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O******e
发帖数: 4845 | 3 我是一直不太明白为什么要去用RNAi治病，一是它特异性太差－－副作用太大；二是
knock down某个或某些基因能治病的理念早已过时；三是knock-down efficiency很难
持久；四是RNAi delivery是个大难题。
RNAi就是一研究工具，跟knock-out or transgene一样。拿去治病不是开玩笑么。 |
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w******e
发帖数: 1187 | 4 1. why do you think it lacks specificity? just curious
2. a LOT of therapies are based on manipulation of one gene/one protein bah.
..
3 & 4 are true. However, there are multiple administration routes and
multiple
target organs which lead to different area under curve |
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w***a
发帖数: 4361 | 5 1,2,3都不是问题，第四个问题谁解决好了谁再拿一次炸药奖。 |
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l*********s
发帖数: 5409 | 6 RNAi is appealing due to theoretically easiness to design specific drugs.
However, it is not very often a certain disease is simply caused by
overproduction of some proteins.
bah. |
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w******e
发帖数: 1187 | 7 the same problem applies to other regimens too bah. what if you don't know
which kinase/receptor to inhibit?
BTW, I don't know other ways that may specifically increase the expression
of certain gene variant like RNAa or ASO (except gene therapy, which is
probably more notorious I guess hehe)
btw, I'm not even in the RNAi field myself. just an intrigued bystander:) |
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l*********s
发帖数: 5409 | 8 The effect of small molecules are localized to motif/domain of proteins,
while RNAi targets the whole protein. I think the first approach will be
less toxic in general as proteins are usually multi-functional. |
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w******e
发帖数: 1187 | 9 the whole point of say having a kinase is probably the kinase motif,
isn't it? multi-functional proteins are mostly undruggable bah |
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s*r
发帖数: 2757 | 10 对呀 对呀，很多小分子要都是针对某个pathway来的，
oncogene请展开说说你的2
bah. |
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l*********s
发帖数: 5409 | 13 It is true, but not the whole story: within in same motif family the
affinity to targets vary broadly due to size and shapes. Optimization the
specificity is what synthetic chemistry is about.
Sure it would nice to work on simple disease, but the questions is you don't
have much freedom of choice: Easy targets are gone/picked first. You have to deal with the complexity of biological networks. |
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O******e
发帖数: 4845 | 14 真正的单基因疾病很少很少，我们做了这么多年的应该清楚，很多文章宣称的哪个基因
突变
导致哪个疾病，其实证据非常不足。
再往大了说，很多疾病不是简单的“基因"或“遗传”问题，牵扯到太多的因素。而
RNAi
is designed to target only one or a few genes.
这个跟kinase inhibitor drugs区别还是很大，因为好的inhibitor只是抑制部分功能
；而
knock-down是把整体的蛋白水平降低，这个的影响会非常广泛和难以控制。 |
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l*********s
发帖数: 5409 | 15 Exactly. In terms of graph theory, the biological system is such a highly dense network that removing nodes have a much more profound impact than removing edges(interactions) |
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d*****r
发帖数: 2583 | 16 but there's no big progress on the systems bio either.
maybe the math is not enough.
then we are totally screwed.
the
don't
have to deal with the complexity of biological networks. |
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t*******o
发帖数: 424 | 17 是不是有笔误啊，第一个edges是不是应该是nodes...
dense network that removing edges have a much more profound impact than
removing edges(interactions) |
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l*********s
发帖数: 5409 | 18 Maybe. But making no progress for a while is just natural. Nothing can grow
exponentially to infinity. |
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l*********s
发帖数: 5409 | 19 Yeah, it is a typo, thanks for pointing out |
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d*****r
发帖数: 2583 | 20 so the conclusion is, it will suck for a long time,
before any major progress on the complexity network is made.
grow |
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w***a
发帖数: 4361 | 21 问题是做了这么多年，很多疾病相关的signaling pathway已经逐渐明了。target就在那
里，问题是不drugable。
RNAi的好处太多了，不是单个基因控制的diease，你就多弄几条siRNA target多个基因
，甚至整条pathway。这个用small molecular是不可想象的。要说off target effect，
small molecular就更没法控制了。至于RNAi的作用是short term而非long term，这点
跟small molecualr也一样，而且实际上你也不希望吃点药就permanently knock out你的
某个基因吧？
对于RNAi therapy，其实就是个delivery的问题。 |
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s*r
发帖数: 2757 | 22 治疗的话从来没有说要完全治好
对于多基因疾病，从单个基因逐个入手，一个一个改善，不也可以吗 |
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d*****r
发帖数: 2583 | 23 no. the key concept of network complexity is:
linearly adding up single element is never going to be equivalent to, and
not even remotely close to, the network as a whole. |
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s*r
发帖数: 2757 | 25 做systems biology的就彻底不承认还原论了?
照你这么说,所有的linear models on observational studies都是无用
在一个广泛联系的系统里面，所有的main effect都没有意义? |
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l*********s
发帖数: 5409 | 26 For small molecule, side effects are controllable though you cannot predict
with great certainty what kind of modifications will work. But for RNAi, it
is theoretically not controllable at all.
