但主要与复杂疾病和慢性疾病相关。这包括代谢性疾病如糖尿病，心理健康疾病，心血管疾病，癌症以及自身免疫性疾病。因此，它涵盖了各种慢性疾病的范围。

早筛网：在癌症早筛中，与许多其他方法相比，通过DNA甲基化检测进行早期筛查有哪些独特的优势？

Moshe Syzf院士：

人们一直在使用几种方法，比如来自肿瘤细胞的某些蛋白质，如PSA或AFP。人们还使用遗传学，有一些基因在癌细胞中发生突变，你可以在血液中找到这些DNA。然而，现在看来，DNA甲基化是癌症最可靠的标记。DNA甲基化和癌细胞的变化相关性比突变更加显著，并且几乎在每种癌症中都发生。它们在癌症DNA和正常DNA之间产生了如此大的差异，以至于我们的新一代测序技术可以轻松地检测到它们。这就是为什么我相信DNA甲基化将成为癌症早期筛查最可靠的方法。

早筛网：目前在DNA甲基化检测中还需要解决哪些科学问题或技术细节？

Moshe Syzf院士：

我认为我们已经取得了非常重要的进展，新一代测序技术（NGS）使我们能够以非常高的分辨率观察DNA甲基化，这个方法非常好。然而，它相对来说是一种较慢的方法。测序需要大约16到18个小时，有时候甚至需要24个小时。问题是，我们能否创造出POC(point of care)设备，以更快的方式获得序列，并区分癌症和非癌症。其他问题还有物流问题，比如如何获取血液，如何确保血液在到达公司之前不会降解。我们现在使用的方法对于实验室研究来说是很好的，但挑战在于我们如何从实验室研究转向对数百万人进行筛查？因为如果早期筛查成为我们认为每个人都应该做的事情，那就是数十亿人，我们有没有能力做到？我们的方法是为研究实验室而设计的，而不是为生产而设计的。我们正在努力创建一个稳定、高通量且相对成本合理的平台，将DNA甲基化从研究实验室状态转变为商业可行的临床产品。

早筛网：DNA甲基化检测技术应用于单癌症或多癌症检测时，各有哪些优势和劣势？

Moshe Syzf院士：

单癌症检测可以清楚地告诉你癌症的位置。对于存在明确风险的特定癌症或所有人都存在高风险的癌症，单癌症检测非常有效。例如，肝癌的特定的风险人群就是患有肝病的人。所以这些人应该明确进行肝癌筛查，不应该浪费时间在其他癌症上，他们应该专注于高风险的癌症。女性有特定的风险，如乳腺癌或宫颈癌，男性有前列腺癌的风险。所以我认为应该为这些特定的癌症进行特定的检测。然而，全癌症检测或多癌症检测的优势在于，如果你没有特定癌症的风险，它可以给你一些关于你所在群体中正在出现的癌症的提示，挑战在于如何确定癌症的来源。

早筛网：能否通过一管血或一滴血液来检测所有癌症？如果可以，为什么我们仍然需要单癌症检测？

Moshe Syzf院士：

我认为质量不会很好，因为如果我们需要进行全癌症检测，我们需要太多区域，因为每种组织都会有特定的甲基化区域。如果想覆盖所有区域，我们需要进行大量的甲基化分析，当我们这样做时就会牺牲分析的深度。我们做的区域越少，我们就能深入研究并得到更好的解决方案，但是血浆中的DNA量相当小。对于筛查多种癌症，对分析系统的要求会很高。可以采用探针对特定区域进行筛查，比如我们有四个区域可以检测33种癌症。然后，如果检测到癌症，你可以花更多的钱和精力在许多区域中寻找特定的癌症。

早筛网：您认为癌症早筛的未来发展方向是单组学还是多组学？

Moshe Syzf院士：

很难说，但我认为关联性是非常大的，以至于如果技术得到改进，就没有理由再添加其他东西。我们还必须考虑到实际应用的可行性。我们添加的组学越多，成本就越高，设备的复杂性也越高。但有可能我们将DNA甲基化检测与一些更便宜的抗原检测结合起来，比如PSA或AFP等。这些抗原可能相对便宜，再加上DNA甲基化检测就足够了。这样我们就不需要进行蛋白质组学、转录组学、micro RNA组学的检测了。多组学全面检测对于一些富人来说可能是好事，但不是大规模筛查普通人群的好方法。

