Intelligent Microbes Attack Organelles

B0008190 Organelles in spiral ganglion neuronHuman cells are massively larger and more complex than bacteria and yet microbes keep up relentless intelligent warfare. Previous posts documented surprisingly sophisticated, multi level attacks by microbes using protein molecules and micro RNA against plants and animals.

Recently, new microbe techniques have been discovered that specifically target organelles of the human cell. These complex assaults can directly manipulate genes to produce unique proteins. These altered proteins change normal functions to produce new types of activity helpful to the microbe. This activity, somehow, occurs in complex pathways with cascades of interacting proteins. Microbes, also, use epigenetic tags on DNA and histones. In order to use epigenetic techniques, microbes are able to target specific enzymes that alter the function of genes through the histones and other structures protecting them. These assaults alter the gene expression by placing specific tags blocking the functions of regions of DNA. This is done either indirectly by altering the normal enzymes that perform these functions, or directly by placing and removing the tags with their own produced molecules.

PD FEATURE WIK 800px-SalmonellaNIAIDTo perform these sophisticated  manipulations, many levels of interacting codes are utilized. It is hard to imagine how unicellular microbes can understand the effect that a tag will have on the underlying gene that will alter the specific amino acid sequence to alter the exact shape of a protein. This particular protein shape, then, has very particular functions in complex cascades in the human cell. Also, these molecules are injected into the cell by extremely complex secretion systems that look similar to a syringe. This is highly intelligent activity for a small single celled creature. 

Despite extremely complex functions in the cell’s nucleus, mitochondria, endoplasmic reticulum and Golgi, these very small intelligent microbes are able to manipulate and commandeer organelles for their own advantage. Attacks are extremely precise and allow the microbe to hide inside the cell compartments to reproduce by disabling surveillance and immune responses. Throughout evolution, both eukaryote cells and microbes developed methods of attack and cellular level immune defenses. This post will describe how intelligent microbes attack organelles.

Organelles Have Particular Territories and Functions

B0009522 Organelles in an eukaryotic animal cell, illustrationThe eukaryote cell is very organized into compartments. These discrete regions of the cell have specific functions. Microbes manipulate the organelle’s unique functions to gain advantage over the cell.

Mitochondria produce energy and manage programmed cell death (apoptosis); the nucleus maintains and regulates the complex use of DNA and RNA; the endoplasmic reticulum (ER) handles and sorts new proteins and lipids; the Golgi directs secretory pathways where materials are carried to every section of the cell in vesicles.

Microbes have developed specific proteins that are secreted to attack each of the organelles—called effector proteins—which alter the cell’s functions. The secretion of these proteins is through one of 7 different elaborate secretion systems, but especially types 3 and 4 are utilized in this battle between cell’s organelles and bacteria. Microbes are able to direct secretions precisely and at the exact time that can be most effective. 

From Jacopo Werther

From Jacopo Werther

One of the microbe strategies is to make proteins that are very similar to the cell, but that alter function in various ways. They develop these either through evolution in the midst of battle with the cell or by acquiring the genes.

An example occurs with the amoeba, which makes proteins that are very close to those usually only found in animals and secretes them into the cell. Legionella sends more than 300 different proteins into a human cell. These proteins are otherwise only found in human cells. Other bacteria have been found with the same exact genes by horizontal gene transfer among many microbes. Some microbes, such as Chlamydia and Legionella produce proteins with sections that are similar to a variety of different human proteins and have multiple effects. 

A previous post described the ubiquitin system of labeling molecules in the cell, which has thousands of variations. The cell designates functions and destinations for molecules by using this very complex tagging system. Microbes have picked this up and use this same tagging system in warfare with cells to counteract functions. See the post describing intelligent warfare using ubiquitin and another labeling system called sumolyation.

Targeting an Organelle

From Maite.plummer

From Maite.plummer

In the normal function of the cell, tags are placed on newly produced proteins and other molecules to show what organelle will be receiving them. Bacteria copy this approach and secrete signals via the type 3 secretion system (T3SS) for the nucleus (NLS or nucleus localization signal) and the mitochondria (MLS or mitochondrial localization signal). The type 4 secretion system (T4SS) can inject DNA. Injection of proteins and genetic material can occur from outside of the cell by E coli and this goes with a tag directly to the mitochondria. Other intracellular bacteria inject both outside and then inside the cell. Salmonella has multiple proteins injected and Legionella has 300 different proteins with different functions.

Another technique is delivery of toxins without secretion systems either outside or inside the cell. Listeria has a toxin that cuts a hole in the cell membrane and internal membranes.

Targeting the Cell Nucleus

B0004343 Organelles in a pancreas cellDNA is wrapped twice around histone protein for protection and must be unspooled when used. Molecular tails on the histones can regulate whether the spool will be opened to allow particular genes to operate, or not. These tails are important in regulating enzymes that place a wide variety of epigenetic tags on the histone proteins. There are now known to be more than fifty different kinds of tags and placements on the protein, such as methylation, acetylation and ubiquitination on a lysine amino acid and the phosphorylation on serine and threonine. These tags are generally called post-translational modifications (PTMs). These have major effects on regulating the operation of genes.

While the effects of each type of PTM is very complex and just being discovered, somehow microbes already understand them and hijack this system, particularly related to the cell’s response to identifying the microbe in the cell. The cell has a pattern recognition system to identify microbes called pathogen-associated molecular patterns (PAMPs) that stimulate immune pathways with cytokines. The microbes attack both the cascades that stimulate inflammation and, also, the histone tags.

From Lxu27

From Lxu27

Major microbes, such as mycobacterium tuberculosis, influence the enzyme for acetylation (histone deacetylase or HDAC). They directly influence the gene that makes this enzyme. This is a remarkably complex mechanism for a microbe to utilize. Another microbe, A phagocytophilum, stimulates two genes that make two different HDACs causing less acetyls on histone 3. This decreases the function of two critical genes for the cell’s defense.

