A common issue that many evol-cancer researchers are focusing on is the effect of micro-environment on cells when talking about competition among somatic cells and their strategies, but I don't think it's the most essential one to be emphasized. An intuitive argument is, if a bunch/lineage of somatic cells have adapted to stable environments, how come they could quickly switch to another set of strategies that fit the new fluctuating environment? It's hard to accept such a scenario UNLESS this plasticity (or capability of switching strategies) itself is also an outcome of evolution. As a result, the focus should be what have made that plasticity possible, (only) based on which we can talk about how cell strategies are manipulated by the micro-environment. It's like a classical disputation between the niche theory and the neutral theory in community ecology. I won't talk too much on it because the disputation may not have finished yet. The point is that under niche theory you know definitely some environmental factors are making influence but nothing helps you find what they are and how they function. Now the same difficulty is seen here in evol-cancer research. Whether it's my prejudice or not, I would prefer to focus on internal causes before any external causes are considered.
http://mirnablog.com/micrornas-in-plants-vs-animals/ It is becoming increasingly clear that microRNA are important regulators of gene expression within the animal kingdom. However, microRNA are also found in plants, behaving more like small inhibiting RNA (siRNA) during target gene knockdown. A recent review published in Genome Biology aims to discuss the differences between animal and plant microRNA and highlights the important role of each within the two kingdoms. Axtell et al. serves to showcase the important similarities and differences between microRNA in separate kingdoms and uses the model plant organism Arabidopsis thaliana as an example of classic plant microRNA function. In plants, microRNA are transcribed by RNA polymerase II as in animals, but the entire process of microRNA biogenesis is undertaken within the plant nucleus. The mature microRNA are exported out of the nucleus by Hasty, an exportin 5-like protein found in plants. A major difference between plant and animal microRNA falls within target recognition. Axtell et al. reviews the target recognition process between plants and animals; notably the direct mRNA cleavage of a microRNA target in plants due to near-perfect base complementation between the microRNA and its target. This differs vastly in animals where protein repression is believed to occur by translation inhibition as well as mRNA degradation. Hybridization of microRNA to target in animals is less stringent near the 3’ end of the microRNA strand and relies on the canonical 7-8 nucleotide “seed sequence” to drive microRNA target recognition. After highlighting the similarities and differences between plants and animals, the review dives into some evolutionally perspectives and driving factors of microRNA evolution in plants and animals. Interestingly, Axtell et al. discusses events that lead to the emergence of new microRNA genes in plants and animals. Briefly, it is more common in plants for microRNA genes to emergence via mechanisms of inverted duplication events, where as in animals it is more common for microRNA hairpins to evolve from mutational events in “unstructured” sequences of the genome. These evolutionary driving factors and mechanisms for newly acquired microRNA genes can perhaps help researchers identify novel microRNA targets within gene loci of interest. Even though most research in microRNA regulation of target genes is primarily focused on animal gene regulation, and specifically within human disease states, acknowledging the breadth and scope of microRNA regulation across kingdoms may provide useful insights into microRNA research. Axtell, MJ., et al. Vive la difference: biogenesis and evolution of microRNAs in plants and animals. Genome Biology. 12 (2011): p. 221-234. http://genomebiology.com/2011/12/4/221 Incoming search terms for this article: http://mirnablog.com/micrornas-in-plants-vs-animals/
It just sounds natural that a bunch of somatic cells in a multi-cellular body can be viewed as a population while evolutionary/ecological theories can be used to look into the population dynamics of these cells, and it sounds tempting that theoretical works my find their application in cancer research and possibly better treatment strategies. The first conceivable scenario is that we can measure the fitness of each individual (cancerous or peripheral) cell, given its life-history strategy is well defined, and then trace how this fitness may change when the micro-environment is changed due to cancer progression and/or effects of adopted therapy. Once it is understood how to selectively suppress the fitness of the most malignant cells and avoid relapse of evil survivors, better strategies of treatment will be designed accordingly (Robert Gatenby). Actually people have already gone beyond the above scenario, asking deeper questions, e.g. how cancer have evolved and been avoided in the history of metazoan life forms? Now it isn't a novel idea that cancer cells are just betrayers in a cooperative multi-cellular body, seeking their own opportunities to maximize offspring cells, rather than contributing to the whole metazoan individual and waiting for itself to be replicated in the next generation of the whole body. Cancer cells can be viewed as an atavistic phenomenon in an evolutionary perspective based on the knowledge that multiple cellular organisms originated from single-cellular organisms. But the tricky question is, how multi-cellular organisms could emerge successfully in the first place? This refers to the question that how a multiple cellular body win battles against betrayers who always emerge from inside to seek a “free life”. So the question is transformed into a classical economic/ecologic question, where the focus is the maintenance of cooperation in a competitive population or community. To be cautious, we may not say a “body”, or a population of cells, as one part of the players of this battle. One alternative subject may be the germ-line cells as the monopolist betrayer, in contrast to other cell lineages who all become its slaves (Paul Rainey). Or from the genetic (selfish gene, refer to Richard Dawkins) viewpoint, the genome is the sole bearer of strategies in the battle between its different carriers. One apparent observation is that multi-cellular organisms like human have never 'evolved' a perfect mechanism to prevent cancer through the whole life span. Logically, they don't have to achieve this goal, as long as it can keep its integrity until successful (or optimal times of) reproduction. My guess is that both cooperation and betrayal are locally optimal/stable strategies for a cell. Figure 1. A diagram of cooperation and betrayal as locally stable strategies. A conceptual barrier exists to help prevent betrayers from emerging within a multi-cellular body. On one hand, it is easy to understand that being cancerous or malignant is locally stable, as they always have more offspring within a time interval than their neighbor competitors. This is the major concern in using population dynamics models to help design better protocols of chemotherapy. On the other hand, being cooperative should also be a locally stable strategy for any single somatic cells. Its only my guess and I haven't read this from other researchers so far. If being cooperative is not locally stable, then it is hard to imagine how multi-cellular organisms can emerge and thrive in the first place, unless we accept it possible to teach a hen to swim by throwing it into water a million times. So it is understandable that we can draw a diagram as in Figure 1, where there are two locally stable strategies for a cell and there is a barrier between them, which help multi-cellular bodies maintain their integrity and resist emergence of betrayers to some extent. The message given by the barrier is, "if you are not a really evil betrayer, you'd better be a cooperator." It is noted that here we are considering fitness only at the inter-cellular level, where the fitness at the whole body/population level is not explicitly involved, but implicitly considered. So one interesting question is if there is indeed such a barrier, and if so, how it is embodied in terms of biochemistry and molecular cellular biology (possibly also in genetics and epigenetics). If we find where this barrier is, then we will know how to utilize this barrier to help reduce the betrayer cells in the patient. My future work is based on this simple hypothesis, but my scheme framework is a bit more complex, as conflict between mitochondrial and nuclear genomes is also considered in order to comprehensively understand life-history traits of a cell. This was already introduced in an earlier post, and I will keep it updated in future posts. p.s. Some similarity is seen between game theory models and dynamical systems models, as they are essentially the same thing but with different emphases. Normally game theory works with game players at the same level, or usually it doesn't clarify if players are at the same or different levels (with different sets of candidate strategies). Specifically the ESS theory works with a population of symmetric players based on replicate dynamics. On the contrary, the dynamical systems theory works with all players (nodes) at different levels, each with a distinct set of candidate strategies to interact with one another ( via connections), while there is usually only one individual player at each level (each node includes a single player ). Both theories work you out "stable states" or more broadly "attractors" including cyclic and strange attractors, which provide the groundwork from where you can explore more complex dynamics. I wish these will finally help us harness the behavior of cell systems and tumour tissues.
When making preparation for an interview, I asked a few questions to myself. I couldn't answer them very well, but just tried to give some comments. 1. The first question is what 'evolutionary theories' really mean. I could only answer this question based on what I have learned. Certainly my favorite is evolutionary game theory, where ESS (or say replicator dynamics) forms the only central rationale. However, traditionally ESS is only dealing with symmetrical players with the same set of candidate strategies. When looking into interacting players at different levels, we need to extend the models of ESS to deal with asymmetric players with different sets of candidate strategies. Now we at at the gate of systems biology, where not only multiple categories of game players are included but also the outcomes will be more diverse -- a single-point steady (perhaps stable) state may not always be reached, but instead the whole system may show periodical, strange, noisy or just complex states. These may all be claimed to be part of theories in evolutionary biology, and become useful in tackling practical questions. Some other theories in ecology and evolution may also help, but I don't think they have enough power to make predictions. 2. A tricky question prompted into my mind is, at which time scales am I talking about the outcomes of conflict and/or competition at different structural scales? It's not a complicated question, but hard to be clarified in words. I haven't come out with a good answer yet but I would say the very difficulty is just the reason why we need the method of agent-based modelling, where running of simulation and its results will tell us what happens. 3. The third question is where the "strategies" are embodied. At this moment I could only say ATP production, resource allocation, and/or the balance between fermentation and OXPHOS. But in future within a specific topic we may find other metabolic and/or signaling pathways where different strategies may make sense. Essentially, as a strategy, it should be inheritable/replicable to some extent and be carried by a well defined individual agent/player, and there must be a set of alternative strategies potentially shared by a group of players.
