On Ontophylogenesis or "Cellular Darwinism"

[proximity1]

Sleep studies suggest additional evidence of stochastically-based cellular behavior --

 

From the most recent edition of a french-language radio-magazine, « Sur les épaules de Darwin », (« On the Shoulders of Darwin ¹»), a weekly (Saturday) radio programme hosted and narrated by Jean Claude Ameisen² of the France Inter network, some interesting references are made (listen to the programme's digital recording @ 7:00 mins. to 9:00 mins.) to studies by Guilio TONONI³ (and other researchers) currently a research professor at the University of Wisconsin, Madision.

 

Two studies , (one⁴ in which laboratory rats are the subjects (Local Sleep in Awake Rats) and another⁵ ( Regional slow waves and spindles in human sleep ), in which human subjects are studied) offer complementary results which can be seen to suggest that transitions from sleeping and waking states are in fact arrived at through stochastically-presented transitions over a continuum in which the brain shows spatially-dispersed neuronal activities whcih are split between those cells which in scans exhibit a sleep state as others exhibit a waking-activity state. Ultimately, sleep or waking comes about in the averge total of the brain's affected neurons gradually shifting to one or the other condition Thus, at one and the same time, there are found « localalized » conditions of neurons which are in a sleep or a waking state ; and this presents itself in a manner that corresponds to the same stochastic characteristics as those defended in J.J. Kupiec's studies.

 

1http://www.franceint...ter?play=480877

 

2http://fr.wikipedia...._Claude_Ameisen

 

3http://tononi.psychi...iulioTononi.php

 

4http://www.ncbi.nlm....les/PMC3085007/

 

5http://www.ncbi.nlm....pubmed/21482364

Edited October 21, 2012 by proximity1

[Ringer]

Sleep studies suggest additional evidence of stochastically-based cellular behavior --

 

From the most recent edition of a french-language radio-magazine, « Sur les épaules de Darwin », (« On the Shoulders of Darwin ¹»), a weekly (Saturday) radio programme hosted and narrated by Jean Claude Ameisen² of the France Inter network, some interesting references are made (listen to the programme's digital recording @ 7:00 mins. to 9:00 mins.) to studies by Guilio TONONI³ (and other researchers) currently a research professor at the University of Wisconsin, Madision.

 

Two studies , (one⁴ in which laboratory rats are the subjects (Local Sleep in Awake Rats) and another⁵ ( Regional slow waves and spindles in human sleep ), in which human subjects are studied) offer complementary results which can be seen to suggest that transitions from sleeping and waking states are in fact arrived at through stochastically-presented transitions over a continuum in which the brain shows spatially-dispersed neuronal activities whcih are split between those cells which in scans exhibit a sleep state as others exhibit a waking-activity state. Ultimately, sleep or waking comes about in the averge total of the brain's affected neurons gradually shifting to one or the other condition Thus, at one and the same time, there are found « localalized » conditions of neurons which are in a sleep or a waking state ; and this presents itself in a manner that corresponds to the same stochastic characteristics as those defended in J.J. Kupiec's studies.

 

1http://www.franceint...ter?play=480877

 

2http://fr.wikipedia...._Claude_Ameisen

 

3http://tononi.psychi...iulioTononi.php

 

4http://www.ncbi.nlm....les/PMC3085007/

 

5http://www.ncbi.nlm....pubmed/21482364

 

It's been long known that areas of the brain show large amounts of activity when sleeping and others show very little activity, as well as vice versa. This has absolutely no bearing on the way proteins are expressed. Also, just so I'm following correctly, are you saying that the areas of the brain that are active/inactive are random?

[proximity1]

It's been long known that areas of the brain show large amounts of activity when sleeping and others show very little activity, as well as vice versa. This has absolutely no bearing on the way proteins are expressed. Also, just so I'm following correctly, are you saying that the areas of the brain that are active/inactive are random?

 

 

RE: "It's been long known that areas of the brain show large amounts of activity when sleeping and others show very little activity, as well as vice versa. "

 

True. But the point here is something rather more than simply that there are variable states and areas of brain activity at the same time over the scope of the entire brain. The point here is that the individual neuron activity is, just as the basic conceptions defended in Kupiec's research indicates, of a non-stereospecific kind, of a probabilistic character, rather than a deterministic kind of process.

 

E.g. (from the radio program's digital file, as noted below):

 

 

