Tuesday, April 10, 2012

Do Molecular Machines Deliver Toxins of Power?

Machines Had To Evolve First
In the search for the origin of the toxins of power, the Toxins of Power Blog has an attitude of "leave no meme unturned", "leave no molecule unturned", "leave no microbe unturned", and of course "leave no stone unturned."

In that regard, we looked at posts that deal with the study of memetics.

That inquiry included a look at historical attempts to establish the discipline of memetics, as well as some suggestions for the future of that discipline, in the context of using those theories in some manner that would aid us in our search for the origins of toxins of power.

After some theoretical fun with memetics, we picked up the microscope and took a look at the utterly astounding world of microbes.

But we had to move along, taking the search deeper, and while searching deeper we ran across a statement by a scientist whose paper flatly said that any complete inquiry into evolution would necessarily include chemistry:
Dr Clarke said: “There are a lot of fundamental questions about the origins of life and many people think they are questions about biology. But for life to have evolved, you have to have a moment when non-living things become livingeverything up to that point is chemistry.”
(Putting A Face On Machine Mutation - 2, emphasis added). The word "chemistry" conjures up beakers, flasks, and people moving around a laboratory in white coats, but it is also, in large part, the study of molecules and atoms (see chemical elements).

A statement by a scientist concerning that episode of our inquiry caught our attention and set another course for us:
“Our cells, and the cells of all organisms, are composed of molecular machines. These machines are built of component parts, each of which contributes a partial function or structural element to the machine. How such sophisticated, multi-component machines could evolve has been somewhat mysterious, and highly controversial.” Professor Lithgow said.
(Are Toxins of Power Machines or Organisms?, emphasis added). Another paper indicated that a closer look, in that direction, was needed:
Many cellular processes are carried out by molecular ‘machines’ — assemblies of multiple differentiated proteins that physically interact to execute biological functions ... Our experiments show that increased complexity in an essential molecular machine evolved because of simple, high-probability evolutionary processes, without the apparent evolution of novel functions. They point to a plausible mechanism for the evolution of complexity in other multi-paralogue protein complexes.
(Evolution ... a molecular machine, Nature, emphasis added). An interesting article in Wikipedia made a simple statement that helped:
The most complex molecular machines are found within cells.
(Molecular Machine). We then had a very distinct place to focus the search toward a distinct mechanism that generated toxins, and we found one:
Writing in the journal PLoS Pathogens, the team from Queen Mary's School of Biological and Chemical Sciences show how they studied the molecular machine known as the 'type II bacterial secretion system', which is responsible for delivering potent toxins from bacteria such as enterotoxigenic E. coli and Vibrio cholerae into an infected individual.

Professor Richard Pickersgill, who led the research, said: "Bacterial secretion systems deliver disease causing toxins into host tissue. If we can understand how these machines work, then we can work out how it they might be stopped."
(Decoding the Molecular Machine, emphasis added). Bingo, that is a perfect fit for a place to stay and study a while (see also Structure and function of mammalian cilia, where the term "molecular motor" is used).

Future posts will fuse the Microbial Hermeneutics series with the Hypothesis: Microbes Generate Toxins of Power series, so as to fine tune the concept of a molecular machine with a toxin of power generating mechanism.

Saturday, February 11, 2012

Microbial Hermeneutics

"What we have here is a failure to communicate" was a famous line uttered in the movie Cool Hand Luke, starring Paul Newman.

In the search for the origin of the toxins of power, we have considered how ideas and memes are communicated, then stored in memory.

We have also considered, at the higher levels of memory, how those memes and ideas can morph in various ways while still there in memory.

Lately, we have been considering some lower levels of brain activity where tiny, unseen components of memes and ideas in memory involve or require microbial signaling and messaging, as well as the proper handling of that microbial communication.

The understanding of thought generation and processing within the brain involves and requires a serious consideration of these most abundant, these tiny, and these unseen components, which microbiologists call either symbiont, or non-symbiont, microbes.

The Toxins of Power Blog's search for the origin of the toxins of power has led to a hypothesis ("The Hypothesis"), after considering just how important those microbes working within us are, especially in terms of their communication with our other cells.