Some microbes go after the larger 3D structure of the DNA in the nucleus. Recent research (see previous post on genetic new genetic complexity) has shown that regulation of DNA is fantastically complex and now includes three-dimensional structures that hold the DNA in various positions inside the nucleus. (Manipulation of this structure by microbes is an entirely new field called patho-epigenetics.) Somehow, microbes understand much more than we do about how DNA is regulated. First the effector protein from the microbe has to get to the nucleus through special tags that take the molecule in through the very complex nuclear pore mechanism.

Multiple microbes, including E. coli, Shigella and Listeria, make proteins that alter the proteins that hold the DNA in place. First they influence the actin structures and then alter histones through special complexes of proteins. Listeria nuclear targeted protein A (LntA) binds to chromatin and stops critical genes that make interferon (IFN). IFN is a critical signal for general immune response.

There are now known to be multiple factors of this type that target the histone and alter their structure, silencing genes. Some of them interfere with extremely complex molecular cascades. One type silences the signals for apoptosis, a cell death signal, which is the ultimate response to a badly infected cell. This leads to lengthy infections.

Pixie~commonswiki wik TEM_of_isolated_T3SS_needle_complexesThe microbe that causes the fatal disease dysentery secretes an effector with T3SS. It affects the phosphorus tag by interfering with the enzyme and alters the number of phosphorus tags on histone 3. This blocks another critical cytokine (NF-κB), which is a signal for inflammation. This same toxin has other elaborate effects on the production of critical molecules in innate immunity.

E coli causes severe diarrhea disease with a similar mechanism through secretion proteins through T3SS. It affects the enzyme that tags a histone with acetyls, called acetytransferase or HAT, and and this lowers its activity. This is another way to negate NF-κB. It, also, affects the vital p53 and interleukin-8 (IL-8)

Direct Attack on Chromatin Structures

From Vojtěch Dostál

From Vojtěch Dostál

Chlamydia alters histones in a different way. Methylation of histones is a major way DNA is regulated either increasing or decreasing the effect of the local genes. This microbe makes a protein that, by itself, alters the tags replacing the effects of the human enzymes.

There are other versions of this technique used by pneumophila, which directly places methyl groups to replace an acetyl and dramatically decreases some gene activity. These affected genes are, also, vital for the production of molecules for the immune system. Another technique places a methyl group on the DNA that makes ribosomes, making more ribosomes that the microbe can use to make its own DNA.  makes a toxin that places methyl groups on 8 places of histone1. This stops the production of materials for inflammation.

Yet, another microbe uses a different mechanism. It makes a proteins ankyrin repeat protein (AnkA) that is secreted by T4SS, goes to the nucleus and accumulates there. It binds directly to DNA at a particular promoter that makes particular peptides used by the immune system. Recently, many different microbes have been discovered with genes for AnkA. ­

Microbes Attack the Endoplasmic Reticulum (ER) and Golgi

B0008518 Rough endoplasmic reticulumThe very complex secretory pathway was described in a previous post. This pathway related to the ER and Golgi provides very complex lipids in combination with proteins for many structures in the cell, including all membranes. It is the ER that tags the new proteins for their destinations and starts them on this secretory pathway including lysosomes and endosomes. These molecules are placed in particular tagged vesicles that bud from the ER membranes and then in the Golgi they are modified, often with the addition of sugars. The Golgi then sorts them again for transport to all parts of the cell in vesicles.

Special molecules serve as switches, through a complex set of enzymes and factors, and form large complexes that help direct this process of tagged transport. Using these switches, there are special transports of these vesicles from the ER surface (anterograde trafficking) and the other direction from the membrane to the ER (retrograde Golgi-ER transport).

There are other factors in regulating this very complex transport process to all parts of the cell. One involves seven different special complex lipids (phosphoinositide lipids) that occur in various compartments of the cell. One type is at the cell’s membrane; another is in the Golgi. These are coordinated through the special transport enzymes.

Microbes Attack the ER

Secretory VesiclesMicrobes that attack the secretory system make a home in a vacuole inside the cell. Please see the previous post about this clever set of microbes that live in vesicles that often is used to destroy microbes by altering it. Legionella alters a vacuole by interacting with the ER vesicles (Legionella-containing vacuole or LCV). The LCV fuses with ER vesicles.

Legionella uses many injected molecules to accomplish this. They use the special lipids for their own purposes by manipulating the switches that control the secretory system. They accomplish this in unusual ways, such as trapping important molecules in the vacuole and then altering their functions by the attachment of tags. They alter the process where the ER makes the vesicles in the secretory pathway through very complex mechanisms. They make specific enzymes that sit on the membrane of the vacuole.

Chlamydia hijacks the Golgi vesicles. Salmonella, also, lives in a vesicle (Salmonella-containing vacuole SCV) in the Golgi. Many others do versions of this.

B0004340 Golgi complex and mitochondriaOther microbes influence other vesicles, those between the ER and the Golgi. Pneumophilia targets this pathway along with the retrograde pathway. It makes proteins that inhibit the functions of the pathways. It manipulates the entire pathways to hide in a vacuole. Their vacuole is remarkable in that it has many unique lipids that should be identified by the cell. But, they produce many proteins (more than ten) that alter the switches regulating the traffic. This microbe demonstrates an extremely sophisticated interplay with the human cell.

Brucella uses another mechanism. They hide in a vesicle from the ER (Brucella containing vacuole or BCV). This vacuole interacts with other lysosomes making a more acid environment, which stimulates the special secretory 4 system that secretes many effectors. This alters the BCV to become just like a regular ER vesicle that replicates itself. They accomplish this by altering the switches at the ER exit sites. They alter the secretory pathway, especially the retrograde pathway.

Attacking the Golgi  

B0004341 Golgi complexChlamydia forms its own special vacuole, called an inclusion, at the Golgi using T3SS. It doesn’t fuse with the vesicles but captures a vesicle and then causes damage in the Golgi that releases a large amount of lipids. Many of these lipids are placed on the inclusion. It alters the lipid metabolism and gathers many proteins into the inclusion that helps it reproduce. It specially stops the apoptosis pathways.

­­Attacking Mitochondria

B0003650 Three mitochondria surrounded by cytoplasmMitochondria are semiautonomous microbes living symbiotically in every eukaryote cell. They have elaborate communication with the cell in many ways, but especially by docking at the ER. (See post on ER mitochondria communication in the neuron). They have two lipid membrane layers and have their own DNA that makes 12 very complex proteins for cellular respiration—the oxidative phosphorylation machines. Originally they made many more proteins but gave up these functions to the cell to focus on their main job of making energy through high-energy phosphate particles.