«In a earlier edition, I told you of a study published last year in the review Nature by the team of Giulio Tononi of the University of WisconsinTononi, has long done research on sleep. This study was not conducted on people but on small rodents, rats. The researchers kept them awake for only four hours (beyond their usual waking hours). They didn't prevent their sleep by waking them. Instead, they introduced into their cages at the end of the evening certain play-things and it is the subjects' attention to, the interest in, these play-things that induced the them to remain awake. They kept themselves awake. During the extra four hours of waking, the animals remained active, attentive, keeping their eyes open. They had all the characteristics of a state of wakefulness, including their brains' global electrical activity revealed by electroencephalogram and which was typical of the state of wakefulness. But the study of the activity of the individual nerve cells of their brains revealed a strange behaviorsome individual brains cells adopted for a tenth of a second a state of rest, the state found during sleep. And the neighboring cells compensated by a slight increase in activity of wakefulness. This brief sleep of some brain cells occurred apparently randomly in disparate regions of the brain. But the more the state of wakefulness endured, the greater the increase in the number of cells which shifted over to and exhibited this state of brief sleep-- as though a very brief state of punctual sleep began to impose itself more and more frequently and involving more and more cells throughout the brain. As though, said Giulio Tononi, as though once past the usual time to sleep, the prolongation of a condition of waking attention modified the state of the brain causing it to cross a threshold, like water beginning to boil at the nearing of the boiling point temperature and air pressure, like sleep "bubbles" beginning to appear more or less all around, more and more often throughout the brain." (program counter: @ 3:13 mins. To 5:30 mins.)

 

 

 

RE: "are you saying that the areas of the brain that are active/inactive are random?"

 

Not exactly, no. I'm suggesting that what is, as I see it, anyway, explanatorily valid for one area of the body's tissue and cellular behavior--Kupiec's studies in various features of cell behavior in emryology, or other cell functions inter- and intra-cell -- is also valid throughout the body's cells and tissues; hence, any dynamic process, such as waking, or falling asleep, as Kupiec's view would predict, occurs, just as in other cells in other tissues, via a probabilistic dimension, so that direct and specific deterministic relationships are, and would be expected to be, impossible to find or to pin-point when examined at the individual cell level.

 

That is why it seems to me that the research cited of Tononi in sleep and consciousness offers us one more example--among what should be virtually countless potential examples of it--of the stochastically-based behavior of cellular activity. It is this that lends to Kupiec's work and that of his fellow researchers, so profound an aspect--but it is not to say that the focus, as in this instance, involves, or concerns one or more areas of the brain, as opposed to others. The example cited above from the radio file indicates that the particular regions of the brain, in the instance described, was not in and of itself the crucial criterion; rather, what is significant is that there was no single affected region as opposed to another or others. It concerned a brain state that was indifferent to precise locale, hence, part of the phenomena's interesting character.

 

Again, what makes this example worth pointing up is that it is exactly what Kupiec's works tells us we should expect to find. So, why, then, would a researcher (or in this case, the program's narrator, put it,

 

"But the study of the activity of the individual nerve cells of their brains revealed a strange behaviorsome individual brains cells adopted for a tenth of a second a state of rest, the state found during sleep." ?

 

Only because, as seen from the generally-accepted view of deterministic biology, cells don't behave and aren't expected to behave in a random, probabilistic, fashion--instead, they're supposed to follow, they're supposed to conform to, one or another form of chemico-molecular "signal" activity which is supposedly specific, precise, and deterministic in character, not a random result spread over vast numbers of aggregate cell populations.

Edited October 22, 2012 by proximity1

[Ringer]

RE: "It's been long known that areas of the brain show large amounts of activity when sleeping and others show very little activity, as well as vice versa. "

 

True. But the point here is something rather more than simply that there are variable states and areas of brain activity at the same time over the scope of the entire brain. The point here is that the individual neuron activity is, just as the basic conceptions defended in Kupiec's research indicates, of a non-stereospecific kind, of a probabilistic character, rather than a deterministic kind of process.

 

I thought Kupiec's research was on cellular development, not cell-cell signaling.

 

 

 

RE: "are you saying that the areas of the brain that are active/inactive are random?"

 

Not exactly, no. I'm suggesting that what is, as I see it, anyway, explanatorily valid for one area of the body's tissue and cellular behavior--Kupiec's studies in various features of cell behavior in emryology, or other cell functions inter- and intra-cell -- is also valid throughout the body's cells and tissues; hence, any dynamic process, such as waking, or falling asleep, as Kupiec's view would predict, occurs, just as in other cells in other tissues, via a probabilistic dimension, so that direct and specific deterministic relationships are, and would be expected to be, impossible to find or to pin-point when examined at the individual cell level.

 

That is why it seems to me that the research cited of Tononi in sleep and consciousness offers us one more example--among what should be virtually countless potential examples of it--of the stochastically-based behavior of cellular activity. It is this that lends to Kupiec's work and that of his fellow researchers, so profound an aspect--but it is not to say that the focus, as in this instance, involves, or concerns one or more areas of the brain, as opposed to others. The example cited above from the radio file indicates that the particular regions of the brain, in the instance described, was not in and of itself the crucial criterion; rather, what is significant is that there was no single affected region as opposed to another or others. It concerned a brain state that was indifferent to precise locale, hence, part of the phenomena's interesting character.

 

Again, what makes this example worth pointing up is that it is exactly what Kupiec's works tells us we should expect to find. So, why, then, would a researcher (or in this case, the program's narrator, put it,

 

"But the study of the activity of the individual nerve cells of their brains revealed a strange behavior—some individual brains cells adopted for a tenth of a second a state of rest, the state found during sleep." ?