早筛网：您的团队最近关注科研成果的转化方面有哪些？

Moshe Syzf院士：

我们的重点是构建平台，不仅仅是一台机器，而是如何与机器一起工作。我们希望实现自动化，因为实验室医学的主要问题之一是技术人员在过程中发生的错误。如果能减少错误，就能大大提高灵敏度。我们发现一旦实现自动化，错误就会减少。除了需要自动化，我们还需要多重复合，即能够在短时间内处理更多样本，并缩短从开始到结束的时间。这是一方面，即平台的IT控制和分析，也许还可以应用一些机器学习和人工智能来分析整个过程。但我们还需要进行更多的测试。因此，我们要研究更多的医学领域，寻找早期标志物。正如我所说的，不仅仅是癌症，我相信心血管疾病方向有很大的潜力，自身免疫疾病或免疫疾病也有很大的潜力，糖尿病也有很大的潜力。因此，我们希望在许多领域发现更多的标志物，并创建一个平台。一方面，当我们有了新的标志物时，我们可以很容易地将它们推向临床产品。

早筛网：您的策略是什么？您使用现有的机器还是发明一些自己的机器？

Moshe Syzf院士：

目前我们使用开放系统，这些系统可以进行更改。NGS我们采用成熟的平台，液体处理和自动化，以及计算机自动化，我们都是自己创造的新方法。

早筛网：请分享一下您对全球癌症早期筛查技术的趋势的看法。

Moshe Syzf院士：

机会巨大。我认为新的筛查技术将取代我们目前所做的很多工作。如果成功，它将减少医院中的癌症患者数量，降低癌症的成本，使癌症成为一种可以管理的常见疾病，而不是像现在一样带来巨大的痛苦和苦难。

早筛网：您能举一些进展的例子吗？

Moshe Syzf院士：

例如，肝癌。早期检测可以挽救100%的人，简单的手术或其他治疗方法可以根除癌症。而晚期检测几乎会导致100%的死亡，所以这关系到生死。如果是宫颈癌和其他我们感兴趣的癌症，早期检测可以使93%的人存活。而晚期检测只有15%的存活率，对人类生活的巨大影响，这不仅仅是因为需要化疗，需要痛苦的治疗。如果我们能早期检测，可能就不需要任何治疗，或者仅需手术就足够了，甚至可能不需要手术。我们没有为早期癌症开发药物，但一旦我们开始早期检测，可能会开发出全新的治疗早期癌症的药物，这些药物比我们用于晚期癌症的药物毒性要小得多。

早筛网：您如何看待中国癌症早期筛查市场？

Moshe Syzf院士：

中国市场非常庞大，癌症在中国是一个真正的问题。因此，我认为这个市场非常有潜力。市场足够大，有很多公司可以在这个市场上开展工作，而且医疗的集中化、大型医院和卫生的集中控制也为这种方法做好了准备。一旦政府政策确认这是正确的方法，这将为他们节省大量的费用和努力，中国可能会成为全球最大的早期癌症检测市场。

早筛网：您如何看待DNA甲基化在长寿方面的应用潜力？

Moshe Syzf院士：

我们还开发了一种用于长寿的DNA甲基化测试，其他公司也有类似产品。很明显，随着年龄增长，我们的DNA甲基化会发生变化，而且有些人的变化速度比其他人快。有一些数据表明，如果DNA甲基化变化得更快，可能意味着你的寿命会较短。

随着这些工具的改进，我们将能够测试不同的干预措施，并在长时间内进行实际的测量。即使现在如果我们有一种长寿的干预措施，你永远不知道它是否有效，因为你必须等待50年才能知道它是否有效，因为这太长了。但是如果你有一个即时的测量标准，我们可以进行干预并测试。我们是否改变了寿命？然后再进行另一种干预，然后结合这些干预措施。这将加速我们对长寿方法的发展。

早筛网：甲基化可以逆转吗？

Moshe Syzf院士：

这就是甲基化的美妙之处。我们从父母那里获得的遗传信息是固定的，只有通过基因编辑才能改变，但这不是一个合理的方法。但是表观遗传学是通过可逆的过程完成的。酶会添加表观遗传修饰，也会移除修饰，因此你可以制造这些酶的抑制剂并改变它们。这些抑制剂已经在临床试验和临床实践中使用。例如，有一种名为维达莎（Vidaza）的药物用于治疗癌症，它是一种DNA甲基化抑制剂。此外，还有一些营养补充剂可以改变DNA甲基化，例如S-腺苷甲硫氨酸、维生素C或绿茶，它们都可以改变DNA甲基化，而DNA甲基化也可以通过运动、不同的行为环境来改变。在DNA甲基化中存在着巨大的可塑性，而这在遗传学中是没有的。

