Jennifer Lake's Blog

June 25, 2011

Shiga-boom Shiga-boom

Shiga toxin-producing (Stx) O104:H4 killer E.coli strain:
Blame Japan
“A private biotechnology company used their DNA scanning algorithms to determine that E.coli O104 has genomic signatures specific [to]..previously found..strains of the 1996 outbreak in Sakai City, Japan… 103 pieces among the nearly one million genome fragments of the E.coli O104 are also present in phages of enterohemorrhagic E.coli isolated in 1996 in Japan… Orion Integrated Biosciences Inc. has developed this capability to scan unknown DNA fragments and point to their most likely source. The company is funded by the Departments of Defense, Homeland Security and the National Institutes of Health to apply this technology for biodefense purposes.” http://www.orionbiosciences.com/news/ORION-PR-June-05-11.pdf
…back in 1996…
“The Japanese..learned the hard way, 15 years ago, when that health-conscious society was gripped by what may be history’s worst outbreak of E.coli O157:H7. The epidemic sickened thousands, most of them children, and killed at least 12. It also showed critical weaknesses in Japan’s public health system –problems that the government spent years trying to correct. Up to that time, E.coli O157:H7 was virtually unknown in Japan… That all changed in mid-July when health officials in Sakai City, a major port city with a population near a million, received reports… Within a week, thousands were ill, hundreds hospitalized, some with hemolytic uremic syndrome (HUS), requiring kidney dialysis. And some were dying… Meanwhile, the epidemic seemed to be expanding… It was terrible timing. A few years earlier, Japan’s booming economy collapsed. Then, in 1995, an earthquake flattened the city of Kobe, not far from Sakai City. A few months later, terrorists [Aum Shinrikyo ‘yoga’ cult] released deadly sarin gas… Eventually the outbreak sickened at least 9,441 people…” http://www.foodsafetynews.com/2011/01/sprouts-and-historys-worst-outbreak/ A study paper published in 2002 reports the number of infection cases as 17,877: http://aac.asm.org/cgi/content/full/46/11/3478
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But there’s always more to the story. Food Safety News missed reporting on the more unique features of Japan’s 1996 outbreak, which was documented as 22 separate outbreaks between May and October (there were a total of 7 E.coli outbreaks in the previous five years): “In July..a large outbreak of exclusively Stx-1 producingE.coli 0118:H2 occurred in a junior highschool in Komatsu city. This appears to be the first report in the world of clinical infection caused by this organism… 241 [students and staff] were symptomatic… Although Stx-producing E.coli was not isolated from the samples of food and water, it was isolated from a dipper… No subjects developed infection at 11 other schools that had served the same..foods… the source of the primary infection was not identified..” One month after that another type of E.coli, O26:H11, that also anomalously produced only the Stx-1 variant of shiga-toxin (again a world’s first), caused a small outbreak. http://pediatrics.aappublications.org/content/103/1/e2.full
Evidently, something very unusual was going on.
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Stx1 is now a promising treatment for breast cancer: [2009] “The high specificity and apoptosis-inducing properties of verotoxin-1 indicates that the toxin potentially may be used for treatment of  Gb3-expressing breast cancer….Gb3 expression was detected in the vascular endothelial cells of..tumor specimens…” http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2650710/ >>>Gb3 is the glycolipid cell-surface receptor for Stx.
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    What does not seem to have been recorded in the huge wave of Japan’s pathogenic E.coli that year was the presence of O104 E.coli.  The earliest mention of an outbreak of an O104 strain anywhere that turns up in the literature happened in Montana:  “During February-March 1994…Eleven confirmed and seven suspected case-patients were identified..” with a “rare serotype E.coli O104:H21 that produced Shiga-like toxin II” (Stx2-like, or SLTII) http://www.cdc.gov/mmwr/PDF/wk/mm4427.pdf
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News from June 23 put the E.coli toll in Germany at 3,533; 39 deaths, 810 cases of hemolytic uremic syndrome (HUS) and 2, 684 less acute cases. http://articles.latimes.com/2011/jun/23/news/la-heb-ecoli-strain-pathogen-20110623; a same day report notes 5 confirmed cases in the U.S. of a “matching strain” and one suspected case resulting in death. The five were recent visitors to Germany: http://www.ecoliblog.com/e-coli-outbreaks/german-e-coli-outbreak-linked-to-massachusetts-michigan-wisconsin-north-carolina-and-arizona/ [updated June 30 to over 4,200 cases, 50 deaths, 898 HUS]
Something in the air?
