Intelligent Design

microRNA role larger than thought

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Well, not larger than I thought, but larger than most biologists thought. If biologists were engineers and knew something of designed systems they wouldn’t find their thinking was wrong so often.

And sparc, please make a note, microRNAs don’t just target the 3′ UTR.

RNA Interference Plays Bigger Role Than Previously Thought

ScienceDaily (Sep. 18, 2008) — In a paper published online in the journal Nature, IBM and the Genome Institute of Singapore (GIS) reported findings from a joint research study that provides new information on how stem cell differentiation is controlled by microRNAs.

The two teams have shown that microRNAs — small molecules that are an important regulatory component in the machinery of living cells — have roles that go well beyond what was previously thought.

In 2006, IBM scientists developed a mathematical model that led to a conjecture about an expanded role for microRNAs. The team decided to test the hypothesis by focusing on mouse stem cells. IBM used computation to guide the experimental effort that GIS carried out.

The work is expected to provide new insights on stem cell differentiation as well as on the role of microRNAs in cell process regulation and the onset of cancer, neurodegenerative disorders, diabetes and other diseases. The research is also expected to suggest future avenues for novel diagnostics and the development of therapeutics.

“We have made yet another step towards understanding the intricate nature of microRNAs and the roles they play in the regulation of cellular processes,” said Isidore Rigoutsos, manager of the Bioinformatics Group in IBM Research’s Computational Biology Center. “The finding that microRNAs can extensively target locations in the amino acid coding regions of a transcript is an exciting discovery and reveals another important aspect of microRNA activity.”

GIS Senior Group Leader Bing Lim added, “We learn from this study that the targeting of coding regions by microRNAs can also have a real impact on cells. We observed that a single microRNA forced into the powerful embryonic stem cell can impose differentiation. This is exciting because one could envisage using microRNAs as a small molecule to control the differentiation of stem cells, or to make new stem cells. The fun part of this research was the visualization of a trend of thought from computational prediction all the way to cell transformation.”

Details of discovery

For more than a decade, microRNAs were assumed to interact primarily with their targets through the 3′ untranslated region (3’UTR) of the targets’ mRNA. The nucleotide sequences of the targeted locations were believed to be generally conserved across different organisms whereas interactions with mRNA regions beyond the 3’UTR were thought to be atypical.

Some of the new research findings suggest that microRNA targets in the amino acid coding region (CDS) of a gene’s mRNA may in fact be as frequent as those in the mRNA’s 3’UTR, providing experimental evidence to a conjecture put forth in an earlier publication by the two teams. It also shows that a gene’s CDS serves as template of microRNA targeting activity, in addition to its coding for the corresponding protein’s amino acid sequence.

Working with three microRNAs whose expression increases upon differentiation of mouse embryonic stem cells (ESCs), the teams showed that Nanog, Oct4 and Sox2, three transcription factors that are central to maintaining the pluripotency of mouse ESCs and determining the initiation of differentiation, are controlled through their CDS region by the three studied microRNAs. By introducing mutations at the identified target locations, the two teams showed that they could prevent the down-regulation of these transcription factors and delay stem cell differentiation.

For the majority of the validated microRNA targets, their sequence is not conserved in the rhesus monkey and mouse counterparts of Nanog, Oct4 and Sox2. This suggests that seeking putative microRNA targets by aligning the instances of a gene across different organisms will underestimate the number of bona fide microRNA targets.

Additionally, the studied microRNAs generally have multiple targets in the CDS region of the same gene possibly suggesting an underlying need for redundancy that can ensure the downregulation of the intended target.

Finally, several of the studied targets stride exon-exon junctions: this finding suggests that microRNAs play a role in the selective targeting of a gene’s splice variants.

“This discovery has vast implications for the role that computational models can play in biological science,” said Ajay Royyuru, senior manager for the Computational Biology Center at IBM Research. “Computational biology allows scientists to develop theories using powerful computers and even preliminarily prove those theories prior to conducting experiments in wet labs – which reduces the time spent on trial and error throughout the process of scientific discovery.”

GIS Executive Director Edison Liu said, “This work is a great example of how future medical discovery will progressively require the joint efforts of computer scientists working in conjunction with biologists. The complexity of the control of human cells through regulatory networks demands computational modeling in order to decipher the signals from the noise. But in the end, it still boils down to doing the lab experiment.”

16 Replies to “microRNA role larger than thought

  1. 1
    mullerpr says:

    I know this is off the topic but I just like to know if someone at Uncommon Descent can share some views on the recent New Scientist article titled:

    Viruses: The unsung heroes of evolution

    http://www.newscientist.com/ch.....ution.html

    I am not a biologist but enjoy UD very much. Personally I think this “new song” praising viruses contribution to evolution has never really been sung because it creates more problems for the Darwinian concept of evolution, than solving any issues.

    It would be very nice to see a post explaining this concept from an ID perspective.

    Kind regards,
    Michael

  2. 2
    Winston Macchi says:

    Good timing.

    Victor Ambros, Gary Ruvkun, and David Baulcombe just got the Lasker.