早筛网：目前有没有一种实用的干预方法，我们可以在进行干预之前测试DNA甲基化，干预之后再进行一次测试评估效果。

Moshe Syzf院士：

我们现在正在使用DNA甲基化时钟，我们有这样的产品。我们称之为APH（一种DNA复制酶抑制剂阿非迪霉素（Aphidicolin，Aph）），有几家公司与我们合作。除了公司，还有一些研究实验室，正是为了进行时钟的测量而合作。

早筛网：有什么有趣的发现吗？

Moshe Syzf院士：

有几篇论文表明某些干预措施可以逆转生物钟，尽管这仍然存在争议，因为这些研究规模较小，还有更多工作需要完成，也有一些个案证据。有人报告说，他们改变了饮食，更多地采用素食，增加了运动量，从而逆转了DNA甲基化时钟。我们还知道一些药物，如二甲双胍，它是一种治疗糖尿病的药物，但它可能可以改变生物钟，使人变得更年轻。

早筛网：最后一个问题我们来展望一下癌症早期检测的未来。您认为2到3年后市场上的早期癌症检测会是什么样子？

Moshe Syzf院士：

我认为需要超过2到3年，因为医学是非常保守的，要改变态度非常困难，而且这是一种完全改变态度的过程。但我相信，每个年龄段的人都会每年或半年进行早期癌症检测，然后政府将建立体系。一旦检测到癌症，人们可以立即得到治疗和随访，从而立即采取行动。最终，他们将意识到这将能节省大量的资金。即使在开始时需要花费许多的资金，但它从长远看将节省很多资金。

早筛网：非常感谢您的分享。

English Version

ZAODX：When did you start studying DNA methylation? What was the opportunity to focus on this research direction at that time?

Prof. Moshe Syzf:
I started at around 1974, I was a student in a dentistry and I needed to write a thesis. So by accident, I just found a professor who was starting to work on DNA methylation and I started working on it. And then it excited me from the beginning. Having another mark on DNA we always learned that DNA has four bases, but now it has a 5th base, but that base comes in a different way. So that suggests that DNA has two layers of information, one genetics, and one something else. When we started, we had no idea what DNA methylation is doing. But we guess it must be important.

ZAODX：
What health or disease state is the DNA methylation associated with, and which disease can it be applied to in the future?

Prof. Moshe Syzf:

So really, I believe it's associated with any disease, because any disease involves change in gene expression, and changes in gene expression usually also involve changes in epigenetics, and DNA methylation is part of it, but mostly with complex diseases and chronic diseases. And it includes metabolic diseases like diabetes and it includes mental health diseases, it includes cardiovascular diseases, it includes cancer, but also autoimmune diseases. So it really covers the whole span of chronic diseases.

ZAODX：
In the field of cancer early screening, what are the unique advantages of DNA methylation compared with many other methods?

Prof. Moshe Syzf:
There are several methods that people have been using like certain proteins that come from tumor cells, like PSA or AFP. And people are also using genetics and there are some genes as some mutations that happen in cancer cells and you can find that DNA in the blood. However, it seems now that DNA methylation is the most robust marker of cancer. The changes in DNA methylation and cancer cells are dramatic much more than mutations and happen almost in every cancer. And they create such a difference between cancer DNA and normal DNA that our new techniques of next generation sequencing can easily detect them. That's why I believe DNA methylation will be the most robust method for early screening of cancer.

ZAODX：
At present what scientific problems or technical details still need to be solved in DNA methylation detection?