 

Only because, as seen from the generally-accepted view of deterministic biology, cells don't behave and aren't expected to behave in a random, probabilistic, fashion--instead, they're supposed to follow, they're supposed to conform to, one or another form of chemico-molecular "signal" activity which is supposedly specific, precise, and deterministic in character, not a random result spread over vast numbers of aggregate cell populations.

 

Would you happen to have a link to the actual study, because it sounds like what they're saying is that neurons entered an absolute refractory period and the surrounding neurons compensated by sending stronger signals which isn't surprising. The results may be surprising, but that doesn't mean they are not deterministic because the phenomena just may not have been studied before. Again I would really like to look at the actual paper.

[proximity1]

 

 

RE: "I thought Kupiec's research was on cellular development, not cell-cell signaling."

 

 

RESPONSE: Cell-signaling is a supposed phenomenon the validity of which Kupiec challenges--at least as it is apparently thought to operate according to the present-day paradigms of molecular biology. Thus, you either aren't aware of the point and import of the work done by Kupiec--both as I've summarized it here and, more especially, as it's fully detailed in the links to his work that I've previously posted--- or, if you're aware of it, you haven't understood it, it seems to me.

 

 

RE: "Would you happen to have a link to the actual study, because it sounds like what they're saying is that neurons entered an absolute refractory period and the surrounding neurons compensated by sending stronger signals which isn't surprising. The results may be surprising, but that doesn't mean they are not deterministic because the phenomena just may not have been studied before. Again I would really like to look at the actual paper."

 

 

RESPONSE: Yes, since I already posted a link to the study (see above at footnote reference N° 4 in Post N° 26)--or, that is, a link to a page which describes and summarizes the study and which, itself, carries a link to the full final published form of the paper (in the journal Nature, again, as already explained in the post to which you've replied)-- here is your link to the Nature page:

 

http://www.ncbi.nlm....nks&id=21525926

 

You'll need some form of full access to Nature's reports to see the complete study, but I gather that you have such access.

 

 

"prox."

Edited October 23, 2012 by proximity1

[proximity1]

Journal Nature Article Title : « The Single Life : Sequencing DNA from individual cells is changing the way that researchers think of humans as a whole[1]”

 

November 2012, Vol. 491, pp. 27-29

 

Pdf link: http://www.nature.com/polopoly_fs/1.11710!/menu/main/topColumns/topLeftColumn/pdf/491027a.pdf

 

By Brian Owens, Nature assistant news editor, London

 

 

““People are becoming very interested in what is the variation from cell to cell,” says Navin, now at the University of Texas MD Anderson Cancer Center in Houston.” …

 

 

TUMOUR DIVERSITY

 

 

“In his first effort with breast-cancer tumours1, Navin[2] was able to sequence only about 10% of the DNA — not enough to see individual point mutations, but good enough to study larger segments that are commonly duplicated or deleted, called copy number variants.

 

 

"The results suggested that the tumour was made up of three major populations of cells, which emerged from the root tumour population in leaps and spurts at different times during the tumour’s growth. “It suggested a model of evolution where, instead of having lots of gradual intermediates, we saw hundreds of chromosomal rearrangements that occurred probably in very short periods of evolutionary time,” he says.”

 

[1] http://www.nature.co...pdf/491027a.pdf

 

[2] Navin, N. et al. Nature 472, 90–94 (2011)

Edited November 1, 2012 by proximity1

[proximity1]

« Single-moleculte imaging of DNA pairing by RecA reveals a three-dimensional homology search » (Journal Nature, 482, 423-427 (16 February 2012)

 

Anthony L. Forget and Stephen C. Kowalcyzkowski

 

 

citation : http://www.nature.co...nature10782.ris

 

doi:10.1038/nature10782

 

« The mechanism by which the RecA family of DNA strand exchange proteins (which include T4 UvsX, archaeal RadA and eukaryotic Rad51) locate DNA sequence identity is unknown. Ensemble studies have constrained possible mechanisms by establishing that ATP hydrolysis is not needed^{3, 4} and 1D sliding is not operative⁵. Consequently, the manner by which the RecA nucleoprotein filament promotes the efficient, rapid and accurate search for homology has remained undefined for decades⁶. Single-molecule methods have the potential to provide new insight into this long-standing question. In fact, magnetic tweezer experiments showed that the endpoint of homologous pairing can be detected as a change in the length of a single dsDNA target molecule^{7, 8}. However, the mechanism by which homology was found and DNA pairing occurred was not shown. Therefore, we sought to directly observe the manner by which RecA nucleoprotein filaments locate their homologous target in dsDNA. ... »

 

 

 

 

… …

 

 

 

 