  3. 3
    gpuccio says:

    “This work is a great example of how future medical discovery will progressively require the joint efforts of computer scientists working in conjunction with biologists. The complexity of the control of human cells through regulatory networks demands computational modeling in order to decipher the signals from the noise. But in the end, it still boils down to doing the lab experiment.”

    I like this comment. We should perhaps keep trace of how practically every day research gives us new facts which are utterly incompatible with the darwinian view, and which increase the already monumental knowledge about the complexity of cell network regulations.

    The key point is that all researchers usually comment about how they have found something which “controls” or “regulates” complex functions, like differentiation. The interesting thing is that that claim is never true. What they have found is only some new level of complex effectors, in a causal regress which seems almost infinite. So transcription factors “regulate” transcription, and miRNAs “regulate” the translation of transcription factors, and so on. What nobody seems to notice is that a long list of effectors is not in itself a regulation procedure. “Control” or “regulation” are the results of some intelligent procedure, which attains specific intervention by specific effectors according to some plan. Biologists seem to ignore the concept of procedures, probably because they have no clue about where to look for them. They are apparently still under the spell of believing that simple negative or positive feedbacks can explain everything, with a little bit of luck.

    So, we should really keep trace of the almost infinite causal regress of regulations, and of the total absence of interest in procedures and regulating codes. After all, if it is true that computer scientists will work ever more in conjunction with biologists, the problem should arise sometime.

    I have nothing against the wet work in the labs. It is precious. But, in the end, we really need to understand its results.

  4. 4
    DaveScot says:

    Winston in the comment above is referring to the Lasker prize being awarded to those fellows very recently for the discovery of microRNA in 1993.

    Interestingly, Harvard denied tenure to Victor R. Ambros in 1993 right after he discovered microRNA. Because denial of tenure is pretty much the same as being asked to resign within the next year Ambros took a faculty position at Dartmouth. Ambros also went on to become elected to the National Academy of Science.

    This raises the question of what was Harvard thinking when they denied Ambros tenure? I’m thinking they caught Ambros attending church or maybe wearing a St. Christopher’s medallion on a chain around his neck or something equally horrific. Any guesses?

  5. 5
    sparc says:

    And sparc, please make a note, microRNAs don’t just target the 3? UTR.

    Thanks for the hint Dave. I am allways willing to learn. Still, I don’t see how this would prove intelligent design. The same is true for V. Ambros as you will see in his most recent Nature Medicine review (which doesn’t contain the new exciting results).

  6. 6
    sparc says:

    Just one final question with regard to the length and complexity of miRNAs: On which side of Behe’s edge of evolution would ID consider miRNAs to lie?

  7. 7
    gpuccio says:

    sparc:

    “On which side of Behe’s edge of evolution would ID consider miRNAs to lie?”

    miRNAs as final effectors are not very long (21-23 nucleotides, for a search space of about 4^22, that is 10^13). Indeed, they derive from primary transcripts which are much longer through a complex process.

    But the real issue is: how do miRNAs regulate? Where is the information which allows such a fine tuned post-transcriptional regulation of the different genes by means of different miRNAs? How is the generation and maturation of miRNAs regulated? And so on.

    So, even if a single molecule of miRNA could in itself well be in the range of random variation, the general regulatory network which makes such an ntelligent use of the different kinds of miRNAs is certainly hugely beyond any darwinian explanation.

  8. 8
    DaveScot says:

    sparc

    miRNAs might be relatively short chains but they don’t do anything without a vast complex of pre- and post- processing. The RNA Induced Silencing Complex (RISC) to which miRNAs are eventually integrated into before they can do anything is in itself far beyond Behe’s edge of evolution.

  9. 9
    Upright BiPed says:

    The RNA Induced Silencing Complex (RISC) to which miRNAs are eventually integrated into before they can do anything is in itself far beyond Behe’s edge of evolution.

    Somweone please tell me how this does not falsify the Darwinian paradigm. Is it the case that such falsification is not allowed?

    How does the discovery of protozoa conserving the genetic toolkit for building tissues only used in metazoa not falsify the Darwinian paradigm?

  10. 10
    Upright BiPed says:

    By the way, I am not asking the question as an exercise in futility, I actually want to know.

    Anyone?

  11. 11
    DaveScot says:

    Upright

    Somweone please tell me how this does not falsify the Darwinian paradigm.

    Depends on how you define “Darwinian paradigm”. It puts a strain on the imagination to think these molecular machines arose by a random dance of atoms. There’s nothing but a constant stream of further complexity being uncovered at the molecular level.

    As all these wonderfully complex interdependent machines are discovered at an exponentially increasing rate the “task” of chance & necessity grows greater while the opportunity (age & size of the earthly biosphere) remains constant. The strain builds.

  12. 12
    Upright BiPed says:

    The ruling party slug line is that Darwin will be falsified when we find “rabbit fossils in the Cambrian.”

    Cute.

    But, when we find that protazoa have conserved the genetic material of metazoan animals, we have in fact, found a rabbit in the Cambrian.