Mitochondria travel in the cell to provide energy where it is needed through elaborate signaling. In the neuron, large numbers use the axon transit system on microtubules (see the post on mitochondria travel in the neuron and transport along the axon). Mitochondria have an elaborate life cycle including fusing with others and breaking apart to make new ones. Their shape is altered by their functions—round and small for transport and long for many components. They have critical functions involved in maintaining calcium levels; manufacture of materials for proteins, lipids and nucleotides; and regulation of apoptosis or cell death.

B0006053 MitochondrionRecent research shows that they are critical for signaling in the fight with microbes including viruses

There are special proteins that have both signal tags for the nucleus and the mitochondria. They are not finished but exist in unfolded states with chaperones that can help them fold at a moment’s notice. The receptors notice these proteins and take them in to the mitochondria through pores. They are cut, folded and sent to very particular locations in the mitochondrial machinery sub compartment.

Microbes, such as tuberculosis and E. coli, use these same tags that send it to the mitochondria. This is a new area of research and not much is known about the tagging for the mitochondria. E. coli makes two effectors that go to the mitochondria by this described mechanism. One type decreases the function of the energy making and doesn’t affect apoptosis. The other type triggers apoptosis in the intestine and makes holes in the intestinal barrier.

Pneumophila makes a toxin secreted by T4SS that enters macrophages and attacks the mitochondrial second membrane. They form pores in the membrane that allow in too many metabolites, such as the high-energy particles to dissipate from the mitochondria.

B0004342 Mitochondria in the cell cytoplasmCholera uses a T3SS secretion to send an effector to the mitochondria where it alters calcium flow, stops mitochondria from clumping together near the nucleus and affects the response to viruses.

Another microbe inhibits apoptosis with a T4SS injected toxin, attacking mitochondria in white blood cells. The mitochondria cuts it, allowing it to travel into the center of the mitochondria through five membranes to the critical matrix. There it alters the critical cytochrome c mechanism and slows apoptosis. Another attacks autophagy mechanisms by sending toxins to autophagosomes.

Another toxin is beta-barrel proteins transported into mitochondria and placed in the membranes. They stop the energy process and kill the cell. Porins are, also, imported into mitochondria making holes in the membranes affecting cell death.

Mitochondria Control Cell Death (Apoptosis)

Org1012 wik ApoptosomeAlpha-proteo-bacteria were the ancestors of mitochondria 1.5 billion years ago. Despite giving up many functions to the larger eukaryote cell, they kept the molecules for cell death. The most common attack on mitochondria relate to stopping programmed cell death or apoptosis. Mitochondria are uniquely involved in the decision whether or not to use this final response of the cell to being hopelessly infected. Microbes mostly often want to keep the cell alive in order to use its machinery and to stop apoptosis.

The individual cell commits suicide to aid the larger organism in killing off dangerous microbes that have created a home in the cell. 60 billion human cells die each day. Apoptosis is a form of death that is pre programmed and in taking apart the cell, it doesn’t create inflammation and a scar as other types of cell death would. The cell shrinks, including the nucleus, where DNA is broken into pieces and the membrane forms blebs. The enzymes that perform these functions are caspases, which cut more than 600 different molecules into pieces including other caspase enzymes.

The apoptosis process starts when a large multi protein complex is assembled—the apoptosome—triggered by a protein from the mitochondria (cytochrome c) and one from the cell (APAF1 or apoptotic protease-activating protein). Cytochrome, normally, is part of the respiratory cycle and moves electrons. When it is sent into the cytoplasm it joins to trigger apoptosis. There are, in fact, several other molecules from the mitochondria that can do this and these all come through pores in the mitochondria membrane. The well-known protein BCL-2 that is linked with protection from cancer controls these pores. Many factors can trigger this process including damage to DNA with defective repair, toxic medications, radiation and other signals. Microbes have many toxins that affect this process in both directions. ­

Intelligent Microbes Attack Organelles

B0004797 Electron micrograph of Escherichia coli, close-upTo specifically attack the fundamental organelles of the cell, microbes use extremely sophisticated techniques that involve multiple levels of DNA codes, manipulation of histone codes, an understanding of how proteins are folded, and how newly produced versions of these proteins will interact in vastly complex pathways and cascades in human cells. They, also, build incredibly complex secretion weapons to send these molecules to particular places in the cell. Much of this is extremely difficult for humans to decipher and is currently unknown.

How do small microbes, a thousandth the size of a human cell, understand how to do this? Meanwhile, our cells must understand the extremely varied attacks of a large number of different microbes and counteract them.

How can anyone not see the intelligent behavior in these microbes and in our cells?

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  • It is hard to imagine how unicellular microbes can understand the
    effect that a tag will have on the underlying gene that will alter the
    specific amino acid sequence to alter the exact shape of a protein. –
    See more at:
    http://jonlieffmd.com/blog/intelligent-microbes-attack-organelles?utm_source=General+Interest&utm_campaign=22d3e38c0a-RSS_EMAIL_CAMPAIGN&utm_medium=email&utm_term=0_471703a831-22d3e38c0a-79440661#sthash.QehzL3wF.dpuf

    • Roy Niles

      Where were you taught that “ecological variation is linked to ecological adaptation only via the physiology of nutrient-dependent reproduction.” To be nutrient dependent only means that all biological species will need some form of food or they won’t live to reproduce. But ecological variation is linked to an organism’s physical surroundings, where nutrition may depend on the organism’s abilities to find the food and eat it – in other words to not be a fish out of water, or to find oneself in water out of fish.
      Or to attempt to communicate meaningfully with the chef by sending out what some nut had told you were intelligent smells.

      • As you know, I have published a series of reviews that link everything known to serious scientists about physics, chemistry, and the conserved molecular mechanisms of RNA-mediated cell type differentiation from atoms to ecosystems.

        Jon Lieff has done the same thing with his blog posts by focusing on cellular communication that links physics and chemistry to the molecular mechanisms of cell type differentiation. Please show some respect for the amount of time he spends providing the content here, and comment on it.