Prof. Moshe Syzf:

I think we have made very significant advances. Sequencing allows us to look at DNA methylation, very high resolution, and the method is very good. However, it is relatively a slow method. So sequencing takes almost 16 to 18 hours, sometimes 24 hours. And the question is could we create the point of care and your devices that could get the sequence in a much faster way and differentiate between cancer and non-cancer. There are other logistic issues is how to get the blood, how to make sure the blood is not degraded until it gets to the company. The need to automate and to streamline the methods that we are using now are good for a research lab. And the challenge is, how do we move from a research lab to screening millions of people? Because if early screening becomes something that we think everybody should do, you're talking about billions of people, we don't have the capacity to do that. Our methods are built for a research lab. They're not built for production. This is exactly what we're trying to work on is to create a platform that will be robust and high throughput and relatively reasonable costs that will allow taking a DNA methylation from a research lab state to a commercially viable clinical product。

ZAODX：
Based on DNA methylation detection technology, what are the advantages and disadvantages when applied to single cancer or a multi cancer detection?

Prof. Moshe Syzf:
Single cancer detection gives you a clear answer where the cancer is. And single cancer detection is very good for situations where there's a clear risk for a specific cancer. So for example, liver cancer, there's a very specific risk group people with liver disease. So these people should definitely be screened for liver cancer. They shouldn't waste time on other cancers. They should focus on what is the high risk. Women have specific risk like breast cancer or cervical cancer, and men have risk for prostate cancer. So I think specific tests should be done for these. However, the advantage of a pan-cancer test or multiple tests is that if you're not at the risk for specific cancer, it gives you some idea of a cancer that emerging in your group, the challenge would be to actually identify the source of the cancer.

ZAODX：
Is it possible to screen all cancer through a tube of blood or a drop of blood ? If we can do that, why do we still need a single cancer test?

Prof. Moshe Syzf:

I think the quality will not be good. Because if we do too many regions which we need for a pan cancer, each tissue will have a specific region of methylation. If you want to cover everything, we'll need to do a lot of methylation analysis. When we do that, we compromise the depth of the analysis. The fewer regions we do, the deeper we can go and get a better solution, but also the amount of DNA in sulfate plasma is quite small. It's a big demand on the system to screen for many cancers. So there's a way to screen for a common probe. So what we do is we have four regions that can detect 33 cancers. Then if there is cancer detection now you can spend more money and more effort to find the specific one by looking in many regions.

ZAODX：
Will cancer early screening focus on single-omic or multi-omics?

Prof. Moshe Syzf:

It's hard to say, but I think the relation is so robust that if the technology would improve, there would be no reason for additional stuff. We also have to think that it has to be practical. The more omics we add, the more expensive it gets, the more sophisticated the equipment should be. But it is possible that we will combine DNA methylation tests with some cheaper antigen-based tests, like PSA or AFP, so it might be that those antigens are relatively cheap plus DNA methylation will be enough. So we will not need to do proteomics and transcriptomics and micro RNA omics. That will be good for a few rich people, but it will not be a good way to screen the population.

ZAODX：
I see, what is your team's recent focus on the transformation of scientific research results?

Prof. Moshe Syzf:

Our focus is on building the platform. It's not just a machine, but it's how you work with the machines. So we want it to be automated because one of the main problems with laboratory medicine is errors of technicians, errors that happen in the process. If one can reduce the errors, one could increase dramatically the sensitivity. We found that once we automate, the errors are reduced, we need to automate, we also need to multiplex, so be able to do more and more samples in a short time and to shorten the time that it takes from the beginning to the end of the process. This is one side, the platform, the IT control of the platform, the IT analysis, and perhaps applying some machine learning in artificial intelligence to analyze the process. But also we need to get more and more tests. So to study more and more areas of medicine where we can find early markers. And as I said, it's not just cancer. I believe there are good potential for cardiovascular disease, good potential for autoimmune disease or immune disease, a good potential for diabetes and mental health. So there're many areas we want to discover more markets. On one hand, when we have new markets, we can easily push them into a clinical product.

ZAODX：
What's the strategy? Do you use the established machines or you invent some of your own machine?

Prof. Moshe Syzf:

So at this stage we use open systems. So we open systems that we can change.So our sequencing we still stick to mature machine. Although there are other systems coming up, because we are not sure about their accuracy yet. And methylation has to be very accurate because inaccuracy can make a mistake calling the cancer. But as far as the liquid handling and the automation, also the computer automation, we all created the novel we created ourselves.

ZAODX：
Could you please share the technical trends you see in global cancer early screening?

Prof. Moshe Syzf:

The chance is huge. I think it will replace a lot of what we're doing. If it will be successful, it will reduce the number of cancer patients in hospitals. It will reduce the cost of cancers, it will make cancer just a regular disease that is manageable. It's not tremendous pain and suffering as it is sometimes now.