In an ongoing series here on this blog we have hypothesized that one source of toxins of power is microbial signal or message malfunction:
Not only that, The Hypothesis is further condensed to state that a toxin of power is generated in one or both of these processes, within either symbiont or non-symbiont microbes, by way of "bad messaging" during common, constantly ongoing, human - microbe communications.
(Hypothesis: Microbes Generate Toxins of Power). "What?", the most abundant life form which is also the oldest life form, microbes, still experience the phenomenon of a failure to communicate like Cool Hand Luke did?

Concerning this aspect of the subject matter of communication, which we could call the struggle for clear communication, Dredd Blog has discussed human, language-based hermeneutics in the post "Hermeneutics For The Blogosphere" (cf. Modern Hermeneutics).

So in this post, here on Toxins of Power Blog, we will consider the notion of microbial hermeneutics as an aid to improving The Hypothesis.

Upon further research, I actually found an interesting paper, "Mixed Messages: How Bacteria Resolve Conflicting Signals", concerning microbial communication:
Imagine a graduate student with two thesis advisors. One suggests focusing on the experiments. The other suggests some mathematical modeling. What should the student do? The first strategy might involve doing a little of each, effectively ‘‘averaging’’ their advice. Prioritizing one mentor over the other could be a second option. Finally, when the best choice is unclear, it may be best to flip a coin. Bacteria, which live in complex environments, face similar problems and must respond optimally to multiple conflicting signals.
(Molecular Cell, Volume 42, Issue 4, p. 405, PDF, HTML). The Earth is rife with signals and communication, for example, a while back the cherry blossoms in Washington D.C. were blooming at the beginning of February 2012, a month or so earlier than the climate there calls for.

At that same time, around the nation, the ongoing "snow drought" and warm temperatures were sending signals to the flora and fauna which, as it turns out, were confusing communications that affected a proper understanding of what should be done (blossom, sprout, or stay dormant a while longer?).

That is because it can be dangerous when flora and/or fauna receive signals which normally indicate that spring is here, then as a result errantly go into "spring mode", to be later damaged by what is then a surprising, and seemingly untimely cold snap.

Likewise, the most abundant kind of cell in us, microbes, can also receive ambiguous messages, as shown in the paper "Resolution of Gene Regulatory Conflicts Caused by Combinations of Antibiotics", for example when we improperly use antibiotics:
Regulatory conflicts occur when two signals that individually trigger opposite cellular responses are present simultaneously. Here, we investigate regulatory conflicts in the bacterial response to antibiotic combinations.
(Molecular Cell, Volume 42, Issue 4, p. 413, PDF, HTML). The communication is quite complex:
Quorum sensing is the regulation of gene expression in response to fluctuations in cell-population density. Quorum sensing bacteria produce and release chemical signal molecules called autoinducers that increase in concentration as a function of cell density. The detection of a minimal threshold stimulatory concentration of an autoinducer leads to an alteration in gene expression. Gram-positive and Gram-negative bacteria use quorum sensing communication circuits to regulate a diverse array of physiological activities. These processes include symbiosis, virulence, competence, conjugation, antibiotic production, motility, sporulation, and biofilm formation. In general, Gram-negative bacteria use acylated homoserine lactones as autoinducers, and Gram-positive bacteria use processed oligo-peptides to communicate. Recent advances in the field indicate that cell-cell communication via autoinducers occurs both within and between bacterial species. Furthermore, there is mounting data suggesting that bacterial autoinducers elicit specific responses from host organisms. Although the nature of the chemical signals, the signal relay mechanisms, and the target genes controlled by bacterial quorum sensing systems differ, in every case the ability to communicate with one another allows bacteria to coordinate the gene expression, and therefore the behavior, of the entire community. Presumably, this process bestows upon bacteria some of the qualities of higher organisms. The evolution of quorum sensing systems in bacteria could, therefore, have been one of the early steps in the development of multicellularity.
(Quorum Sensing In Bacteria, emphasis added). It would seem, then, that microbial hermeneutics is not only the oldest form of hermeneutics, but is also a very critical and basic form of hermeneutics:
An alternative view is that cells use simpler ‘‘rules’’ to determine
appropriate gene expression levels in response to conflicting signals. But what do these ‘‘rules’’ look like, how complex are they, and to what extent can they be used to predict the response of cells to novel signal combinations?
These issues are increasingly critical throughout biomedical science. Single-cell organisms such as bacteria can live in extraordinarily diverse environments, in and out of hosts, and surrounded by other microbial species and the antibiotics that many of them produce. In this milieu, signal integration abilities are critical to survival. Similarly, in metazoan development, individual signaling pathways rarely work in isolation; rather, cellular responses depend on combinations of inputs from multiple pathways ...
(Molecular Cell, Volume 42, Issue 4, p. 405, emphasis added). Reiterating The Hypothesis, it does not seem to be too much of a stretch to say that toxins of power are possibly a result of message malfunction at this deep level of communication within us, since it is clear that "bad messaging" can and does happen there.