        There is no reason to follow me everywhere and keep sniping, Roy Niles.

        • Roy Niles

          Yes, you publish your own reviews of your own ridiculous theorizing. I didn’t follow you here, as I’ve commented here before as to the accuracy of the science and especially the intelligence of the author. And Jon Lieff has never published anything that supports your made up junk science.
          Please show some respect for a good scientist and don’t pollute his blog with this pseudo-scientific baloney.

          • Dr. Lieff has published on alternative splicings and on biophysically contrained protein folding. See for example: http://jonlieffmd.com/blog/alternative-rna-splicing-in-evolution

            Our 1996 Hormones and Behavior review led the way on this: “Small intranuclear proteins also participate in generating alternative
            splicing techniques of pre-mRNA and, by this mechanism, contribute to
            sexual differentiation in at least two species, Drosophila melanogaster and Caenorhabditis elegans (Adler and Hajduk, 1994; de Bono, Zarkower, and Hodgkin, 1995; Ge, Zuo, and Manley, 1991; Green, 1991; Parkhurst and Meneely, 1994; Wilkins, 1995; Wolfner, 1988).
            That similar proteins perform functions in humans suggests the
            possibility that some human sex differences may arise from alternative
            splicings of otherwise identical genes.”
            http://www.hawaii.edu/PCSS/biblio/articles/1961to1999/1996-from-fertilization.html

            Note the number of cited works to show that we were reporting facts, not theories. Dr. Lieff also reports the facts.

          • Roy Niles

            Where does any of that self cited pseudo-stuff justify what you first wrote here – that “ecological variation is linked to ecological adaptation only via the physiology of nutrient-dependent reproduction”??
            Where has Dr Lieff written anything that supports that, other than in your pseudo-scientific dreams?
            You’re commenting here under the hopeful pretext that his lack of any comments in return will appear to justify your efforts to in the end use “intelligent” pheromones as a basis for producing and selling magically effective perfume.

          • I do not have any perfumery clients. I have a model of biologically-based cause and effect that links atoms to ecosystems via the conserved molecular mechanisms Dr. Jon Lieff has also detailed.

            For comparison, what aspect of alternative RNA splicings do you understand?

          • Roy Niles

            Here’s one of your many ads: “James Kohl owns Pheromones.com, and he has published books and award-winning research journal articles about human pheromones. With colleagues he was the first to show that a mixture of human pheromones increases the flirtatious behaviors of women, and increases their level of attraction to the man wearing the mixture – during a real-life social circumstance lasting 15 minutes.”

            As to what I know about alternative RNA splicings, I know that it is a regulated process during gene expression that results in a single gene coding for multiple proteins, and it has nothing to do with the pheromones that, within your “model of biologically-based cause and effect,” you have claimed are instrumentally essential to controlling the evolutionary process of biological forms.

            Dr. Lieff has NOT detailed any “conserved molecular mechanisms” that match what you have claimed were designed to do in another of your ads as follows:
            “Kohl has integrated experimental evidence that pinpoints the ecologically adapted neurophysiological mechanism that links olfactory/pheromonal input to genes in hormone-secreting cells of tissue in a specific area of the brain that is primarily involved in the sensory integration of olfactory and visual input, and in the development of personal preference for food and other people.”

            Baloney.

          • You claimed I had “perfumery clients.” I own the domain and lease it as a means to support my research interests, since I am not funded by taxation or donations.

            People who have acquired funding are issuing retractions like this one, having been caught in their ignorance of cell type differentiation. If you received funding from tax dollars to support your ridiculous claims, you would probably be in prison by now — if you are not, already.

            Retracted a Few Years Laterhttps://www.genomeweb.com/scan/retracted-few-years-later

          • Roy Niles

            More baloney. Your so-called research interests have been developed as a way to further support your perfume making business, or are you going to claim now that you’ve never had a factory where the various perfumes that you have been selling for years are manufactured?
            As to the probability of being in prison because of ridiculous claims, the irony is that your whole shtick has been carefully contrived as a fraud that doesn’t cross the line that makes false advertising not only a civil fraud but a crime.
            I’m a retired private investigator and catching con artists was my business. I can smell your type a mile off. You are very careful about not saying or doing anything that can get you sued, just as all in the questionable business of health enhancing cosmetics have to do these days.
            Using Dr. Lieff to support this fraudulent activity is getting a bit too close to that actionable line. Or can you show us where he’s given you consent to do so?

          • Please tell us how cell type differentiation occurs in the context of your former profession. My claims are supported by two decades of published works and a career as a medical laboratory scientist. That’s my “type” Roy Niles. Your type can be compared to all types of biologically uninformed science idiots.

          • Roy Niles

            It doesn’t occur the way you claim it does in my profession or in any other profession they way you fraudulently claim it does. The tipoff is that you have never actually explained how your version of cell type differentiation works – you just pontificate that your advice on the subject is sacrosanct, and add that having been a medical laboratory assistant in a pseudo-scientific lab is all the proof you need to validate your cockamamie theories.
            And again, can you show us where Dr. Lieff has given you consent to use his name in this rather futile attempt to authenticate your claims as being in any sense consistent with his legitimately acquired expertise?

          • More than 500 blog posts at my domain attest to my expertise, Roy Niles. I don’t need anyone’s permission to post here, because I also have a publication history that attests to my expertise.

          • Roy Niles

            Your history of publications by yourself about yourself is hardly an “attest” of expertise. To attest is to provide clear evidence of your status, and the “body of facts” that you’ve pretended to be evidence have so far never been more than self invented stories about yourself that go no further than to deny the accuracy of all the documented evidence on file within the peer reviewed works of all other bona-fide scientists in the field of biology that you in fact do not belong and never have belonged to..