本文亦发布于本人 英文博客 。 During the last two months Ihave read several papers on miRNAs. I noticed miRNAs because they compose an important part of gene regulatory networks and recent discoveries have shown miRNA manipulation can do the job of the transcription factor (TF) routine (developed by Yamanaka 's group since 2006) in cell reprogramming (Anokye-Danso et al., 2011) . It will be beneficial to understand how miRNAs could do the similar things as what TFs can do in terms of gene expression regulation, as well as how different they are in their ways of functioning. Professor Oliver Hobert wrote a review in 2008 elaborating the similarities and differences between miRNAs and TFs in their ways of gene expression regulation. From his review I learned that miRNAs and TFs both compose similar motifs of regulatory networks in terms of topology and that they might have the same target genes. Besides this, miRNAs may cross link with TFs widely, composing more complex motifs and functioning coordinatingly with TFs, rather than play as a separate layer of the regulatory networks. As learned from Hobert 's review , the differences between miRNAs and TFs lie in several aspects. 1) The target loci. -- The sizes of TF targets are often 'dozens of kilobases' while those of miRNA targets are less than 1Kbp. Besides, TFs usually bind with the 5' upstream region of the target gene while miRNAs usually bind with the 3' UTFs of the target messenger RNAs. 2) Efficiency, precision and speed. -- TFs have to be translated in cytoplasm (escaping any possible miRNA repression) and then transported back into nucleus to perform their functions, while miRNAs can function just within the cytoplasm, or even more precisely in particular compartment of the cell. As the result, TF regulation may experience more noise and a higher possibility of interruption, while miRNAs may function with less noise and more instantly upon any signals from outside. 3) Reversibility. -- miRNA-mediated repression may be relieved more rapidly (if possible) than TF-mediated repression. 4) In terms of evolution -- miRNAs have smaller sizes and a non-conding nature thus may be more likely to emerge by mutation than TFs which have longer target-recognizing sequences. 5) In terms of related phenotype defects -- miRNAs are less likely to cause essential developmental failures than TFs (see cited original reports from Miska et al. 2007 and www.wormbase.org ). I keep my doubt to this claim because 80% * 90% seems not so different from 70%, although I wish I could accept it. In addition, some of the above points are side-supported by another review by Peterson et al. in 2007 . In the fantastic paper, the evolutionist authors correlated miRNAs with the evolutionary history of multi-cellular organisms and found that the emergence of miRNAs generally reduce expression noise of the related genes. And indeed, bigger miRNA families emerged more rapidly in more recent taxa, which is related to higher complexity due to more preciesly controled differentiation of new sets of terminal cell types. So generally, could we say that miRNAs are more recently evolved, more related to terminal cell types, more related to precisely, rapid and reversible gene expression regulation than TFs? And, as evolution is going on, is it possible that miRNAs could play the roles of TFs and finally replace the latter? At first glance it is contradictory to the claim in the above 4) that most miRNAs don't play vital roles in development. And it seems miRNAs are only the leaves and fine twigs while TFs construct the major branches of the 'tree' of regulatory networks. But considerring the recent advances of miRNA-mediated reprogramming, things are not so impossible and small twigs can also grow to be big branches. Personally I think, even if it is untrue and impossible, at least it gives some hint to future bio-technology, by which we could devise an organism without TFs but only miRNAs composing its genome regulatory networks.
Dear Colleagues: Still reviewing my future options, and in the process of seeking solutions, stumbled across this blog site ( The Daily Impact ) on the New American Evolution . Hate to particularly encourage some of you leaning in the Doomsday direction, but you'll no doubt identify with this gloomy message. This attitude must be infectious, for my latest Huffington Post article on climate change policy appears to suggest that there is no hope for timely decision-making. Aloha. Pat Pat's Daily Blog
Question 1: 有一种药物，1000例绝症里面只能治愈1例，请问统计学上显著否？这个药物是否值得开发？能用否？总比治不好强吧？ If there is a drug, by which only one case in 1000 cases of fatal disease canbe cured, I ask whether the differences arestatistically significant? Isthe drugworthdevelopment? Better than nothing? Question 2: 有单细胞生物变成多细胞生物的，有单细胞生物保持单细胞状态的，那么，有多细胞生物变成单细胞生物的吗？ 如果有，我支持中性演化学说就多一点；如果没有，我还是相信进化有一个总体的方向性的。 There are single-celled organisms which becomemulti-cellular organisms, there are single-celled organisms which keep single-cell state, then,is there any multi-cellular organism which evolve to a single-celled one? If yes, I support a little more on the neutral theory of evolution; if not, I still believe thatEVOlution has a general direction.