Furthermore, even the misinterpretation of a valid signal, because of inadequate microbial hermeneutic techniques, could have as much of an adverse impact as an improper signal in the first place could have.

Therefore, I also consider the realm of microbial hermeneutics to be a valid suspect as a source for toxins of power.

Before continuing, notice how similar this concept of microbial hermeneutics is to the scenario of a jury receiving mixed, conflicting messages from expert testimony in a courtroom trial.

Like microbes trying to resolve conflicting signals, the jury must use legal, and other, hermeneutics to resolve the conflict between or among experts, even though the jury is not composed of experts (The Pillars of Knowledge: Faith and Trust?).

Since this post is getting to be a bit long, I will close for now.

In the next post of this series we will consider a more complex area of microbial signaling and communication, which is the incredible "cell factories" that are better known as "stem cells."

They certainly seem to be another possible area where toxins of power could be generated, and therefore, should also be considered.

The next post in this series is here.

Wednesday, January 4, 2012

Hypothesis: Microbes Generate Toxins of Power - 5

For a hypothesis to be valid it must be falsifiable, and it must make predictions or explanations which match experimental or other data.

So, near the end of this post, I will propose some follow up research and/or experiments to do just that.

I will also suggest what those experiments and/or research efforts should show, so as to make it easier to test whether or not The Hypothesis is viable enough to pursue further.

But first, let's bring the history of The Hypothesis up to date.

Prions have been eliminated from The Hypothesis as a source for the toxins of power, thus we are left with either microbes or phages as originators of a toxin of power.

We have data that indicate a likely locus or focus point for this origin, which is the brain:
Microbial colonization of mammals is an evolution-driven process that modulate host physiology, many of which are associated with immunity and nutrient intake. Here, we report that colonization by gut microbiota impacts mammalian brain development and subsequent adult behavior ... our results suggest that the microbial colonization process initiates signaling mechanisms that affect neuronal circuits involved in motor control and anxiety behavior.
(Hypothesis: Microbes Generate Toxins of Power, emphasis added). The full import of that research is that, following colonization, communication of various sorts takes place between and/or among human cells and microbes, which impacts the amygdala, and other limbic system areas:
We therefore studied the expression of these genes in the frontal cortex, striatum, amygdala, and hippocampus of GF and SPF mice, by means of in situ hybridization technique. In GF mice, NGFI-A mRNA expression was significantly lower in various subregions of the prefrontal cortex, including the orbital frontal cortex (Fig. 4 A and A′); as well as in the striatum (GF vs. SPF: 329 ± 33 vs. 586 ± 18, P < 0.0001), hippocampus (CA1 region, GF vs. SPF: 258 ± 15 vs. 499 ± 22, P < 0.0001; CA3 region, GF vs. SPF: 166 ± 13 vs. 236 ± 6, P < 0.001; dentate gyrus, GF vs. SPF: 76 ± 4 vs. 113 ± 5, P < 0.0001) and amygdala (GF vs. SPF: 126 ± 17 vs. 212 ± 19, P < 0.01) compared with SPF mice. Similarly, GF mice had significantly lower BDNF mRNA expression in the hippocampus, amygdala (Fig. 4 B and B′), and cingulate cortex (GF vs. SPF: 162 ± 6 vs. 193 ± 10, P < 0.05), which are key components of the neural circuitry underlying anxiety and fear ... Our results suggest that during evolution, the colonization of gut microbiota has become integrated into the programming of brain development, affecting motor control and anxiety-like behavior.
(Hypothesis: Microbes Generate Toxins of Power - 2). The same method that was used to strengthen the appendix - microbe relationship hypothesis of Dr. Parker will work for testing The Hypothesis as well.