“There seems to be little or no published work on the inhalation toxicity of Shiga toxin. However, there are often indirect effects on the lungs when the toxin is taken in as a food contaminant.” http://www.cbwinfo.com/Biological/Toxins/Verotox.html; “E.coli can grow in the air, using oxygen as a terminal electron acceptor..” http://www.ecoliblog.com/e-coli-watch/what-is-e-coli-1/
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 “Ricin and Shiga toxin share a unique mode of action, causing irreversible damage to host ribosomal RNA. Our understanding of how these bioterror agents cause tissue damage is incomplete… the mechanism(s) by which these signal transduction pathways are stimulated will be assessed using Shiga toxin mutants and isolated Shiga toxin subunits.” [grant award to Tufts Medical Center by U.S. Dept of HHS] http://projectreporter.nih.gov/project_info_description.cfm?projectnumber=5R01AI059509-04
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   Food and water are always the assumed vectors for E.coli contamination but if lung ‘effects’ from ingestion of the more toxic (HUS-causing) particle, Stx2, are indistinguishable from inhaled Shiga toxin then the Lords of the Air could whip up another perfect storm and blame it on ‘behavior’. The data on Stx (shiga-toxin) inhalation is currently similar to, and perhaps less than, the knowledge-ceiling of anthrax before the post 9-11 attack, given that no aerosol attack of Stx2 has ever happened before. At least no registered terror groups have ever launched a shiga toxin attack, but in case they do…well, the establishment looks almost prepared. Real time experience with countermeasures afforded by this new opportunity should be a good lesson, after all, the outbreak is erupting under the watchful eye of major defense contractors.
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The new O104 strain is “not new” according to the CDC and “There is no reason to think that this strain was modified intentionally… The combination of Shiga toxin and enteroaggregative features has been seen before; 1) in E.coli O104 identified in Europe and Asia in the last decade, and 2) in a different strain of E.coli that caused a small outbreak in Europe in the 1990s. While this combination is uncommon, it is not new.” http://www.cdc.gov/nczved/divisions/dfbmd/diseases/ecoli_o157h7/index.html#difference
   How new does new have to be? Toxic E.coli is new and became a reportable pathogen in 1982. Speculation about its emergence suggests it may have appeared in the 1950s. Looking at the volume of studies and papers on toxic E.coli generated at Harvard, for example, proves just how new the science is. There is nothing before 1997 and presumably no public funding either. Students and staff just don’t work on ‘unimportant’ diseases. http://connects.catalyst.harvard.edu/profiles/profile/concept/Escherichia+coli+O157
To wit : [2001] “Shiga toxin-producing E.coli (STEC) such as E.coli O157:H7 are important emerging pathogens in the United States… The genes encoding these potent toxins are present on viral particles known as bacteriophages… treating them with certain antibiotics leads to an increase in toxin expression. The antibiotics also lead to increased movement of the viruses…” http://www.reeis.usda.gov/web/crisprojectpages/192539.html; that’s called a bacterial “SOS” response, and a warning not to self-medicate with antibiotics –read the Colloidal Silver post too;  natural garlic ‘allicin’ has shown to be effective against shiga toxin bacteria.
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Current CDC estimates for Stx-producing E.coli infections in the U.S. stand at 186,000 cases annually http://www.marlerblog.com/lawyer-oped/non-o157-e-coli-in-beef—how-does-fsis-justify-it/; up from approx. 110,000 annually a decade ago.
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Where did  Shiga toxin come from?