拉马克主义 (Lamarckism) 是生物进化学说之一，为法国博物学家拉马克所创立。他认为生物在新环境的直接影响下，环境变化了，习性改变，使得生活在这个环境中的生物有的器官由于经常使用而发达，有的器官则由于不用而退化，这就是用进废退。这种由于环境变化而引起的变异能够遗传下去，这就是获得性遗传。并认为这样获得的后天性状可传给后代，使生物逐渐演变，且认为适应是生物进化的主要过程。 在 DNA 结构被发现后，人们通常认为遗传性状由基因决定，拉马克主义被认为是把获得性状遗传给后代的过程过于简单化，于是落在故纸堆里没人问津了。长颈鹿脖子越用越长，这几乎都被作为笑谈了。 Denis Nobel 举了一个精彩的例子，我将其译为一个中国版本，让我们重新认识拉马克主义。 镜花缘之 拉马克 vs. 达尔文 镜花缘中的秀才唐敖和林之洋、多九公三人出海游历各国，假设他们出行是由纳米公司赞助，所以乘坐的是纳米船，看到的风土人情都是细胞的尺度。某日，唐和林、多九公道了某处岛屿，岛上的居民千奇百怪 200 多个村落，有圆滚滚的大胖子，有细竹杆的瘦高条，有干巴巴的老头子，有水汪汪的妙龄女子。奇怪的是，岛上的居民的基因都完全相同，并无二致，但是他们的模样千奇百怪。村落相异，模样不同，有的做挑夫，有的去浇水，有的管纺线，有的去打仗。而同一个村落的居民，由其环境而定，都长得一模一样。并且他们生的子女，都继承了环境而定的模样，高矮胖瘦，完全一样。唐、林等人大为惊讶，这不是拉马克主义 (Lamarckism) 的明证么？遗传性状居然不由基因所决定，获得的后天性状居然可以传给后代。 这该不是偶然罢。他们起舵再行，到了另一座岛屿。让他们更为惊讶的是，这座岛屿上的居民也大约是 200 多个村落，居民的基因全然相同，但形态各异，并且它们的基因与上一座岛屿居民的基因并不相同。他们再到另一座岛屿，情况依然。最让人惊讶的是，这些岛屿跟大陆板块一样，会发生漂移。当两座岛屿足够近的时候，便会出现一条水路，然后有一队勇士手持锋利的梭镖，奋勇向另一座岛屿前进，环境险恶，许多人在途中便丧生。终于有勇士突破禁备森严的宫殿，此时闪电划过长空，勇士与宫殿融为一体。不久这座宫殿一分为二，二分为四，最后成长为一座新的岛屿。 Fig. 1 人体大约有 200 多种不同的细胞 我想此时你已经猜到，这些岛屿并非他指，正是我们人类本身。人体大约有 200 多种不同的细胞，包括骨细胞、神经细胞、皮肤细胞、心脏细胞等等，其形态千奇百怪，但所包含的基因却全然相同。已经分化的骨细胞等繁衍后代，虽然基因相同，仍然保持骨细胞的形态。这种获得的后天性状，不由基因而发生的隔代遗传，决不是什么奇谈怪论，而是正统的生物学发现，只不过是在细胞层面上罢了。虽然同样的基因由父代传给子代，但是基因本身并不能决定骨细胞、神经细胞等的性状。基因被打上了某种化学的标记（ chemical marking, for example, a methylation of Cytosines etc. ），这些化学标记才真正决定了子代细胞的性状。而更有意思的是，当人体在制造生殖细胞的时候，所有基因上的化学标记都会被抹去，这时的细胞的基因，重新恢复了可以生成一切其他细胞的可能。 总之，决定生物的性状，的确有超越基因的因素存在。真正改变生物性状的基因工程，绝非简单的将所谓单一功能的基因切过来，粘过去就性状改变那样简单。现在的转基因工程，对相近物种把握还比较大，对于相异物种，大部分还是靠运气 (shotting in the dark) 。为什么转基因试验，包括克隆试验一般成功的几率都非常低，正是这个道理。 (待续)
标签: evolution