The team testing Dr. Parker's hypothesis used existing medical records, so I propose using that same method to test The Hypothesis, as follows:
1 - examine medical records of people who have been exposed to power (presidents, congress members, judges) covering a time when they behaved improperly in their official capacity;

2 - compare those to medical records of people who have not been exposed to power, at a time when those people were behaving properly;

3 - generate data about the differences in brain chemistry, structure, and brain function between the two groups, focusing on the limbic system, especially the amygdala.
NOTE: the reason for analysis of medical records of those exposed to power, during times of improper official behavior, is because The Hypothesis contains a premise that certain good behaviors are anti-toxins to the toxins of power (See: Tables For The Toxins In Power).

If The Hypothesis is correct the NGFI-A mRNA, BDNF mRNA, chemicals, and other factors mentioned above (Hypothesis: Microbes Generate Toxins of Power - 2) should reveal data supportive of The Hypothesis.

The next post in this series is here, the previous post in this series is here.

Tuesday, December 20, 2011

Hypothesis: Microbes Generate Toxins of Power - 4

In the previous post of this series, concerning The Hypothesis at issue, we considered prions as a source for the toxins of power.

In this post I will condense The Hypothesis down a bit, by eliminating prions as a source of the toxins of power.

In so doing, I will refine The Hypothesis so that now The Hypothesis is that either phages impair microbes, or that microbes malfunction individually without phage impairment, to generate a toxin of power.

That is, either one of those two specified dynamics are to be considered as a source for the generation of a toxin of power.

Not only that, The Hypothesis is further condensed to state that a toxin of power is generated in one or both of these processes, within either symbiont or non-symbiont microbes, by way of "bad messaging" during common, constantly ongoing, human - microbe communications.

Prions are properly eliminated from The Hypothesis because the impairments prions cause in humans are too deadly, and are very rare.

Likewise, consideration of prions as a source of the toxins of power would not comport well with the facts that have been set forth previously, concerning memes in memory.

Those facts, concerning memes in memory, basically describe "non-toxic ideas" that somehow morph into "toxic concepts", while stored in memory.

Remembering also that the morph of an idea is not fatal to the person it takes place in (at least in the sense we are concerned with in The Hypothesis); remembering that the morph of memes in memory do not cause physical impairment (in the sense we are concerned with in The Hypothesis); and finally, remembering that prions do cause fatality and/or do cause grave physical impairment as a matter of course, we can now properly leave prions out of The Hypothesis.

Further, prion diseases such as kuru cannot be neutralized with behavior of the sort set forth in Tables For Toxins In Power, which immunizes the host from a toxin of power for a limited time.

Thus, prions are hereby eliminated from further consideration in The Hypothesis as valid sources for the toxins of power.

What we end up with, then, is a hypothesis that the toxins of power work more like a moderately wild storm that comes and goes, leaving a temporarily modified mental and/or emotional scenario in its wake, rather than utter destruction.

The most likely place for commensurate intensity in such a storm, which would result in an altered meme landscape stored in memory, is in the microbes that have an effect on the conditions within the amygdala during messaging.

Those microbes that are in constant communication with human brain cell systems and/or microbes signaling the amygdala, and elsewhere, do not operate as a constant attack to kill, maim, and destroy them, as prions tend to do in their environment.