« ...Next, we attempted to detect homologous pairing in real time using single-molecule TIRFM. Preformed RecA nucleoprotein filaments were introduced into a flowcell to which λ DNA molecules were tethered, buffer flow was stopped, and the reaction was monitored in real time (Fig. 1B, b). Although the dsDNA was readily visible, we failed to observe any interaction between the fluorescent nucleoprotein filaments and extended λ DNA, even for reaction periods longer than 1 h. However, we noticed that in addition to the desired doubly tethered extended λ DNA molecules, some DNA molecules were attached only by one end (Fig. 1B, c). When flow was stopped to score pairing with the doubly tethered λ DNA molecules, these singly tethered molecules relaxed to a randomly coiled state. Unexpectedly, when these unconstrained DNA molecules were subsequently re-extended by buffer flow, 80% (n = 20) revealed a stable pairing product (Fig. 1B, c). This finding suggested that either a free DNA end or a random coiled DNA was needed for pairing. In the same field of view, there were also λ DNA molecules that had both ends attached, but at a relatively close end-to-end distance (Fig. 1B, d). When the flow was stopped, we observed that these molecules also participated in homologous pairing during the time that flow was off, demonstrating that a free DNA end was not required. These unanticipated results revealed that DNA pairing did not occur on DNA that was extended to near its entropic elastic limit, and suggested that the DNA homology search required the 3D states that are accessible in randomly coiled DNA. Collectively, they suggested that a coiled conformation of the target dsDNA is crucial. ...»

 

 

 

 

… « To understand the nature of the complex that limits the rate of DNA pairing, we varied the length of RecA nucleoprotein filaments. Shown in Fig. 3c is a comparison of the time courses for 162-, 430- and 1,762-nucleotide nucleoprotein filaments. Increasing the ssDNA length approximately fourfold, from 430 to 1,762 nucleotides, increased the observed rate of pairing approximately 3.8-fold. However, when the length of the ssDNA was decreased to 162 nucleotides, we did not observe any stably bound homologously paired products after incubations for 10 min at the closest bead-to-bead distance possible (2 µm), despite this substrate being active in ensemble DNA pairing reactions (Supplementary Fig. 2). We conclude that the length of the RecA nucleoprotein filament is a crucial factor in the rate-limiting step of homologous pairing. ...»

 

… « Our results clearly establish that both the 3D conformation of dsDNA and the length of the nucleoprotein filament are important determinants of the rate for DNA homologous pairing. These findings lead us to propose a model termed 'intersegmental contact sampling' to describe the search for homology by a RecA nucleoprotein filament (Fig. 4d). One of the key features of the model is that the RecA nucleoprotein filament has a polyvalent interaction surface that is capable of binding simultaneously and non-specifically, but weakly, with non-contiguous segments of dsDNA. The second related feature of this model is that 3D conformational entropy of the dsDNA greatly enhances the probability that DNA sequence homology will be found through iterated homology sampling, using multiple weak contacts, by this polyvalent filament. This model is compatible both with our key experimental findings, which we expect would apply to the search in the presence of ATP as well, and with the involvement of heterologously bound intermediates that have been inferred from biochemical studies^{15, 16}. Our data show that dsDNA extended to near contour length fails to produce homologously paired products. This observation provides an explanation for the observation that the formation of stable DNA pairing products in single-molecule studies using magnetic tweezers required negative plectonemic supercoils in the DNA target ^{7, 8}. By contrast, when a ssDNA–RecA filament was extended to near its contour length, homologous pairing with fully homologous coiled dsDNA occurred which is compatible with our finding that the coiled structure of dsDNA is essential to the homology search.

 

Here we established that as the end-to-end distance of the dsDNA was decreased, allowing it to assume a more random coil-like 3D conformation, the rate of DNA pairing increased because the local DNA concentration increases, and the likelihood that DNA segments will be in close proximity also greatly increases. The increased local DNA concentration results in a greater statistical probability that a single nucleoprotein filament can simultaneously interact with and sample multiple regions of the same DNA molecule. This, in turn, is manifest as a kinetically more efficient homology sampling process. In further support of the intersegmental contact sampling model, when the length of the ssDNA in the nucleoprotein filament is increased, the observed rate of pairing, as well as the number of nucleoprotein filaments with multiple, transient, heterologous intersegmental interactions is increased. This shows that longer nucleoprotein filaments can simultaneously and independently sample more segments of the target dsDNA than shorter nucleoprotein filaments. »

 

… «Seminal work on the DNA target selection by transcriptional regulatory proteins identified sliding, hopping and intersegmental transfer as potentially facilitating mechanisms ^{17, 18}. Here we have established intersegmental transfer as the operative pathway used by RecA to find DNA sequence homology; this behaviour is distinct from the sliding and hopping used to enhance the rate of target location by most regulatory proteins, which are typically univalent or bivalent with regard to site binding ¹⁸. Our approach now provides a framework for future studies on the previously mysterious homology search by recombination proteins. It is applicable to studies of more complex systems such as eukaryotic Rad51, as it can provide insight into the function of the many accessory proteins that enhance DNA pairing⁹. Finally, the imaging strategy and flow-free cell design can easily be adapted to visualize target location and mechanism of processes as diverse as DNA replication and repair, RNA interference, transcription and protein translation, in which the 3D conformations of nucleic acids are undoubtedly important. »

 

 

My comment:

 

These assumptions and experimental findings square nicely with the work done and described (or cited) previously by Kupiec and Sonigo (2000, esp. Ch. 4, « L'indentification cellulaire », pp. 104-121,) where, as do the authors in the text cited here above (at their footnote Ref. 18) , Kupiec & Sonigo also cite the work of O.G. Berg ( in their case, Kupiec & Sonigo cite Berg and P.H. Von Hippel, « Diffusion-controlled macromolecular interactions », (1985) ) and discuss the importance of the model of coiled DNA as it relates to positionally random effects and proximity as stochastic factors in cell processes.