          • Role of olfaction in Octopus vulgaris reproductionhttp://www.ncbi.nlm.nih.gov/pubmed/25449183 “Future work on O. vulgaris olfaction must also consider how animals acquire the odours detected by the olfactory organ and what kind of odour the olfactory organ perceives. The OL acting as control centre may be target organ for metabolic hormones such as leptin like and insulin like peptides, and olfactory organ could exert regulatory action on the OL via epigenetic effects of nutrients and pheromones on gene expression (Kohl, 2013; Elekonich and Robinson, 2000).” — p. 61

            Eleckonich and Robinson linked the 1996 review: “From Fertilization to Adult Sexual Behavior” http://www.hawaii.edu/PCSS/biblio/articles/1961to1999/1996-from-fertilization.html

            from invertebrates to vertebrates as did the work that cited Kohl (2013). See also, the author’s copy of my invited review of nutritional epigenetics. Nutrient-dependent pheromone-controlled ecological adaptations: from atoms to ecosystems https://dx.doi.org/10.6084/m9.figshare.994281

            Please find someone who can treat your mental disorder effectively Roy Niles.

          • Roy Niles

            More trickery from you, Kohl, to pretend that some actual scientists found value in your work. The “hawaii” paper was co-authored by you! Elekonich and Robinson did NOT support your new take on cell type differentiation nor on your assertions that pheromones themselves were functional entities.
            You are a poor “scientist” and an even worse prefabricator where your scientific concoctions are concerned.

          • Elekonich and Roberts (2005) took our model further and linked it to the life history transitions of the honeybee model organism, which is what I did in my 2013 review that Polese et al (2015) used in the context of linking all invertebrates to all vertebrates.

          • Jon Lieff has put all the links from atoms to ecosystems into the context of the complexity of the immune system, which directly links the de novo creation of olfactory receptor genes to cell type differentiation in all animals.

            See: Feedback loops link odor and pheromone signaling with reproduction http://www.ncbi.nlm.nih.gov/pubmed/16290036

            Therein lies the problem for people like Roy Niles. De novo gene creation is the “holy grail” of biology and we linked it from RNA-mediated events to cell type differentiation 20 years ago. Theorists have always hated being confronted with facts, and that’s why Roy Niles is here — he thinks he needs to express his hatred, or it will consume him. He does not know that it will, anyway.

          • Roy Niles

            “Feedback loops link odor and pheromone signaling with reproduction.” If you are pretending to believe that signaling systems are causative functions, you’re a fraud, and if you really believe that pheromones are functional systems, you’re not
            a scientist.

          • A Cellular System for Spatial Signal Decoding in Chemical Gradients http://dx.doi.org/10.1016/j.devcel.2015.10.013

          • Roy Niles

            The above citation states that “Our work discovers how a conserved set of components assembles a network integrating signal intensity and directionality to decode the spatial information contained in chemical gradients.”
            Can you even begin to understand what decoding the signal information means? It doesn’t mean the signal has decided what the information is that it was assigned to carry, OR that a signal had in any way intelligently produced the message, or that it either added or detracted to it, except perhaps by accidentally garbling it.
            In short, you don’t seem to know a damned thing about cellular communication in general. Which to me is just more evidence that you didn’t come here to learn a thing, just as you regularly go to a number of these other scientific sites to irrelatively post your perfume sales propaganda.

          • Roy Niles

            Chemists know, but then you know you’re not a chemist either, and we all know that.

          • Roy Niles

            Chemists know, but then you know you’re not a chemist either, and we all know that.

          • Roy Niles

            The above citation states that “Our work discovers how a conserved set of components assembles a network integrating signal intensity and directionality to decode the spatial information contained in chemical gradients.”
            Can you even begin to understand what decoding the signal information means? It doesn’t mean the signal has decided what the information is that it was assigned to carry, OR that a signal had in any way intelligently produced the message, or that it either added or detracted to it, except perhaps by accidentally garbling it.
            In short, you don’t seem to know a damned thing about cellular communication in general. Which to me is just more evidence that you didn’t come here to learn a thing, just as you regularly go to a number of these other scientific sites to irrelatively post your perfume sales propaganda.

          • 2004 Nobel Laureate, Linda Buck was a co-author on that one, you moron.

          • Roy Niles

            A moron is someone who cites a paper co-authored by legitimate scientists that actually disproves the fraudulent theories that the moron thinks it proves.

          • Roy Niles

            “Feedback loops link odor and pheromone signaling with reproduction.” If you are pretending to believe that signaling systems are causative functions, you’re a fraud, and if you really believe that pheromones are functional systems, you’re not
            a scientist.

          • Roy Niles

            De novo gene creation has nothing at all to do with your version of cell type differentiation and especially with a theory that has inactive pheromones acting as creative entities.

          • Jon Lieff has put all the links from atoms to ecosystems into the context of the complexity of the immune system, which directly links the de novo creation of olfactory receptor genes to cell type differentiation in all animals.

            See: Feedback loops link odor and pheromone signaling with reproduction http://www.ncbi.nlm.nih.gov/pubmed/16290036

            Therein lies the problem for people like Roy Niles. De novo gene creation is the “holy grail” of biology and we linked it from RNA-mediated events to cell type differentiation 20 years ago. Theorists have always hated being confronted with facts, and that’s why Roy Niles is here — he thinks he needs to express his hatred, or it will consume him. He does not know that it will, anyway.

          • Roy Niles

            “in the context of linking all invertebrates to all vertebrates;” blah, blah, blah.
            Again, you are unable to show the offering by you of any evidence to support your take on cell type differentiation and especially on what you’ve continuously alleged to be the functional capacities of pheromones.

          • Pheromones control the nutrient-dependent physiology of reproduction in species from microbes to humans.

            Human pheromones and food odors: epigenetic influences on the socioaffective nature of evolved behaviors http://www.socioaffectiveneuroscipsychol.net/index.php/snp/article/view/17338

          • Roy Niles

            Pheromones have no control of anything, unless you think a signal flag has control of its signaler, or worse, that a signalling system, by definition somehow understands the message that it’s carrying. Ask Jon Lieff to tell us that you’re right and I’m wrong. Oh, right, you don’t need his permission to offer bogus science on his website, do you.

          • http://dx.doi.org/10.1134/S1022795414010037
            The mechanisms and importance of the antimutagenic effect of female house mouse chemosignals are discussed.