That is, I do not see the source of the toxins of power as a dedicated pathogen, but rather, I see it as a temporary malfunction in an otherwise non-pathogenic process within ongoing, common human - microbe communications:
Scientists originally expected that the communication between animals and their symbiotic bacteria would form its own molecular language. But McFall-Ngai, an expert on animal-microbe symbiosis, says that she and other scientists have instead found beneficial relationships involving some of the same chemical messages that had been discovered previously in pathogens. Many bacterial products that had been termed “virulence factors” or “toxins” turn out to not be inherently offensive signals; they are just part of the conversation between microbe and host. The difference between our interaction with harmful and helpful bacteria, she says, is not so much like separate languages as it is a change in tone: “It’s the difference between an argument and a civil conversation.” We are in constant communication with our microbes, and the messages are broadcast throughout the human body.
(On The New Meaning of "Human"). Let's review, then, what we have to work with, what we have constructed so far.

Like the germ hypothesis, which became the germ theory, our first observation starts at the "highest" level: someone noticing something not noticed before.

In the toxins of power context, it began when someone noticed that people exposed to power are affected by exposure to that power.

Next comes the voicing of that observation, as Lord Acton did, but also as James Madison did, so that others can begin further observations.

Notice how detailed James Madison's observations were:
01) war (generates anti-freedom germs):
02) war (is parent of):
03) armies (that generate):
04) war-debts, war-taxes (which bring):
05) many (99%) under domination of few (1%);
06) executive power surge;
07) seducing the minds (propaganda);
08) subduing the force of the people;
09) inequality of fortunes;
10) opportunities of fraud;
11) degeneracy of manners and morals;
12) (and eventually) end of freedom.
(See Greatest Source of Power Toxins?). These are detailed observations made by great statesmen, then written down in the history textbooks for our perusal.

Notice that in his quote from the link above, James Madison uses the language of medical diagnosis of an infection which a doctor might use.

By indicating that war generates "the germ" of many social infections, which are the origin of many social maladies that destroy freedom, James Madison reveals symptoms like a disease emerging from a state of war between nations.

Actually, he warns us to carefully and deliberately avoid such events, because they could lead to an epidemic, which would remove the freedom from any free nation exposed to it for too long, to eventually replace that freedom with tyranny.

These observations of these great statesmen may have, at first, originated from "a gut feeling".

Competent microbiologists today are not afraid to consider and express "a gut feeling", even in the highly sophisticated research associated with human - microbe symbiosis:
"My gut feeling is that some aspects of this process are unique to M. gryphiswaldense and not generalizable to all magnetotactic bacteria ..."
(Microbiologist Arash Komeili, Scientific American, 12/15/11). But such "gut feelings" early on in high level observations need to be later confirmed by related, yet deeper observations.

In the case of microbes being involved in human maladies, by either direct microbe malfunction, or by phage-induced microbe malfunction, that deeper observation is not beyond ultimate scientific discovery, even when it is just out of reach at first:
Current knowledge is insufficient to explain why only a proportion of individuals exposed to environmental carcinogens or carrying a genetic predisposition to cancer develop disease. Clearly, other factors must be important, and one such element that has recently received attention is the human microbiome, the residential microbes including Bacteria, Archaea, Eukaryotes, and viruses that colonize humans. Here, we review principles and paradigms of microbiome - related malignancy, as illustrated by three specific microbial - host interactions. We review the effects of the microbiota on local and adjacent neoplasia, present the estro-bolome model of distant effects, and discuss the complex interactions with a latent virus leading to malignancy. These are separate facets of a complex biology interfacing all the microbial species we harbor from birth onward toward early reproductive success and eventual senescence.
(Microbiome and Malignancy, Cell - Host & Microbe Journal, PDF is here). Even the varied aspects of cancer, in terms of developing or not developing cancer, are now considered within the context of the "human - microbe ecosystem".

Thus, we should move forward to put The Hypothesis through the tests necessary to allow it to mature into a theory, or fail.

For too long of a time now we have known that Microbes R US, and for too long of a time now, toxins of power have had their way with us.

The previous episode of this series is here, the next post in this series is here.

Friday, December 16, 2011

The Pillars of Knowledge: Faith and Trust?

We don't often reflect upon the reality that our "knowledge" is either faith based or trust based, which fundamentally constitutes nothing more than the essence of "belief".

