International Circulation: Do we know of any other mechanisms?
《国际循环》：还有其他机制吗？
Heusch: That is the major problem. We know hundreds of mechanisms from thousands of studies， literally. But they are all in isolated cells， isolated sub-cellular systems， they are in experimental animals ranging from far away zebra fish to monkeys or pigs or dogs. However， there is very little transfer in all these single signal transduction mechanisms that we have pinpointed in animals in various preparations to human hearts. Very little is actually known for the human heart and this is， in my view， the explanation why mechanical interventions work but the translation into drugs and into chemicals has been largely failing. People have focused on individual signaling molecules that have a certain importance in the reductionist model， but they are not explaining the full picture of the entire complex of the signal transduction cascade. Therefore， when we are translating it to the human being， it fails.
Heusch教授：这是主要的问题。实际上通过大量的研究，我们了解到了成千上万个机制。但是，这些机制来自于单个细胞、分离的亚细胞器，来自于形形色色的试验动物，从斑马鱼到猴子、猪和狗。但是，来自动物制备物的单一信号转导机制转化到人体心脏的还非常少。对于人体心脏，我们的了解还非常有限，我认为这就是缺血预适应、缺血后处理和远隔适应虽然有效，但是转化为药物的努力大部分失败的原因所在。可能是由于人们关注了动物模型中有一定重要性的单个信号分子但是没有解释清楚整个复杂的信号转导级联反应的整体图像，因此当应用于人体时，就会失败。
International Circulation: I have a question about why there are so few drugs out there. Is it because the human model is vastly more complicated?
《国际循环》：现在新药很少，这是因为人体模型过于复杂吗？
Heusch: First of all， translating across species is a big problem. That is one issue. The second issue is that the signal transduction， as far as we can schematize， is very complex. The expectation to just hit a single signaling button and assume that this will work was na?ve to begin with. That is why the mechanical intervention that recruits the entire signaling scheme works in humans， but just taking and picking out one single signal and adding that as an exogenous drug has not worked so far. The only drug trial that has worked is the one using cyclosporin A. There is an explanation for its effectiveness， because cyclosporin A hits a target very far downstream， where all the signals converge on the mitochondria. That is also the only signal that is working in humans. It is both the complexity of the signal transduction scheme and the translations from animal preparations to the humans that present difficult complications..
Heusch教授 ：首先，显然药物由一个种属应用到另一个种属是个大问题。其次，我们目前所了解到的信号转导通路非常复杂，因此只针对单一信号分子并认为这样会有效是个天真的想法。因此，机械上干预整个信号通路对人体有作用，但是只针对一个信号分子的药物是无效的，到目前来讲还是如此。目前唯一一个被临床试验证实有效的此类药物是环孢素A。同样地，考虑到信号通路的复杂性，对此也有解释，因为在该信号通路中，环孢素A针对的是一个非常下游的靶点，该靶点是所有信号交汇之处，该靶点位于线粒体上，该信号是唯一一个在人体和动物都发挥作用的信号。因此，是信号转导通路的复杂性以及将动物研究的结果推及到人体这两方面使得新药的研发变得复杂化。
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