            They cite our award-winning review: Human pheromones and food odors: epigenetic influences on the socioaffective nature of evolved behaviors

          • http://www.sciencedirect.com/science/article/pii/S0968432814000031 Investigating biomolecular recognition at the cell surface using atomic force microscopy

            They cite our award-winning review: Human pheromones and food odors:
            epigenetic influences on the socioaffective nature of evolved behaviors

          • This is the most likely extension of our 2001 review, which now links atoms to ecosystems in all genera.

            That concept was popularized in https://www.youtube.com/watch?v=gwy2lD1reos&feature=youtu.be

          • Roy Niles

            Covering up nonsense with other nonsense is not even clever.

          • The parody comes from Dr. Z’s lab. So did this. Structural diversity of supercoiled DNA http://dx.doi.org/10.1038/ncomms9440 They linked atoms to ecosystems after I did but with the same details from physics and chemistry to conserved molecular mechanisms of RNA-mediated cell type differentiation in all living genera.

          • Roy Niles

            Show us where on that paper they report the same evidence and conclusions that you have in any of your “reviews.” I certainly can’t find it, and I’m sure that whatever you find won’t match anything that you are able to confirm that you’ve discovered.

          • Roy Niles

            Why don’t you tell us instead what you wrote about pheromones that has anything at all to do with biomolecular recognition at the cell surface?

          • Roy Niles

            That paper makes reference to “chemosignals from isolated adult female mice of the CBA strain.”
            Chemical signals carry messages through various signalling systems, but again, it’s not the chemical that causes change, it’s the nature of the signalling itself. Otherwise you’re arguing that morse code functions as an evolutionary cause.

            The paper then indicates that “It has been shown that the frequency of chromosomal aberrations in irradiated (4 Gr) males after exposing them for 24 hours on bedding soiled with female chemosignals is lower than in irradiated males in cages with clean bedding.”
            In other words mice don’t like bedding that has been made to stink. And thus a stink, in your opinion must have purposefully created the evolutionary consequences of the change it has purposefully or even accidentally caused to the environment.
            By that sort of reasoning, you’ve determined that in the end, everything has a role in changing everything. And then that everything is thus done for that purpose.
            You’re not only a bad scientist, Kohl, you’re an even worse philosopher. But so far, you’re sliding by as a con artist. You’d be well advised not to push your luck in that respect, however.

          • Pheromones control the nutrient-dependent physiology of reproduction in species from microbes to humans.

            Human pheromones and food odors: epigenetic influences on the socioaffective nature of evolved behaviors http://www.socioaffectiveneuroscipsychol.net/index.php/snp/article/view/17338

          • Roy Niles

            “in the context of linking all invertebrates to all vertebrates;” blah, blah, blah.
            Again, you are unable to show the offering by you of any evidence to support your take on cell type differentiation and especially on what you’ve continuously alleged to be the functional capacities of pheromones.

          • Roy Niles

            Your history of publications by yourself about yourself is hardly an “attest” of expertise. To attest is to provide clear evidence of your status, and the “body of facts” that you’ve pretended to be evidence have so far never been more than self invented stories about yourself that go no further than to deny the accuracy of all the documented evidence on file within the peer reviewed works of all other bona-fide scientists in the field of biology that you in fact do not belong and never have belonged to..

          • Roy Niles

            More baloney. Your so-called research interests have been developed as a way to further support your perfume making business, or are you going to claim now that you’ve never had a factory where the various perfumes that you have been selling for years are manufactured?
            As to the probability of being in prison because of ridiculous claims, the irony is that your whole shtick has been carefully contrived as a fraud that doesn’t cross the line that makes false advertising not only a civil fraud but a crime.
            I’m a retired private investigator and catching con artists was my business. I can smell your type a mile off. You are very careful about not saying or doing anything that can get you sued, just as all in the questionable business of health enhancing cosmetics have to do these days.
            Using Dr. Lieff to support this fraudulent activity is getting a bit too close to that actionable line. Or can you show us where he’s given you consent to do so?

          • You claimed I had “perfumery clients.” I own the domain and lease it as a means to support my research interests, since I am not funded by taxation or donations.

            People who have acquired funding are issuing retractions like this one, having been caught in their ignorance of cell type differentiation. If you received funding from tax dollars to support your ridiculous claims, you would probably be in prison by now — if you are not, already.

            Retracted a Few Years Laterhttps://www.genomeweb.com/scan/retracted-few-years-later

    • IntelligentAnimation

      Neo-Darwinists, like you implied, are not really serious scientists. They either just believe what they are told without questioning it or looking at evidence or they have some sort of anti-religion agenda. Either way, they are not known for any sort of accomplishments or advancement in the Biological sciences.
      What posts like this one emphasize is not merely that Neo-Darwinists are wrong, but HOW wrong they are. Not only do cells have the clear ability to edit their own genomes consistently functionally, but invading microbes also fully understand the mechanisms in play and attempt to outsmart the host cell.
      Its a chess game that humans are only recently learning how it is played and have a long way to go to catch up from many decades of Darwinian nonsense. I found it to be an interesting twist that it is the host cell trying to commit suicide for the sake of the multi-cellular organism, while ironically, it is the invading pathogenic microbe that is trying to stop apoptosis and keep it alive.
      You mention cell differentiation, which I have often found to be a valid discussion with Neo-Darwinists. While they won’t directly admit that somatic cell mutations are non-random and based on need, they do their best to dodge the subject because they don’t really have the selection excuse to hide behind.
      With 60 billion new cells a day and 10’s of quadrillions in a lifetime, the human race could not possibly survive for even a few days if mutations were random in somatic cells.

      • Thank you for your intelligent comment on Dr. LIeff’s well-detailed explanation of what was also just placed into the context of the innate immune system that protects all organized genomes from microbe-driven entropy.

        Noncoding RNA –NORAD– Regulates Genomic Stability by Sequestering PUMILIO Proteins http://dx.doi.org/10.1016/j.cell.2015.12.017

        This could be the subject of another detailed blog post by Jon Lieff, or research by others to learn more about how RNA-mediated events are linked from atoms to ecosystems in all living genera via the equivalent of the aerospace missile defense system with the same acronym.

