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Author
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Topic: A research proposal arising from ID hypothesis
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Terence A-H Tan
Member
Member # 234
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posted 16. April 2004 18:58
Hi. At Micah's suggestion, I'm posting my idea here in Brainstorms instead of the Members Discussion Board. Hope it will trigger predominantly more creative inputs for further discussions and collaborative practical experimentations instead of negativism.
Terence Tan
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A lot has been questioned about the usefulness of ID theory in terms of its scientific translational practicalities. I often wonder why this is so and why there seems to be a mental block of ideas. Perhaps some of this mental block is placed by the nature of ID itself. Perhaps some of this mental block is placed by ourselves. Perhaps some of this mental block is placed and reinforced by our opponents. For want of time and the need for three meals a day to sustain my fragile life, I shall not even attempt to probe and explore into the philosophical nature and etiologies of this mental block.
I shall however make some attempt, within my field of interest and study, to use ID theory as a foundation for creative ideas and the design of potential experiments. Whether this naive attempt is philosophically legitimate or not, I shall leave this to the expert philosophers to debate. My goal here is to help spurn new practical ideas based on ID theory for ID scientists and my satisfaction would lie more in practical experimental discussions and manifestations of the same rather than philosophical arguments of legitimacy.
In fact with regards to the translation-ability of ID theory, my personal views are these. That in science, one must differentiate carefully between what constitutes scientific methodology and what constitutes scientific philosophy. It is scientific methodology coupled with creativity and serendipity that has brought about modern day technological advancements rather than scientific philosophy.
So the translation-ability debate is actually between 2 different scientific philosophies and not between 2 different scientific methodologies. In my opinion, science progresses more because of its unified methodology rather than its diversified philosophies. My rationale is this, how often do we use scientific philosophy eg. evolutionary mechanisms to dictate and direct the design of experiments ? Surely not all the time and probably even less than 10% of the time. For hypothesis generation is most of the time based on the logics of vertical thinking and the creativity of lateral thinking with no connections to evolution whatsoever.
But can we use ID theory as a logical and creative basis for hypothesis generation in order to conduct potential experiments of discovery ? My opinion is why not ?
I shall give a simple and cheap experimental example below to illustrate my point. My hopes is that this may perhaps stir some interest for the ID molecular biologists among us to facilitate further practical discussions and preliminary experiments.
So, let's say I imagine or predict that one day we're going to discover miRNAs in serum/plasma, cerebrospinal fluid or even within mature non-nucleated red blood corpuscles (these have not happen yet), and the discovery of these will spur new experiments that will show the existence of intercellular long distance communication via nucleic acids. Why do I imagine this ? It’s because I believe that if I were the designer of the human body, I would pretty much think that this form of cellular communication is highly efficient and quick, much more so than modified proteins and steroids. And it’s definitely not because I’m thinking of evolutionary mechanisms. Now, on the other hand, if this hypothesis of mine is serendipitously discovered one day by some evolutionist scientist in the next few years, they're going to explain their hypothesis in terms of evolution.
Getting back to scientific methodology, as a scientist, what do I do to proof my hypothesis ? I'll design a scientific experiment to prove my hypothesis of course. (Which I can do so easily except that I don't have the time and resources right now to do it but if circumstances were to permit, I would definitely like to prove this hypothesis of mine someday unless someone else in ID would like to try it first, in that case, be my guest). Now the design of the experiment and its methodology has got no methodological relation whatsoever with the underlying hypothesis. We can say that the ID hypothesis led to the experiment, but the scientific experimental methodology used is the same regardless of the diversity of scientific philosophies.
So in my opinion, I would say, yes ID theory can be used as a legitimate base to create new hypothesis and design new experiments of discovery. So can evolutionary theory. So can the absence of any underlying scientific philosophy eg. if one’s goal is mainly to continue to try and delineate the entire specifics of a particular signal transduction pathway. The experimental methodology used will be the same, but the underlying theoretical methods of hypothesis generation differs.
Because my background is that of an oncologist in training, the below unrefined (due to lack of time) preliminary research idea pertains towards cancer.
A TRANSLATIONAL RESEARCH IDEA
SPECIFIC OBJECTIVES
To determine whether micro-RNAs are present in human plasma, cerebrospinal fluid and mature erythrocytes.
BACKGROUND AND RATIONALE
Two recent discoveries in nature have opened new doors to investigate and further our understanding of gene regulation and transmission of molecular information.
The first discovery belongs to the category of small noncoding RNAs called microRNAs (miRNA). These are short 20-22 nt RNA molecules that are excised from 60-80 nt dsRNA hairpin precursors by the Dicer family of RNase III enzymes. The subsequent formation of a miRNA ribonucleoprotein particle complex (miRNP) analogous to RNA-induced silencing complex (RISC) then leads to homologous translational repression or transcript cleavage.