 

(There are some hyperlink formatting problems I haven't been able to correct in this text. Sorry. )

Edited November 13, 2012 by proximity1

[proximity1]

Readers of this thread should find interesting reading in a special issue of

 

Progress in Biophysics and Molecular Biology, Volume 110, Issue 1 (2012)

 

Special Issue: Chance at the Heart of the Cell

 

 

Edited by Jean-Jacques Kupiec, Olivier Gandrillon, Delphine Kolesnik and Guillaume Beslon

 

One of the articles, "What Makes Cells Differentiate?" by Andras Paldi, is accessible in its entirety to non-subcribers (pdf format) ; others, with access via an institution can view the full texts of the 19 articles concerned--the titles of which you can consult via the second of the links, above.

Edited December 5, 2012 by proximity1

[proximity1]

Here's a recommendation for a text which anyone in need of a well written, well organized and well-presented introduction to the full range of main issues concerned here will find very helpful, I think.

 

I refer to David L. Hull and Michael Ruse, editors of The Cambridge Companion to the Philosophy of Biology.

 

Published in October of 2007, it's not unreasonably out of date. Further, the topics allow the reader with only a general interest and no specialist knowledge to find a clear presentation of many if not all of the central issues in contemporary biological sciences—especially those areas which are centers of controversy.

 

While nothing can replace a reading of Kupiec for anyone interested in his work, the Cambridge Companion is, at this writing, the best all-in-one-place introductory presentation that I am aware of and it occurs to me that some readers need such a work to give them an entry to the issues.

 

Here is a link to the « pdf » file for the front-matter, includes introduction and table of contents.

 

 

Here is the text's Chapter heads and their contributing authors (from the publisher's web-page) :

 

Introduction David L. Hull and Michael Ruse
1. « Adaptation » Tim Lewens (Clare College, Cambridge*)
2. « Population genetics » Roberta L. Millstein and Robert A. Skipper
3. « Units and levels of selection » Elisabeth A. Lloyd
4. « What's wrong with the emergenist statistical interpretation of natural selection and random

drift ? » Robert N. Brandon and Grant Ramsey
5. « Gene » Paul E. Griffiths and Karola Stotz
6. « Information in biology » Peter Godfrey-Smith
7. « Reductionism (and antireductionism) in biology » Alexander Rosenberg
8. « Mechanisms and models » Lindley Darden
9. « T eleology » Andre Ariew
10. « Macroevolution, minimalism, and radiation of the animals » Kim Sterelny
11. « Philosophy and phylogenetics: historical and current connections » Maureen Kearney
12. « Human evolution: the three grand challenges of human biology » Francisco J. Ayala
13. « Varieties of evolutionary psychology » David J. Buller
14. « Neurobiology » Valerie Gray Hardcastle
15. « Biology explanations of human sexuality: the genetic basis of sexual orientation » Christopher

Horvath
16. « Game theory in evolutionary biology » Zachary Ernst
17. « What is an 'embryo' and how do we know it? » Jane Maienschein
18. « Evolutionary developmental biology » Manfred D. Laubichler
19. « Molecular and systems biology and bioethics » Jason Scott Robert
20. « Ecology » Gregory M. Mikkelson
21. « From ecological diversity to biodiversity » Sohotra Sarkar
22. « Biology and religion » Robert T. Pennock
23. « The moral grammar of narratives in history of biology: the case of Haeckel and Nazi biology » Robert J. Richards.

 

_______________________

 

From time to time, I'll cite passages from these essays in posts as supporting examples, pro and con.

Edited December 7, 2012 by proximity1

[proximity1]

With relevance to a recent news report in the New York Times concerning T-Cell therapy for lymphoblastic lukemia, the following article presents some interesting insights on the processes involved:

 

By Pierre Sonigo, the article (here in English) was later adapted for inclusion (Chapter 5, "Cellules en liberté," written by Sonigo) in a text jointly written by Sonigo and Jean Jacques Kupiec, "Ni Dieu, ni gène: pour une autre théorie de l'hérédité, " (2000 (November), Editions du Seuil / Points Sciences, Paris)

 

Title: Immune Cell Performances And Metabolism, an Ecological Interpretation

 

 

(excerpt)

Advantages and requirements of specialized predation : antigen presentation in the immune system

 

How do the proposed definitions of self and non-self accommodate experimental observations and knowledge concerning T-cell molecular mechanics ? T-cells are MHC restricted : they recognize antigens only when processed by proteolysis and presented in the context of an homologous MHC molecule. T-cell receptors are generated by random genetic recombination. Thymus cells carry MHC molecules loaded with diverse peptides from the organism. During embryogenesis, three fates are observed : T-cells that do not react with MHC die. T-cells that react with a high affinity to MHC also die (see a later paragraph for discussion about mechanisms of cell death). Only T-cells that react with an intermediate affinity are positively selected to constitute the T-cell repertoire (reviewed and discussed in refs. 13-16).