        It is obvious to all serious scientists that random mutations cause damage to DNA that must be repaired in the context of the physiology of reproduction and fixation of the RNA-mediated amino acid substitutions that differentiate all cell types in all individuals of all living genera. A google search for “RNA mediated” is all that is required for others to start linking physics, to chemistry, and molecular epigenetics to cell type differentiation, which is what I have done for more than 20 years.

      • the_professeur

        I will have to admit to not seeing the term “Neo-Darwinists” outside of this comment thread. You seem to believe they are a unified group outside of “serious science” and gullible or have an anti-religious agenda.

        The whole of genetic research is an outgrowth of ideas initiated by Darwin’s research (and further refined in 1969 Ghiselin’s selective retention laws).

        Science is only recently understanding biology on the micron level due primarily to newer and better equipment, not due to anything Darwin published. While it seems that the variables he put forth may still apple at the micron level, it would be too premature to not question it.

        Regarding your last statement on mutations. Have you seen any of the photos of children born after the Chernobyl nuclear accident? While hugely affected by mutations from the radioactive fallout many still live 10 years on—not days as you suggest. A testament, I feel, to the power of life.

        While (ROS) reactive oxygen species damages our DNA relentlessly, the body is adapt at repairing much of that damage. We are constantly evolving as individuals and as a species. This is written in our genetic history.

        • IntelligentAnimation

          Professor: “The whole of genetic research is an outgrowth of ideas initiated by Darwin’s research”.
          Not only is this not true, but Darwin knew nothing of genetics at all. Mendel, his contemporary, may deserve the high honor you just gave Darwin, but evolutionary science did nothing but go backwards by following Darwin.
          The concept of Neo-Darwinism does not account for DNA repair. Of course, the Neo-Darwinists had no choice but to incorporate DNA repair into their randomness-causes-order foolishness (a very rough fit), but the idea of Darwinian evolution is random change that only seems non-random due to selection.
          Chernobyl was in 1986. If the children only lived 10 years, that means they did not survive it, but I was specifically referring to SOMATIC cell mutations anyway when I pointed out that the human race could not survive Darwinian randomness for a few days. So please don’t twist my words.
          Of course, if mutations were only random in the germline, life would survive for years, barely, but why would the germline have copy errors, while somatic cells do not?
          Lastly, even in radioactive disasters, most genetic changes are still not random, so your argument is poor all the way around. Your example only shows how getting even CLOSE to actual Darwinism is disastrous.
          Neo-Darwinism, a combination of random messy failure and a failure rejection system, is the most destructive force imaginable, not a magical perpetual creation machine. There is no value to science in anything Darwinian.
          Yes, Neo-Darwinists are a problem for serious science, a MAJOR problem. The anti-religion advocates are as bad or worse a problem as the religion advocates. Such atheism advocates as Dawkins, Moran, Tyson, Coyne or Myers are trying to force agenda-driven twists of science. They are the problem, not the answer.
          Neo-Darwinism and all materialistic attempts at distorting Biology are anti-scientific and damaging to medical knowledge, causing death and suffering. All slants infesting science are unacceptable.

    • the_professeur

      I can see how one may make a leap of logic in associating reproduction and food availability, for there is some connection. However, a tight association requires a vast oversimplification of data already at hand.
      Reproduction increases in microbes when food in more available, and random mutations is the process by which the microbe becomes better at extracting food from a host, either by forcing the host to create easier to assimilate nourishment, or to better overcome the host’s defenses, as a couple methods Dr. Lieff presented in the above article.
      It’s my opinion that the world is more complex than we imagine, in fact it’s more complex than we *can* imagine. Whether I look into earth sciences, astrophysics or particle physics, I find the deeper I peer, the more complexity I find. It is the same with microbiology and other sciences.

      • Re: “…random mutations is the process by which the microbe becomes better at extracting food from a host…”

        Who has presented any evidence of biologically-based cause and effect that links atoms to ecosystems via random mutations linked to adaptations?

        Why would you express such a ridiculous opinion under the nym the_professeur when all you profess is ignorance.

        • the_professeur

          Not intending to ignore your hostile reply, however it contained a question to me posed in such a way that made it incomprehensible unless you are using unique definitions for some of the terms.

          My posit is that variations in microbe actions and host reactions over enough generations can resemble “intelligent behavior” when it may be nothing more then random mutations driving the evolving selection process.

          My statements are intended to be within the confines of microbial biology, and not higher life forms, as that was keeping within the scope of Dr. Lieff’s article.

          I understand you have a vested interest in promoting a certain point of view while I do not. However if you feel you cannot conduct yourself in a scholarly manner and must resort to name-calling, don’t bother replying to this comment.

          • Thanks. I’m not using any definitions or assumptions. Your statements are not within the confines of anything known to serious scientists about microbiology. Ignorance inspired my hostility.

            I asked. “Who has presented any evidence of biologically-based cause and effect that links atoms to ecosystems via random mutations linked to adaptations?”

            Lenski’s experiments link the innate immune system to nutrient-dependent pheromone-controlled ecological adaptation in the context of weekend evolution of the bacterial flagellum.

            Is that what you claim resembles “intelligent behavior?”

            https://www.youtube.com/watch?v=gE8fKOozG40

  • the_professeur

    Much of the confusion regarding “intelligent behavior” with regard to microbes begins with one’s definition of term. A poorly-fed microbe may adapt to feed better on the potential food at hand, Over time, the microbe becomes better at bypassing the food source’s defenses—just as the host becomes better at defending itself from the microbe.

    A microbe, with food at hand will reproduce at approximately every twenty minutes. At each reproductive cycle the new microbes evolve slightly, nudging the population incrementally closer to feeding more successfully.

    With hundreds of thousands of years to continuously adapt, the microbe may appear to be exhibiting “intelligent behavior”.

    In the 1990’s Dr Adrian Thompson of the Department of Informatics at the University of Sussex, England, performed an interesting experiment using a new form (at the time) of logic chip called a Field-Programmable Gate Array (FPGA).

    http://www.damninteresting.com/on-the-origin-of-circuits/
    https://en.wikipedia.org/w/index.php?title=Field-programmable_gate_array&action=edit

    “In a unique laboratory in Sussex, England, a computer carefully scrutinized every member of large and diverse set of candidates. Each was evaluated dispassionately, and assigned a numeric score according to a strict set of criteria. This machine’s task was to single out the best possible pairings from the group, then force the selected couples to mate so that it might extract the resulting offspring and repeat the process with the following generation. As predicted, with each breeding cycle the offspring evolved slightly, nudging the population incrementally closer to the computer’s pre-programmed definition of the perfect individual.