   It was first isolated from an E.coli-like bacterium in 1896 Japan, and named Shigella for its discoverer, Kiyoshi Shiga. Four types of Shigella bacteria, all causes of dysentery (Shigellosis), have been characterized: Shigella dysenteriae, Shigella flexneri, Shigella boydii and Shigella sonnei, the most complex of which is Shigella flexneri, isolated by Simon Flexner c.1900 in the Philippines. Among the four types, S.flexneri toxin induced neurological damage and most often led to kidney failure and death. Flexner soon became the founding director of the Rockefeller Institute for Medical Research (RIMR) in New York. http://polioforever.wordpress.com/the-rockefeller-institute/
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The shiga toxin that is spreading in E.coli nowadays is carried by the lambda** phage, a viral particle and the most particularly interesting-to-science component of E.coli bacteria that has opened the secrets of genetic transference. Lambda phage was discovered by Esther Zimmer Lederberg, the wife of Joshua Lederberg, in 1950. http://www.estherlederberg.com/LambdaP.html
**”Lambda..is the 11th letter of the Greek alphabet…related to..the Cyrillic letter ‘El’..  http://en.wikipedia.org/wiki/Lambda
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 …”If the devil were to work overtime in a plot to confound scientists in their quest for a causative agent to a serious disease of unknown origin, it is doubtful whether he could have come up with anything better than the phage…”
 Head I        Head II
Joshua Lederberg, a Rockefeller University president and National Science administrator, is cited in this blog as the editor of a collected genetics publication about mutation: https://jenniferlake.wordpress.com/2009/08/11/mutation/ ; http://en.wikipedia.org/wiki/Joshua_Lederberg  In 1946, Joshua Lederberg codiscovered bacterial conjugation, the process credited to transferring Shiga toxins to E.coli.  He was also the principal coordinator of the first “artificial intelligence” project applied to chemobiology – the mid-60s DENDRAL super-computer at Stanford which set the groundwork for current Nano-Cogno-Bio-Information systems that plot “beyond conception” formulas for artificial life creation. Lederberg styled himself as an exobiologist. http://profiles.nlm.nih.gov/BB/Views/Exhibit/narrative/ai.html
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“From 1979 to the present, Lederberg has been a Trustee of the Sackler Medical School at Tel-Aviv University, and, since 1990, has been a Beverly Sackler Foundation Scholar at Rockefeller University. In 1994, he headed the Defense Department Task Force on Persian Gulf War Health Effects, “which concludes that there is insufficient epidemiological evidence for a coherent Gulf War
Syndrome.” http://www.smokershistory.com/Lederber.htm
“..as chairman of the..Task Force on Persian Gulf War Health Effects.. Lederberg was also on the board of directors of the American Type Culture Collection, or ATCC…[that] made 70 government-approved shipments of anthrax..to Iraqi scientists..” http://chss.montclair.edu/english/furr/pol/lederber.html
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Bacteriophage lambda has been used as a host vector for [the] generation of genomic..libraries for quite some time; ..generated primarily because of the phage particles’ ability to efficiency infect bacteria in vitro [lab dish]. Some research workers prefer to use the original lambda as a vector while others..like to propagate the gene fragments in a cosmid vector.” http://www.biocompare.com/Articles/ProductReview/867/Packagene-Lambda-DNA-Packaging-System-From-Promega.html
   The link below is a patent that promises a lambda vector system that can deliver recombinant DNA into the mitochondria of mammalian cells http://www.freepatentsonline.com/7741112.html; the lambda “taxi” can be virtually stripped of its own genetic material and used to import any select package of genes to almost any cell of choice, including genes that code for specific “receptors” to a range of viruses. These techniques offer the treatment paradigm of “virotherapy”, where viruses deliver genetic ‘correction’ to targeted cells.
    For a long time, antibiotics served as “tracers” in recombination studies by inducing resistance in the objects of study which could thrive and be isolated from cultures that were otherwise poisoned by an antibiotic– thus, not only do cellular entities accumulate antibiotic resistance as a type of mutation, but so do their interchangeable parts,  compounding their antibiotic-resistance profiles. For example, a citation from a Finnish study covering infections reported 1990 to 2000 notes E.coli “sensitivity to 12 antimicrobial agents.http://www.ncbi.nlm.nih.gov/pmc/PMC88246 .  State-of-the-art recombination genetics is readily taking up “marker” protein genes like the green fluorescent protein (gfp) from jellyfish, ostensibly as a safer alternative and infinitely fascinating as another paradigm in transgenetics. Still, antibiotics are very useful genetic expression ‘promoters’ and continue to be used in bioengineering.