MicroRNAs have been shown to regulate gene expression in several organisms. Collectively they have been shown to be involved in the processes of development, differentiation, cell proliferation and apoptosis in different species. This has led to propositions as to their role in oncogenesis. To date, investigators have found frequent deletions and down-regulation of miR15 and miR16 at chromosome 13q14 in chronic lymphocytice leukemia and reduced accumulation of miR143, miR145 in colorectal neoplasia.
There are currently a total of 155 human miRNAs discovered and deposited in the miRNA bioinformatics registry and may possibly represent the limits of miRNA isolation from the human genome by conventional methods.
The second discovery is the presence of messenger RNA (mRNA) in the plasma and serum of healthy individuals and cancer patients. Their stability in plasma and serum is a surprised finding as the assumption for years has been counter-intuitive based on the known presence of ribonuclease in blood. Increasingly, cancer-specific circulating mRNAs have so far been investigated as potential bio-markers in breast cancer, colon cancer, lung cancer, malignant melanoma and follicular lymphoma using RT-PCR methodology. The functionality, if any of circulating mRNA is uncertain but the parallel presence of plasma DNA has led some to hypothesize about the functionality of circulating DNA in the process of metastasis dubbed ‘genometastasis’.
It is with these two backgrounds in mind that I propose a simple and cheap molecular fishing expedition for the presence of circulating miRNA in healthy individuals and cancer patients. If the fishing trip is successful, the discovery would not only be insightful per se but should open new possibilities for investigational work. In a similar vein, I propose the same fishing expedition on a yet un-researched area of cerebrospinal fluid and mature erythrocytes. With regards to mature erythrocytes in which no nucleus exist and RNA metabolism is deemed unlikely to occur, it is intriguing that the presence of active ribonuclease inhibitor has been demonstrated.
RESEARCH METHODS
Processing of Plasma (methodology from reference 1 and 2) and CSF
Molecular sequences from miRNA bioinformatics registry (http://www.sanger.ac.uk/Software/Rfam/mirna/index.shtml)
miRNA Probe Construction
(http://www.ambion.com/catalog/ProdGrp.html?fkApp=29&fkProdGrp=303)
miRNA molecular Detection (http://www.ambion.com/catalog/ProdGrp.html?fkApp=29&fkProdGrp=304)
References
1. Tsui NBY, Ng EKO and Lo DYM. Stability of endogenous and added RNA in blood specimens, serum, and plasma. Clinical Chemistry 2002;48(10): 1647-1653
2. Ng EKO et al. Presence of filterable and nonfilterable mRNA in the plasma of cancer patients and healthy individuals. Clinical Chemistry 2002;48(8): 1212-1217
3. Kopreski MS, Benko FA, Kwak LW and Gocke CD. Detection of tumor messenger RNA in the serum of patients with malignant melanoma. Clinical Cancer Research 1999;5: 1961-1965
4. Chen XQ et al. Telomerase RNA as a detection marker in the serum of breast cancer patients. Clinical Cancer Research 2000;6: 3823-3826
5. Silva JM et al. Detection of epithelial messenger RNA in the plasma of breast cancer patients is associated with poor prognosis tumor characteristics. Clinical Cancer Research 2001;7: 2821-2825
6. Silva JM et al. Detection of epithelial tumour RNA in the plasma of colon cancer patients is associated with advanced stages and circulating tumour cells. Gut 2002;50(4): 530
7. Michael MZ et al. Reduced accumulation of specific microRNAs in colorectal neoplasia. Molecular Cancer Research 2003;1: 882-891
8. Calin GA et al. Frequent deletions and down-regulation of microRNA genes miR15 and miR16 at 13q14 in chronic lymphocytic leukemia. PNAS 2002;99: 15524-15529
9. McManus MT. MicroRNAs and cancer. Semin Cancer Biol. 2003 Aug;13(4):253-8.
Terence Tan
4/16/04
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Rex Kerr
Member
Member # 632
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posted 17. April 2004 03:01
The proposal is an interesting one, though I'm afraid that I can't see what it intrinsically has to do with ID. It wouldn't take a lot to get a siRNA into, say, cerebrospinal fluid by accident. And it seems a reasonable way to design a system. So the hypothesis seems to fit comfortably within both ID and classical evolutionary frameworks.
The main comment/question I have is the choice of humans as the experimental animal. I think you'd have access to much greater quantities of bovine cerebrospinal fluid than human, for instance. And in mice or rats there are a variety of experiments you could try to get at the functional consequences of any miRNAs you found.
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Argon
Member
Member # 276
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posted 17. April 2004 10:05
See also one of my comments here.
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Terence A-H Tan
Member
Member # 234
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posted 17. April 2004 12:41
Because this idea of mine arose from ruminations about ID theory, I attribute it to being an ID hypothesis. I doubt if I could have come up with it from ruminating about evolution mechanisms and any retrospective hindsights would be equivalent to game cheating 'theory' ...