 

Let us examine the consequences of the alimentary chain hypothesis, which considers that peptides presented in the MHC constitute an essential food supply for the T-cells. This easily explains death of low affinity cells because they are unable to get peptide food from the MHC and starve. Death of cells with a high affinity receptor are more difficult to explain. High affinity might cause exhaustion of the peptide preys by their T-cells predators, and rapid subsequent disappearance of such predators. It might also cause " mechanical " difficulties in capture and internalization of presented peptides. Finally, the cells with the intermediate affinity will engage in a dynamic equilibrium of food exchange, based on peptides from the self. In the normal situation, the number of T-cells is stable and adapted to the abundance of "self-peptide food" provided by normal cells. This is supported by the presence of autoimmune reactive clones in the normal situation.

 

Destructive auto-reactivity occurs by displacement of this equilibrium to the benefit of T-cells. In the prevalent regulation or signal-based interpretations, auto-immunity is considered as a dysregulation of T-cell reactivity, resulting for example from inadequate signaling (14,15). This explains why autoimmunity might follow cellular destructions of diverse cause (traumatic, infectious, etc...). In the metabolic-based interpretation, self peptides constitute an important metabolic resource for T-cells. The consequences are similar : autoimmunity might also result from a transient increase in self peptide production, increasing in turn the number of self consuming T-cells.

 

When an external resource (potential antigen) is introduced in the system, the succession of events will depend on the amount and diversity of the new molecules. If the amount is low, or the diversity is high, specialization for capture will not be a sufficient selective advantage and all the resources will be captured by non specialized cells (phagocytes). If the amount of a homogeneous resource is high enough to support specialization for it, specific immunity will develop based on selected B and T lymphocytes. This is illustrated by the low efficacy of the specific immune response despite an intense macrophagic activation, when confronted to highly variable pathogens such as Human Immunodeficiency Virus.

 

Interestingly, T-cells do not specialize for capture of the antigen directly. They recognize peptide products of antigen digestion by the phagocytes and antigen presenting cells. As structural diversity of short peptides is lower than structural diversity of larger molecules, the repertoire of antigen receptors (either immunoglobulins or T-cell receptors) will cover more easily a repertoire of short peptides (either linear epitopes or processed antigen, respectively) than a repertoire of large molecules. Processing thus allows a smaller number of cells to cover the whole diversity of possible resources. Direct specialization for large molecules (peptides, glycolipids) will be possible only when they contain structural repetition, as it is the case for example at the surface of infectious agents or for T-independent B antigens (19).

 

Cytokines : a food network

 

Cytokines (from cyto = cell and kine = movement) are proteins secreted primarily from leukocytes that bind to receptors on the cell surface, with the primary result of activating cell proliferation and/or differentiation. Cytokines are remarkable for their ubiquitous and redundant spectrum of activities, as specificity for a given cell type is exceptional. For these reasons, the " cytokine network " is often referred to as a typical example of complex regulated exchange of information between cells, necessary for immune response coordination (see refs. 21,21 for review). It is remarkable that the cytokine network has many features of an alimentary network : specialization without strict specificity, importance for activation and reproduction, succession of local exchanges in a micro-environment. I hypothesize that cytokines constitute a proteic resource for cells, explaining their trophic activity. I called it " cytokine-steak " hypothesis : given the weight ratios, an active dose of cytokine for a cell is equivalent to a nice piece of meat for us ! This food network might have originated as a consequence of the metabolic importance of proteins and amino-acids. Accordingly, cytokines are highly related to amino acid metabolism (22) or nutrition balance (23,24).

 

Would alimentary specialization at the cell level be sufficient to explain the diversity and functions of cytokines and cytokine receptors ? Some answers might come from comparison of animal cells with multicellular animals. Although amino-acids are essential building blocks, their synthesis is unequally distributed amongst the living world. It requires for example nitrogen fixation, a central element in ecosystem formation (25,26). To a greater extent than glucids or lipids, amino-acid and proteins often constitute a limiting resource in the animal kingdom. Animals obtain amino-acids from other organisms rather than by de novo synthesis. In this case, amino-acids will not be captured as free molecules, but included into proteins. Although life uses a limited number of amino-acids, diversity of proteins is susceptible to generate a large variety of food specialization. Animals are indeed adapted for efficient capture of the most abundant protein food in their proximity. For example, some are specialized for vegetal proteins capture, other for animal protein capture. It seems that animals are entirely built around this specialization : teeth, digestion apparatus, locomotion apparatus, metabolic equipment often reflect protein specialization (vegetarian, carnivorous ...).