    Since no one from my network is on a plane to Oxford to collect Dawkin’s reaction for the Sunday morning news magazines, then I am forced to search for the reaction wherever I can find it.

    The Darwinian paradigm is that life started off simple and grew into increasing complexity. In a time of simple cell structure and regulatory function, we find the genetic information required for complex cell structure and regulatory function.

    I want to know why Chuckie is not falsified by finding the code for rabbit parts in the unicelled protazoa that characterize the Cambrian and pre-Cambrian.

  13. 13
    DaveScot says:

    But, when we find that protazoa have conserved the genetic material of metazoan animals, we have in fact, found a rabbit in the Cambrian.

    The protozoa is a modern protozoa. Technically it’s a fossil protozoa that predates metazoans they’d be wanting. No chance of that. If DNA fossilized we could end this controversy one way or another.

  14. 14
    sparc says:

    Gpuccio

    But the real issue is: how do miRNAs regulate? Where is the information which allows such a fine tuned post-transcriptional regulation of the different genes by means of different miRNAs? How is the generation and maturation of miRNAs regulated? And so on.
    So, even if a single molecule of miRNA could in itself well be in the range of random variation, the general regulatory network which makes such an ntelligent use of the different kinds of miRNAs is certainly hugely beyond any darwinian explanation.

    According to the paper I’ve linked to in my first comment Victor Ambros surely wouldn’t agree with gpuccio’s position:

    Even today, we still have a rather inadequate
    understanding of the basis for complete
    conservation of a microRNA sequence.
    One factor is certainly a multiplicity of targets. Nowadays we know that an individual microRNA can typically regulate dozens or even cores of functional targets. This helps to account for evolutionary fixation of microRNA sequences: once a newly evolved microRNA acquires important targets in sufficient numbers to preclude coevolution of the microRNA and target sequences, that microRNA sequence becomes fixed.
    However, this argument does not account by itself for the perfect conservation of all 22 nucleotides
    of a microRNA, given the principle that basepairing to the 5? ‘seed’ part of the microRNA is a dominant factor in microRNA target recognition. Multiplicity of seed interactions would be sufficient to account for the evolutionary fixation of families of microRNAs with similar seeds […]

  15. 15
    Upright BiPed says:

    Dave,

    Thanks for your response. You have to overlook or ignore my frustration. I understand your reply, but at the same time I look at Behe’s EOE and see the stasis observed in the lab. And at the same time I read…

    “This eumetazoan ancestor lived perhaps 700 million years ago. Although it is not preserved in the fossil record (3), we can infer many of its characteristics—flagellated sperm, development through a process of gastrulation, multiple germ layers, true epithelia lying upon a basement membrane, a lined gut (enteron), a neuromuscular system, multiple sensory systems, and fixed body axes—because these conserved features are retained by its modern descendants.

    …and I am left to believe that the specified complexity of known function seen in the modern cell is a perhaps an interesting biproduct of time, but is as inferencially illusionary as design itself.

    sparc

    Your answer does nnot seem to address the underlying question raised by gpuccio.

    But the real issue is: how do miRNAs regulate? Where is the information

  16. 16
    gpuccio says:

    sparc:

    “Victor Ambros surely wouldn’t agree with gpuccio’s position”.

    I don’t expect others to necessarily agree with my positions. My positions are mine. Some will agree, others not. But anybody is welcome to discuss them. Obviously, discussing means expressing arguments.

    Now, regarding the arguments by Victor Ambros you cite, I am not frankly going to discuss them, because in the form you cite them, and probably out of a greate context, they appear more like opinions than arguments. Anyway, if I understand well, Ambros is only debate conservation and fixation of the miRNAs nucleotides. I can’t see how that relates to what I had posted. I wrote:

    “miRNAs as final effectors are not very long (21-23 nucleotides, for a search space of about 4^22, that is 10^13).”

    That means that, in itself, a single miRNA is not beyond the scope of known causes of random variation and natural fixation (which is in no way evidence that it was really generated that way). Let’s say it would be possible, although not likely.

    But then I wrote:

    “So, even if a single molecule of miRNA could in itself well be in the range of random variation, the general regulatory network which makes such an ntelligent use of the different kinds of miRNAs is certainly hugely beyond any darwinian explanation.”

    I think you noticed that, because you emphasize it in your citation of my words. So, where is the answer to that argument, in Ambros’ words? To be more clear, my problem here is not so much how miRNAs acquired their relation with a multiplicity of targets (although that remains a problem, too). My problem is how a complex network of procedures and regulations, where the “correct” genes are “correctly” regulated at the “correct” moment and with a “correct” relationship with everything else which is being regulated, how did that network “evolve”? Let’s remember that regulation and control are very different from simple casual interaction. Many molecules interact in nature, but they control nothing and regulate nothing.

    So, again, at the risk of being boring:

    “the real issue is: how do miRNAs regulate? Where is the information which allows such a fine tuned post-transcriptional regulation of the different genes by means of different miRNAs? How is the generation and maturation of miRNAs regulated? And so on.”

    By the way, I realize that Upright BiPed has anticipated part of my comments, thank you for that, UB.

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