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The toxin-making parts of lambda-bearing genomes have all been isolated and described but scientists have yet to realize the fullness of biochemical conditions that cause the toxin genes to turn on and ‘express’. They do know that “the bacteriophage life cycle is the dominant, if not the only, important factor involved in stx2 expression.” http://www.ncbi.nlm.nih.gov/pmc/PMC95105   Why would (some) scientists want to turn on the deadly shiga toxin-producing mechanism of the genes? There are reasons far beyond the call of medicine. Genetic engineers have very sophisticated needs in their search for knowledge and limited technologies and resources with which to explore them. I imagine there’s nothing quite as effective as handing a major public health threat over to a technically advanced society in order to get some help. The shiga toxin components of genes have enormously useful properties in the genetics industry.
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   Here’s a thought about weaponeering: “The [Stx] protein is robust, stable, relatively easy to manufacture and has been the subject of intense research over many years…This [body of] information..may also be used to develop novel variants of greater effectiveness. The protein does not act through the skin, and effective protection can probably be obtained with a gas mask with activated charcoal filters.” http://www.cbwinfo.com/Biological/Toxins/Verotox.html
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                                                                     CHANGE AGENTS
E.coli research has been a long-standing field of study. ..”The bacterium Escherichia coli is truly the workhorse of biology. Originally isolated in 1922 from a diphtheria patient, the strain of E.coli [completely and recently] sequenced  was used in 1945 in the discovery of spontaneous gene transfer. The strain, known as K-12, was universally adopted for fundamental work in biochemistry, genetics and physiology…E.coli is not the first bacterial genome to be sequenced, but with more than 4.6 million bases, it is the largest and possibly most important… The K-12 strain of E.coli is not pathogenic but closely related strains are toxic.” http://accessexcellence.org/WN/SUA11/ecoli997.php .  Mentioned earlier in “Transgenic Round-up”, recombinant DNA techniques were perfected by the 1970s with E.coli. See the work of Paul Berg and Maxine Singer.
   In the last decade E.coli research has opened a biotechnology platform for wholly new ‘life’ creations with artificial amino acids:
[2001] “Expanding the Genetic Code of Escherichia coli” [from the Scripps Research Institute laboratory of Peter Schultz and Salk Institute fellow Lei Wang] http://www.sciencemag.org/content/292/5516/498.abstract
“..We have evolved [a bioactive agent]..that makes possible the in vivo incorporation of [an artificial synthetic amino acid] into proteins in Escherichia coli… This unnatural amino acid was incorporated with high translational efficiency and fidelity.” http://www.ncbi.nlm.gov/pmc/articles/PMC123203/
“Augmenting proteins with unnatural amino acids could make existing proteins more potent in their actions, or even endow them with entirely new properties that might be useful for industry or medicine. Dr. Schultz’s [E.coli] bacteria, for example, look and act entirely like normal creatures until they are placed in contact with a certain sort of poison. Then, because they are producing an unnatural protein, they survive while all the others die.” http://www.economist.com/node/987697?story_id=987697
“..multiple unnatural amino acids can be added to the genetic code of a single modified organism.”  http://www.sciencedaily.com/releases/2004/05/040512040149.htm
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   Raising the ‘possibilities of meaning’ in E.coli outbreaks occurring after 2004, when the ‘new amino’ insertion techniques became a commodious reality, deserve special attention. Two considerations come to mind; that the E.coli are stealthily vectoring artificial genes and the shiga toxin subunits are installing genetic controls: one vector with multi-use potential. It will take months and years for published study material on the current outbreak strain to make it into the public sphere, even then, the likelihood that new amino acids are factored into standard tests is slim-to-none. For the time being, only the upper echelon labs will have the capacity to identify the rogue material. General researchers fully understand that mutant strains present unknowns which can remain unknown or evade definition for years. If such a probability exists at present, it’s a secret experiment that will bear fruit for its instigators who have in their labs a description of ideal-sounding binary bioweapons. The close structural relationship and gene-swapping properties of E.coli and related “homologous” phage is a biological SureThing, spreading naturally wherever it is
introduced (albeit slowly unless unnaturally assisted).  Stx-producing enterohemorrhagic E.coli (STEC) is also a sure thing– sure to drive victims to seek emergency medical care. There’s going to be lots of samples, lots of DNA, and probable new toxic mutants.