 

In the same way, cells might be adapted to the most abundant protein resource in their proximity, as reflected by the specialization of their surface receptors. Just like animals, cells are limited by an hydrophobic " skin " (lipid membranes) which represents a barrier to hydrophilic substances. Cells had to develop a dynamic system of protein capture using a wide ensemble of " sticky " proteins located at the membrane. These membrane molecules, specialized in binding and internalization of aliments, especially proteins, are exemplified by members of the immunoglobulin superfamily (27). This superfamily is one of the most diverse and abundant protein family. It includes for example adhesion molecules (see also below for adhesion and apoptosis), and cytokine or olfactory receptors. Interestingly, some receptors are related to amino-acid transport proteins (for a recent review, see ref. 28). Finally, what we call a cytokine receptor might be considered as a specialized tool for capture of proteins from the cellular microenvironment. If proteins constitute a limiting resource in the cellular world, like in the macroscopic world, successful capture will condition cellular activity. Would cells be more complex than multicellular animals ? "

_____________________

Pierre Sonigo was among the researchers whose work pioneered the sequencing of the Human Immuno Virus (HIV) at the Institut Pasteur in 1985.

Edited December 10, 2012 by proximity1

[proximity1]

more for the "reading reference file" :

 

from the journal Nature 's EMBO Reports

Cellular promiscuity: explaining cellular fidelity in vivo against unrestrained pluripotency in vitro

by Gerald Schatten

EMBO reports advance online publication 11 December 2012;
doi:10.1038/embor.2012.198

 

 

"The differentiation of pluripotent stem cells into various progeny is perplexing. In vivo, nature imposes strict fate constraints. In vitro, PSCs differentiate into almost any phenotype. Might the concept of ‘cellular promiscuity’ explain these surprising behaviours?"

[proximity1]

for the " 'Reading reference' file" :

 

 

“Clonal clues reveal cancer chaos”Journal name: : Nature Volume: 492Page: : 315Date published: (20 December 2012DOI: doi:10.1038/492315d / Published online : 19 December 2012

Nature link (subscriber access only) : http://www.nature.com/nature/journal/v492/n7429/full/492315d.html

 

 

Related news report concerning this study:

 

Jane Finlayson / University Health Network, Toronto, CANADA

 

http://www.eurekalert.org/pub_releases/2012-12/uhn-csi121212.php

 

 

 

Cancer scientists identify a new layer of complexity within human colon cancer

Shed light on resistance to treatment

(TORONTO, Canada – Dec. 13, 2012 ) – Cancer scientists led by Dr. John Dick at the Princess Margaret Cancer Centre have found a way to follow single tumour cells and observe their growth over time. By using special immune-deficient mice to propagate human colorectal cancer, they found that genetic mutations, regarded by many as the chief suspect driving cancer growth, are only one piece of the puzzle. The team discovered that biological factors and cell behaviour – not only genes – drive tumour growth, contributing to therapy failure and relapse.

The findings, published today online ahead of print in Science, are "a major conceptual advance in understanding tumour growth and treatment response," says Dr. Dick, who holds a Canada Research Chair in Stem Cell Biology and is a Senior Scientist at University Health Network's McEwen Centre for Regenerative Medicine and Ontario Cancer Institute, the research arm of the Princess Margaret Cancer Centre. He is also a Professor in the Department of Molecular Genetics, University of Toronto.

…

By tracking individual tumour cells, they found that not all cancer cells are equal: only some cancer cells are responsible for keeping the cancer growing. Within this small subset of propagating cancer cells, some kept the cancer growing for long time periods (up to 500 days of repeated tumour transplantation), while others were transient and stopped within 100 days. They also discovered a class of propagating cancer cells that could lie dormant before being activated. Importantly, the mutated cancer genes were identical for all of these different cell behaviours.

When chemotherapy was given to mice in which the human tumours were growing, the team made the unexpected finding that the long-term propagating cells were generally sensitive to treatment. Instead, the dormant cells were not killed by drug treatment and became activated, causing the tumour to grow again. The cancer cells that survived therapy had the same mutations as the sensitive cancer cells proving that cellular factors not linked to genetic mutation can be responsible for therapy failure.

The research challenges conventional wisdom in the cancer research field that the variable growth properties and resistance to therapy of cancer cells are solely based on the spectrum of genetic mutations within a tumour, says Dr. Dick. Instead, the scientists have validated a developmental view of cancer growth where other biological factors and cell functions outside genetic mutations are very much at play in sustaining disease and contributing to therapy failure.

The research published today builds on decades of experience by Dr. Dick, who focuses on understanding the cellular processes that maintain tumour growth. In 2004, Dr. Dick published related findings in leukaemia, but in the present study his team was able to compare the importance of genetic events with cellular mechanisms for the first time. It is also the first study of its kind in a solid tumour system.

Dr. Dick says the findings convinced him that the conventional view that only explores gene mutations is no longer enough in the quest to accelerate delivery of personalized cancer medicine to patients – targeted, effective treatments customized for individuals.

"The data show that gene sequencing of tumours to find the spectrum of their mutations is definitely not the whole story when it comes to determining which therapies will be most effective," says Dr. Dick.

 

 

 

" they found that not all cancer cells are equal: only some cancer cells are responsible for keeping the cancer growing "

 

 

 

" they found that genetic mutations, regarded by many as the chief suspect driving cancer growth, are only one piece of the puzzle "

 

 

 

" the findings convinced him that the conventional view that only explores gene mutations is no longer enough in the quest to accelerate delivery of personalized cancer medicine to patients "

 

 

I'm not sure why this qualifies as "news"-- I would revise the headline to read: "Some researchers' recent work show they are beginning to catch up to decade-old fundamental breakthroughs by Kupiec, Sonigo, et al."