    The candidates in question were not the stuff of blood, guts, and chromosomes that are normally associated with evolution, rather they were clumps of ones and zeros residing within a specialized computer chip. As these primitive bodies of data bumped together in their silicon logic cells, Dr. Adrian Thompson— the machine’s master— observed with curiosity and enthusiasm.”

    As a test bed, he procured a special type of chip called a Field-Programmable Gate Array (FPGA) whose internal logic can be completely rewritten as opposed to the fixed design of normal chips. This flexibility results in a circuit whose operation is slow compared to conventional counterparts, but it allows a single chip to become a modem, a voice-recognition unit, an audio processor, or just about any other computer component. All one must do is load the appropriate configuration.

    Dr, Thompson selected a straightforward task for the chip to complete—it must differentiate between two particular audio tones. A traditional sound processor with its hundreds of thousands of pre-programmed logic blocks would have no trouble filling such a request, but Thompson wanted to ensure that his hardware evolved a novel solution. To that end, he employed a chip only ten cells wide and ten cells across— a mere 100 logic gates. He also strayed from convention by omitting the system clock, thereby stripping the chip of its ability to synchronize its digital resources in the traditional way.

    I will save you the details of how the experiment was initiated and ran, you can read that in the link above. Finally, after just over 4,000 generations, test system settled upon the best program. When Dr. Thompson played the 1kHz tone, the microchip unfailingly reacted, and when he played the 10kHz
    tone, the output also reacted properly.

    He pushed the chip even farther by requiring it to react to vocal “stop” and “go” commands, a task it met with a few hundred more generations of evolution. As predicted, the principle of natural selection could successfully produce specialized circuits using a fraction of the resources a human designer would have required. And no one had the foggiest notion how it worked.

    Comparing 4000 generations of the FPGA chip to the reproductive speed of a microbe comes to 55.5 days of microbe life, and remember microbes have had hundred of thousands of years of reproducing and adapting. The FPGA chip used , didn’t have a built-in micro-processor to cause it to “think,” nor did it have the hundreds of thousands of pre-programmed logic blocks of a traditional sound processor. It’s whole resources consisted of 100 logic gates—nothing anyone would consider sufficient for Artificial Intelligence (AI).

    Dr. Thompson peered inside his perfect offspring to gain insight into its methods, but what he found inside was baffling. The plucky chip was utilizing only thirty-seven of its one hundred logic gates, and most
    of them were arranged in a curious collection of feedback loops. Five individual logic cells were functionally disconnected from the rest— with no pathways that would allow them to influence the output— yet when the researcher disabled any one of them the chip lost its ability to discriminate the tones. Furthermore, the final program did not work reliably when it was loaded onto other FPGAs of the same type.

    It seems that evolution had not merely selected the best code for the task, it had also advocated those programs which took advantage of the electromagnetic quirks of that specific microchip environment. The five separate logic cells were clearly crucial to the chip’s operation, but they were interacting with the main circuitry through some unorthodox method— most likely via the subtle magnetic fields that are created when electrons flow through circuitry, an effect known as magnetic flux. There was also evidence that the circuit was not relying solely on the transistors’ absolute ON and OFF positions like a typical chip; it was capitalizing upon analogue shades of gray along with the digital black and white.

    If this “intelligent behavior” can be simulated with only 4000 generations of directed trial and error, what kind of intelligent behavior can a microbe exhibit in 100,000 years, or 2.6 billion generations of trial and error adaption or mutation where each success means more food?

    According to current understanding, even the most advanced microchips fall far short of the resources necessary to host legitimate intelligence. On the other hand, at one time many engineers might have insisted that it’s impossible to train an unclocked 10×10 FPGA to distinguish between two distinct audio tones.

    • IntelligentAnimation

      Microbes don’t just “appear” to be exhibiting intelligent behavior. They communicate, solve problems, avoid threats, remember, seek nutrients, work together on projects and edit genomes constantly within a lifetime, not just over billions of years.

      Prof: “At each reproductive cycle the new microbes evolve slightly, nudging the population incrementally closer to feeding more successfully.”

      Really? Can you give an example of this? Perhaps you are referring to a repeater, where the same genetic data is repeatedly duplicated to produce more proteins for digestion of a particular available nutrient? Even if so, this would hardly be “each reproductive cycle” (every 20 minutes?!) and it would certainly not be a sign of randomness versus intelligent goal-directedness.

      Quite the opposite, wouldn’t you say?

      Your link, like all attempts at “computer simulation of Darwinism” fails to do so. It took hundreds of generations for even slight benefit on a simple task (life has no simple tasks). So all of these little pseudo-life forms would have been dead long before accomplishing anything. This experiment had no method of information loss causing death. It was forced to go either forward or staying put. Apparently ANY arrangement of 0’s and 1’s can continue to live to edit another day.

      Unfortunately life does not have that luxury of immortality. We get a bad mutation and we can die.

      Prof: “I will save you the details of how the experiment was initiated and ran, you can read that in the link above.”
      Unfortunately THEY spared us the details too. It was obvious he had an agenda when he called Darwin’s sloppy, illogical and unscientific luck and death theory “elegant”. Other than that, we don’t know much about how this encoded information accomplished tasks in a manner that is functional. I can take 100 sets of 0’s and 1’s and make changes to them all a few hundred times and it will not differentiate between audio tones. (How do you “slightly” differentiate between audio tones anyway?) nor do anything related to audio tones or anything else, so we are left wondering as to how much “help” he gave his test.
      He had a goal and he set this up for unavoidable success by intelligent manipulation. So, in this regard it was a lot like life, but without the death.
      This reminds me of the “Methinks it is like a weasel” fallacy of Richard Dawkins. It is a goal-oriented certainty they are demonstrating, a certain outcome that would NOT happen without the goal and an intelligent manipulator seeking the goal.
      Methinks that Darwinian is a weasel too.