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“Physicians know not to prescribe antibiotics for O157 infections because the sudden killing of the bacteria can release HUS[hemolytic uremic syndrome]-inducing and potentially deadly amounts of Shiga toxin… that fact could have created one major problem in the early development of the [May 2011] outbreak: It is likely that German hospitals were only screening the first enterohemorrhagic E.coli symptoms for O157 and not O104, which no one would have suspected… ‘In this case, [said Jorge Giron], because it wasn’t O157, the physicians might have thought it was okay to give antibiotics, not knowing that O104 would produce the Shiga toxin… This potential misunderstanding over antibiotics might at least partially explain the high rate of HUS among the ill’ ” http://www.lavidalocavore.org/diary/4763/o104h4-may-change-how-we-deal-with-e-coli >>It might because somehow the unprecedented rate of HUS needs explaining. Previous toxic E.coli outbreaks have produced a rate of HUS around 3-6%, now trending upwards to 10%.  But just as likely to happen only moreso among skilled physicians who know they don’t have O157 on their hands is to give no antibiotics and allow the normally self-limiting infection to run its course– this is especially plausible with adult patients who subsequently made up the majority cases of HUS.  The 1996 Komatsu Japan Stx1 school outbreak (non-O157), linked above, is an example of infected patients receiving no antibiotics (approx. half) and resolving their infections equally well and sometimes better. Mr. Giron’s suggestion just doesn’t fly. The more I look at the German “Egyptian sprout” outbreak, the stranger it gets in comparison to other documented outbreaks. I’m considering the cofactor with radioactive fallout based on past anthrax episodes as an opportune moment-in-time, so I’ve set up a link with microbe-hunting results and I’m adding in the accumulating news.
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Hemolytic uremic syndrome is a severe, life-threatening complication of an E.coli..infection that was first described in 1955… The Shiga toxin triggers a complex cascade of changes in the blood..and there is disruption of the inherent clot-breaking mechanisms… About ten percent of individuals with [toxic] E.coli..infections (mostly young children) goes on to develop Hemolytic Uremic Syndrome.” http://www.marlerblog.com/legal-cases/three-suffering-kidney-failure-hus-from-alabama-e-coli-poisoning/; “The principle organ affected in STEC-mediated HUS is the kidney… The severity of renal injury varies in degree from urinary abnormalities such as hematuria and proteinuria to acute renal failure… The second most important organ affected in the disease is the brain… more serious cerebral complications, including seizures, cortical blindness, and thrombotic strokes, occur in 5 to 10% of patients… A similar percentage of patients may develop life-threatening cardiopulmonary sequelae, including adult [acute] respiratory distress syndrome [ARDS], congestive heart failure and myocarditis. The occurrance of neurological and cardiovascular complications is associated with more severe STEC-induced HUS and a higher risk of mortality during the acute illness. Other organs that are frequently involved in STEC-induced HUS are the endocrine and exocrine pancreas, liver, gall bladder, gastrointestinal tract, and skin. It is evident that STEC-induced HUS is a systemic illness potentially affecting every organ throughout the body.http://cmr.asm.org/cgi/content/full/17/4/926
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“…the outbreak originating in Germany shows 87% of those hit by the disease were women over the age of 20… the German outbreak..displayed ‘several intriguing microbiological characteristics’ and ‘several novel epidemiological and clinical features’..[that] ‘differed remarkably’ from previously described STEC/VTEC infections… Among the ‘completely unexpected’ features was the development of severe neurological symptoms in half of patients within 3 to 10 days of being admitted to hospital..” http://www.irishexaminer.com/ireland/kfojidqlsney/rss2/
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                                                No treatment for humans — vaccines for cows
More information about Shiga toxin E. coli, Alexion* Pharmaceuticals Inc. (et.al.) and the bioweapon potential of Stx is here  http://citizen2009.wordpress.com/e-coli/ (page in progress) and keep this in mind:
“Biotechnology now allows us to genetically engineer animals so that they produce proteins that are human pharmaceuticals. For certain drugs that are difficult to produce using existing methods or are needed in large quantities, production in GE animals offers the most efficient and practical solution. In the case of fighting infectious diseases, GE animal-made antibodies can be produced from animals that have had the human antibody genes transferred to them. These animals can then be vaccinated against human diseases and antibodies can be collected from their blood and used for treating diseases in humans. For example, antibodies can treat infections that are resistant to antibiotics.” http://www.bio.org/foodag/animals/GE_An_Pharm_0908.pdf
“On March 13, 2009, the USDA granted a conditional license for a new tool in the battle against foodborne illness –a vaccine for cows to prevent infection with E.coli bacteria… Cattle themselves do not experience illness from the bacteria. ” http://www.dmaonline.org/CE/food_protection/2009_05.shtml
>>>cattle immunity to STEC  no longer seems to be true –another significant round of ‘firsts’ in 1996 involves cattle infections.