Edited December 27, 2012 by proximity1

[proximity1]

Research Article:

"Parallel Evolutionary Dynamics of Adaptive Diversification in Escherichia coli"

by Matthew D. Herron and Michael Doebeli

link : http://www.plosbiology.org/article/info%3Adoi%2F10.1371%2Fjournal.pbio.1001490

Citation: Herron MD, Doebeli M (2013) Parallel Evolutionary Dynamics of Adaptive Diversification in Escherichia coli. PLoS Biol 11(2): e1001490. doi:10.1371/journal.pbio.1001490

Copyright: © 2013 Herron, Doebeli. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

[proximity1]

[ Note about the author excerpted below (from his website @ ) : "Vinay Prasad MD MPH is a practicing hematologist-oncologist and Assistant Professor of Medicine at the Oregon Health and Sciences University. He is nationally known for his research on oncology drugs, health policy, evidence-based medicine, bias, public health, preventive medicine, and medical reversal."

 

On various important current trends in science research and with comments supporting my previously posted views on the centrality of (as here described) the importance of "serendipty" in all research breakthroughs:

_________________________________

 

(From the New York Times )

 

The Opinion Pages | Op-Ed Contributor

The Folly of Big Science Awards

By VINAY PRASAD

Link : http://www.nytimes.com/2015/10/03/opinion/the-folly-of-big-science-awards.html?_r=0


… … …

More important, by emphasizing the importance of scientific breakthroughs — serendipitous occurrences that rely on decades of research — these prizes play down, and diminish, the way that great medical advances build on one another.
All scholarship is, to some extent, built on prior work — but this is especially true in scientific research. Consider James P. Allison, the winner of this year’s Lasker-DeBakey prize in clinical medical research. His work helped clarify one way cancer cells hide from the immune system.

Around 1990, a team of scientists found a protein on the surface of immune cells and proposed that it stimulated the immune system. Dr. Allison’s lab and a third group suggested that the protein put the brakes on immune responses. A fourth group confirmed that it halted the immune system, rather than stimulating it. Dr. Allison later showed that blocking this protein with an antibody could unleash an immune response in animals that could lead not only to rejection of but also immunity to many kinds of cancers. A decade later, similar antibodies to this protein and other related ones were found to prevail against several types of human cancers.

Dr. Allison’s work is surely impressive. But it occurred alongside and in dialogue with a number of related findings. Researchers analyzed the citations that led to Dr. Allison’s drug and concluded that it relied on work conducted by 7,000 scientists at 5,700 institutions over a hundred-year period. Yet only he was recognized.

 

... ...

 

And there’s yet another problem. By honoring breakthroughs, award committees reinforce the misconception that science is all about discoveries, when the cornerstone of science is replication and corroboration of results, which ensure that a finding is real and not a false lead.

The regular occurrence of false leads also hints at the enormous role serendipity plays in discoveries, which some Nobel Prize winners have acknowledged in their acceptance speeches. In one study of 101 basic science discoveries published in top journals that claimed a drug had promise, just five led to approved drugs. Even the most promising research may never translate into actual medicine. This means that a majority of creative, persistent and passionate scientists do not win awards, and may advance their fields only incrementally, if at all.

That’s because science is hard. It’s like exploring an unknown land; we’ll never know whether over the next hill lies an expansive vista or just another hill. A finding that seems mundane or trivial may become immensely important years later when a parallel discovery contextualizes or clarifies its implications. Medical research is even more elusive. We seek not only to understand the inner workings of human biology, but also to perfect the body and manipulate it to our desires. And, unlike physics, it can’t be advanced by purely theoretical work, or by a single individual.

http://www.nytimes.com/2015/10/03/opinion/the-folly-of-big-science-awards.html?_r=0

http://www.vinayakkprasad.com/

[proximity1]

A Single Cell Shines New Light on How Cancers Develop

By GINA KOLATA

JAN. 28, 2016

 

It was just a tiny speck, a single cell that researchers had marked with a fluorescent green dye. But it was the very first cell of what would grow to be a melanoma, the deadliest form of skin cancer. Never before had researchers captured a cancer so early.

The cell was not a cancer yet. But its state was surprising: It was a cell that had reverted to an embryonic form, when it could have developed into any cell type. As it began to divide, cancer genes took over and the single primitive cell barreled forward into a massive tumor.

Those were the findings of Dr. Leonard Zon of Boston Children’s Hospital, Dr. Charles K. Kaufman, and their colleagues, in a study published Thursday in the journal Science that offers new insight into how cancers may develop. The researchers stumbled on that first cell of a melanoma when they set out to solve a puzzle that has baffled cancer investigators: Why do many cells that have cancer genes never turn cancerous?

 

http://www.nytimes.com/2016/01/29/health/how-skin-cancer-develops-melanoma-zebra-fish.html?_r=0