ZAODX：
Could you give some examples about the advancement?

Prof. Moshe Syzf:

For example, liver cancer. Early detection can save 100% of the people and the simple surgery or even other kind of therapies could eliminate the cancer. Late detection could be almost 100% death, so it's life and death. If you talk about cervical cancer and other cancer, we're interested in, it's the same. Early detection, 93% survival, late detection, 15% survival. So you're talking about really dramatic impact on human life. But it's not just that it's the need for chemotherapy, the need for painful treatment. And if we can detect early, probably we won't need any treatment or just surgery would be sufficient and perhaps not even surgery because we never had real early detection. We didn't develop drugs for early detection, but once we start detecting early, probably we will develop a whole new kinds of drugs that will take care of early cancer and will be much less toxic than the drugs we use for late cancer.

ZAODX：
How do you see the Chinese market for early screening of cancer?

Prof. Moshe Syzf:

The Chinese market is huge and cancer is a real problem in China. And I think this market is rife. It's big. There's room for many companies to work on this market and also because of the centralized medicine, big hospitals and centralized control of health, they are built for that kind of approach. And once governments will decide that's the way to go that this is the way that will save them a lot of cost and effort and China will be probably the largest market in the world for early detection.

ZAODX：
How do you see the potential of DNA methylation in longevity?

Prof. Moshe Syzf:

So we developed also a DNA methylation test for longevity and other companies have it. It's clear that as we get old, our DNA methylation changes, it's also clear that in some people it changes faster than others. And there's some data indicating that if the DNA methylation changes faster, it might be a bad sign that your life is going to be shorter. As these tools improve, we will be able to test now different interventions and actually measure them in a long time, because now if we have an intervention for longevity, you never know if it worked or not, right? You have to wait 50 years to see if it works. That's too long. But if you have an immediate measure, we can do an intervention and test. Did we move the clock or not? Then do another one, then combine the interventions. It will speed up our development of longevity approaches.

ZAODX：
Is the methylation reversible?

Prof. Moshe Syzf:

Yes, of course. That's the beauty of methylation. The sequence is fixed. What we got from father and mother genetics is fixed and it's very difficult to change only with genetic editing, but that's not a reasonable approach. But epigenetics is done with a reversible process. So enzymes add the epigenetic modifications and enzymes remove so you can make inhibitors for these enzymes and change it. They are already in clinical trial, in clinical practice. For example, there is a drug called Vidaza, which is used to treat cancer, which is a DNA methylation inhibitor. And then there are nutritional supplements that can change DNA methylation. For example, S-adenosylmethionine or vitamin c or green tea, they all can change DNA methylation, but DNA methylation could be changed by exercise. It could be changed by a different behavioral environment. There's an enormous place for plasticity in DNA methylation, which we don't have in genetics.

ZAODX：
Do you know a practical intervention method? We can test the DNA methylation before we give the guy an intervention and then after we test it again.

Prof. Moshe Syzf:

What we are using now is the DNA methylation clocks and we have such a product. We call it APH（Aphidicolin，Aph） and several companies are partnering with us, not just companies, but some research labs to do exactly that to measure the clock before and after.

ZAODX：
Is there any interesting discovery?

Prof. Moshe Syzf:

Yes. There are several papers that show that certain in interventions could reverse the biological clock, although it's still controversial because the studies were small, there's more to be done and there is anecdotal evidence. People are reporting that they change the diet to more vegetarian die, they increase their exercise and they reversed the DNA methylation clock. We also know that some drugs like metformin is kind of a nutritional, it's a diabetes drug but it seems to be moving the clock and making people younger.

ZAODX：
That's a very wonderful job. It seems that it can cure all kind of diseases. Last question, let's give a prospect about the future of cancer early detection. What will it be like 2 or 3 years later? What will the market like in cancer early detection?

Prof. Moshe Syzf:

So I think it will take more than 2 to 3 years because medicine is very conservative. And it's very hard to change attitude. This is a whole change in attitude. But my belief is that every person above a certain age will take annually or semi-annually an early detection test and then governments will create structures. So if it was detected, you can immediately get treatment and follow up so that you can act on it. And eventually they will realize that it saves them a lot of money. Even though it costs a little more money in the beginning, it will save a lot of money.

ZAODX：
Thank you very much for your sharing.

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