Actually, the side effects of RNAi is testable with conditional knock out
mice. I think this should definitely be the first step.
在那
effect，
你的 |
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l*********s
发帖数: 5409 | 27 If the model does not correctly account for interactions when they are
significant presence, conclusions from statistical inferences are misleading
at best. |
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d*****r
发帖数: 2583 | 28 the reason linear models are still useful is:
1. some system were built at the beginning to be linear system, there're
a lot of examples in engineering systems, like simple electronic
circuits, or mechanical systems, etc. So of course you use linear
system to study it.
2. some systems are too complicated and nonlinear, we don't have a good
math to study these systems, so we use linear systems to approximate it.
Unfortunately, most of this approximation is purely academic; the
predictions are ... 阅读全帖 |
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y***i
发帖数: 11639 | 29 你这个道理不通啊。多少药是因为有多方面的影响所以才能治病？我想绝
大多数药的治病的机理都是单一的机制。所以RNAi的单一性并不是问题。 |
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O******e
发帖数: 4845 | 30 作为一个可能的新药或者新的治疗方法，RNAi比起以往的药到底好在哪里以致于非得用
它不可？
在我看来，RNAi therapy跟gene therapy面临的问题和治病理念非常类似。 |
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w******e
发帖数: 1187 | 31 the main issue w/ gene therapy is messing up the cell genome and lead
to cancerous mutation bah?
also, how else can you deal w/ undruggable targets or to compensate for
mutated proteins? |
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O******e
发帖数: 4845 | 32 简单的说，一个是增加某基因的表达，一个是减少某基因的表达，但达到这两个目的的
方式－－delivery－－几乎是一样的。你如果只是简单地送几个siRNA oligos过去，
效果很快就没有了；可你如果想用其它方式比如病毒载体，那一样是leading to
cancers了。 |
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y***i
发帖数: 11639 | 33 如果这个技术的效率能提高到实用水平的话，比现在的药的优势是
1。一旦发现致病的信号通路，立刻可以找到相应的shRNA，而现在的针对蛋白质的分子
药物只能大量筛选实验。
2。基本上所有的可以抑制的蛋白质都是酶，分子抑制剂通过结合于活性位点来抑制。
所以大部分蛋白质是没有特异性分子抑制剂的。一个pathway可能有几十个蛋白，但只
有几个可能找到特异性的分子药物。但对RNAi来说没这个问题。
RNAi看上去还是比gene therapy强，当然，你说得对，两者面临的delivery的问题一
样，而且目前看不到出路。 |
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w******e
发帖数: 1187 | 34
the current regimen of RNAi can at least last for a week, at least that's
what ppl claimed. that seems to be a reasonable price to pay for something
w/ NO alternative treatment bah(again, how else do we increase sth?) |
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w******y
发帖数: 8040 | 35 hehe,汤超去年的cell paper很有意思很有启发性
实际上生物体系的design princple可以是非常简单漂亮的
事情的关键是要找到合适的尺度，
用物理人的眼光去看生物体系是非常有启发性的
拘泥于细枝末节是分子生物学科研路越走越窄的主要原因 |
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y***i
发帖数: 11639 | 36 哪天谁用这种系统描述了飞机或者车床的几千几万个元件的关系，我就开始对这种“
design princple可以是非常简单”的说法有信心。
简单系统都没成功过，告诉我不“拘泥于细枝末节”去搞复杂一万倍的系统能成功，
搞瞎米啊。
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w******y
发帖数: 8040 | 37 你根本不懂我说得是什么， 别跟我扯蛋
至少读懂了paper再来发表你的信心轮
re
good
it.
genes
as |
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t*e
发帖数: 47 | 38 我们现在在作mAb-RNAi的project
用mAb去target特异细胞(比如B cell)或者组织,然后导入RNAi,不知道这个delivery行不
行?
在那
effect，
你的 |
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p******g
发帖数: 498 | 39 巨大的差别：gene therapy 要deliver 基因，加上promoter+polyA signal, 至少1kb
以上。
RNAi不过22bp。将近百倍的差别，deliver RNAi 要容易得多。 |
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w***a
发帖数: 4361 | 40 是啊，gene therapy老是用病毒做载体，听起来就很扯。
RNAi delivery虽然现在也挺扯，但是至少大家都不考虑virus vector，另外RNA不存在
整合genome的问题，安全性要好很多。
1kb |
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w***a
发帖数: 4361 | 41 siRNA bind antibody容易，但是siRNA怎么跨膜呢？
行不 |
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B******o
发帖数: 496 | 44 好像叫Alnylam Pharmaceuticals |
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N****n
发帖数: 294 | 45 看着Alnylam的股票猛长，你会觉得那根本不是个问题。 |
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s**********4
发帖数: 82 | 47 请问，公司环境和条件咋样？Master 进去做的工资一般多少啊？有个朋友要去，帮忙
问问。。。。谢谢！ |
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