My goal here is to show that Science can still progress on the foundations of whichever stand or belief system you choose to take for hypothesis generation, be it teleological or evolutionary or both. The purpose of which is to negate any myths that state that ID theory has no use in creating and designing novel practical experimentation. In fact, ID theory can act as a rich soil to germinate new ideas for Science. For the ID scientist who subscribes to ID theory and microevolution, this allows for more permutative combinations of thought processes for creative practical ideas.
It is nice to know that when all the philosophical arguments have run dry, scientists who subscribe to ID theory and scientists who subscibe to evolution can still work hand in hand at the bench top ... ![[Smile]](smile.gif)
The second reason, which is the main reason for this posting actually is for more practical collaborative purposes, as aforementioned, which is to help spur new ideas for ID scientists to pursue and discover at the bench top.
My initial rationale for posting in the Members Discussion Group is to avoid extra exposure to plagiarism outside of ID. After re-evaluating introspectively, I decided that the benefits of the openness of Science should always outweigh bad politics and hence decided to go with Micah's suggestions.
Terence
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Rex Kerr
Member
Member # 632
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posted 17. April 2004 13:05
Fair enough. I think I'd have come up with hypotheses like this one without reference to ID or evolution, or maybe with reference to evolution (from the "hey, we have this system already, I wonder if it made the short hop to being co-opted here?" perspective). I doubt it would have occurred to me from an ID perspective. But whatever works! Inspiration is a fickle thing.
[ 17. April 2004, 13:06: Message edited by: Rex Kerr ]
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Terence A-H Tan
Member
Member # 234
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posted 17. April 2004 13:05
My apologies. Due to the nature of my job, I'm chronically tired.
I guess I forgot to specify what my ruminations were about. Which is this: that if the genetic code or information or language is a specified complexity event, then communication, which is a non-random exchange of information, may be considered a second order specified complexity event thus increasing the improbabilites further. This is however as far as I shall go due to lack of the luxury of time. I shall leave this to the expert philosophers among us.
Terence Tan
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Art
Member
Member # 179
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posted 17. April 2004 17:21
Hi Terence,
A few comments regarding your post - coming from the perecpetive of a grant reviewer (not that this is a full-blown grant, of course; just some suggestions to help and focus things).
With respect to the premise of the project:
"It’s because I believe that if I were the designer of the human body, I would pretty much think that this form of cellular communication is highly efficient and quick, much more so than modified proteins and steroids."
There has to be much, much more than "if I were the designer". Estimates and/or experiments that support the assertion that extracellular RNAs might be a better form of communication than hormones (of any stripe) are essential. Without this, the proposal is doomed. (The premise is better if it sounds like "because ..... shows that ... is less efficient than physiological expectations demand, and because ... show that miRNAs and siRNAs might be excellent facilitators of long-distance communication in cells, it follows that..." .)
I understand that the post was probably a trial balloon of sorts, but the mere identification of short RNAs in the circulation doesn't mean anything. One must distinguish between authentic miRNAs and any of a myriad of possible breakdown products or virus remnants, and one must address the issue of in vivo functionality. As suggested above, a mouse model would be desirable, since one could think about intorducing any discovered RNAs directly into the mouse, and observing any consequences.
Finally, are you aware that an evolutionary perspective not only leads one down the same path, but actually provides some more advanced and focused hypotheses? This is because long-distance movement of RNAs in plants has been studied for some time, and the knowledge base gives us some specific possible players in the "game" to look for. Or at least some plausible mechanisms for transport and stabilization.
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Krauze
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Member # 1119
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posted 17. April 2004 20:11
Hi Art.
"Finally, are you aware that an evolutionary perspective not only leads one down the same path, but actually provides some more advanced and focused hypotheses? This is because long-distance movement of RNAs in plants has been studied for some time, and the knowledge base gives us some specific possible players in the "game" to look for. Or at least some plausible mechanisms for transport and stabilization."
Could you please elaborate on how the "evolutionary perspective" helps one in forming hypotheses in this area?
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charlie d.
Member
Member # 159
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posted 17. April 2004 21:07
quote:
This is because long-distance movement of RNAs in plants has been studied for some time, and the knowledge base gives us some specific possible players in the "game" to look for. Or at least some plausible mechanisms for transport and stabilization.
That's interesting Art - how does this work?
Terence:
I have some thoughts about your idea, but first I'd like to ask some questions, if that's OK.
1. How many copies of siRNA/cell do you think are necessary for downregulating an average gene's mRNA to a significant extent (e.g., 50%)?
2. How many copies of an individual siRNA can be produced on a per cell basis, assuming maximum capacity (let's say, 30% of the cell's RNA was that siRNA)?
3. Assuming that siRNAs diffused freely throughout tissues (let's say membranes are no obstacle to entry, and siRNAs were perfectly stable), how would their concentration vary with distance from source, and given 1 and 2, what would be their range of activity?
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Argon
Member
Member # 276
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posted 18. April 2004 01:07
Note also that some 'naked' RNAs are infectious in plants... (search on 'viroids')
[ 18. April 2004, 01:13: Message edited by: Argon ]
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