Since the secular and non-secular worlds are supposed to be utterly different from one another, for the secular realm such as science, let's call that belief "trust", and for the non-secular realm such as religion, let's call that belief "faith".

Whatever words we use, the essence of "belief" boils down to a dependence on other people, a belief in what other people write or say they know, as the real basis for what we call "our knowledge".

There is a substantial amount of discourse and debate, in some circles, about the impact that this reality should or should not have on us:
"I find myself believing all sorts of things for which I do not possess evidence: that smoking cigarettes causes lung cancer, that my car keeps stalling because the carburetor needs to be rebuild, that mass media threaten democracy, that slums cause emotional disorders, that my irregular heart beat is premature ventricular contraction, that students' grades are not correlated with success in the nonacademic world, that nuclear power plants are not safe (enough) ...

The list of things I believe, though I have no evidence for the truth of them, is, if not infinite, virtually endless. And I am finite. Though I can readily imagine what I would have to do to obtain the evidence that would support any one of my beliefs, I cannot imagine being able to do this for all of my beliefs. I believe too much; there is too much relevant evidence (much of it available only after extensive, specialized training); intellect is too small and life too short.

What are we as epistemologists to say about all these beliefs? If I, without the available evidence, nevertheless believe a proposition, are my belief and I in that belief necessarily irrational or non-rational? Is my belief then mere belief (Plato's right opinion)? If not, why not? Are there other good reasons for believing propositions, reasons which do not reduce to having evidence for the truth of those propositions? What would these reasons look like?

In this paper I want to consider the idea of intellectual authority, particularly that of experts. I want to explore the 'logic' or epistemic structure of an appeal to intellectual authority and the way in which such an appeal constitutes justification for believing and knowing.
"
(Epistemic Dependence, by John Hardwick, Journal of Philosophy, Vol. 82, No. 7, July. 1985). A problem arises when we rely on experts in a situation where those experts disagree with one another, even on the same set of facts:
"Alvin Goldman has criticized the idea that, when evaluating the opinions of experts who disagree, a novice should 'go by the numbers'. Although Goldman is right that this is often a bad idea, his argument involves an appeal to a principle, which I call the non-independence principle, which is not in general true. Goldman's formal argument for this principle depends on an illegitimate assumption, and the examples he uses to make it seem
intuitively plausible are not convincing. The failure of this principle has significant implications, not only for the issue Goldman is directly addressing, but also for the epistemology of rumors, and for our understanding of the value of epistemic independence. I conclude by using the economics literature on information cascades to highlight an important truth which Goldman's principle gestures toward, and by mounting a qualified defense of the practice of going by the numbers."
(When Experts Disagree, by David Coady, Episteme: A Journal of Social Epistemology, Vol. 3, No. 1, 2006). This is an ancient problem which has been handled in different ways that result in divergent solution paths, but with no absolute conclusions.

This blog has discussed the issue of how our jurisprudence deals with conflicting expert testimony in the post Why Trial By Jury?, how experts can be very wrong in the post What Is Pseudo Science? (cf. The Appendix of Vestigial Textbooks), and Dredd Blog has discussed "scientific faith" in various contexts in the post Heretics Deny The Dark Matter of Faith.

The bottom line is that none of us, whether scientists or religionists, should get arrogant about our beliefs to the point of exalting "our knowledge" over the "knowledge" of others.

Instead, we should always remember that expert or non-expert material we rely on does not give us actual, direct knowledge of the vast majority of subjects we deal with:
"Knowledge is invariably a matter of degree: you cannot put your finger upon even the simplest datum and say 'this we know.'"
(T.S. Eliot). The danger of reliance on the seats of power for knowledge is the essence of Toxins of Power Blog posts:
"Events in my life caused me to start questioning my goals and the correctness of everything I had learned. In matters of religion, medicine, biology, physics, and other fields, I came to discover that reality differed seriously from what I had been taught. As a result of this questioning process, I was startled to realize how much of my 'knowledge' was indeed questionable."
(Dr. Thomas C Van Flandern). So, on this blog you will see the words "hypothesis" and "theory" used often, in place of an assertion of absolute knowledge.

It's A Matter of Trust, by Billy Joel