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   Alexion Antibody Technologies was invited to give Congress a very exclusive pitch for Project BioShield funds in 2003, before approval of the program, and now the German health authorities have approved of Alexion running clinical drug trials on the latest E.coli victims. Alexion is giving away an ultra-expensive drug in exchange for access to patients.
*The nuclear power company UniStar bought Alexion Pharmaceuticals’ property in 2007; http://maryland.realestaterama.com/2007/12/19/unistar-properties-defies-slow-real-estate-market-with-purchase-of-311-million-bioscience-facility-ID041.html; does the relationship get cozier? “Arch Chemicals” also shares the site. There must be some advantage in having “the world’s largest owner and operator of nuclear energy facilities” as a landlord. http://unistarnuclear.com/; UniStar was taken over in 2010 by Electricite de France (EdF). “Both EdF and Areva are backed by the French state.” http://www.world-nuclear-news.org/C_EdF_takes_control_of_Unistar_2710101.html
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[Feb 2011] Alexion Chairman Max Link sold 47,367 shares, valued at $95 per share… “he retains 92,898 shares… Dr. Link has been the company chairman since December 2002..[and was] formerly CEO of Corange, the parent company of Boehringer Mannheim Therapeutics..[also] formerly the Chairman and CEO of Sandoz Pharma, Ltd.”…”Ann M. Veneman was appointed to Alexion’s Board..previously she served as Executive Director of the United Nations Children’s Fund (UNICEF)”..[from 2005-2010, after resigning her GWBush appointment as Secretary of Agriculture]
http://newyork.citybizlist.com/18/2011/2/25/Chairman-Max-Link-Sells-4.5M-in-Alexion-Shares–cbl.aspx;
Dr. Max Link also became Chairman of Protein Design Labs Inc.[Fremont,CA] in 2004, when the developer of antibody drugs accrued major revenues from products like Avastin (licensed to Roche subsidiary Genentech): “Avastin is a recombinant humanized monoclonal IgG1 antibody..of mouse origin..produced in a Chinese hamster ovary..” approved in 2004 for colorectal cancer treatment. http://www.discoverymedicine.com/Benjamin-Yang/2009/06/17/drug-profile-avastin
 “Ms. Veneman’s training and experience as a corporate lawyer for agribusiness do not qualify her for the substantial task of leading the agency most responsible for the rights of children worldwide. There is no evidence in her tenure as U.S. secretary of agriculture, secretary of the California Department of Food and Agriculture, or deputy undersecretary for international affairs of the USDA of her interest in the world’s children or their health and well-being.” http://www.sourcewatch.org/index.php?title=Ann_Veneman
   In addition to Alexion Pharmaceuticals, Veneman joined the Board of Nestle, the world’s largest food and beverage producer: “Veneman took the post despite pleas from nutrition advocates who urged her not to lend her imprimatur to the company’s marketing of breast milk substitutes” http://www.newsok.com/ex-unicef-head-joins-nestle-board-despite-protests/article/feed/250068?custom_click=pod_headline_europe; the best preventive to Stx-producing E.coli in children is, naturally, breast milk. In Europe and the U.S., 1971 marked an all-time-low in breast-feeding when only 1% of new mothers chose to persist in natural feeding past their ‘hospital stay’. The successful War on Milk rages on…
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                                                                Deadlier Threshold for Stx
Researchers recently learned that Stx genes multiply exponentially faster than their E.coli hosts:
 [2007] “Demonstration of the ability of [ Stx phage] to form multiple lysogens has two potentially serious impacts. First, multiple integrated prophages will drive the evolution of bacterial pathogens as novel Stx-phages emerge following intracellular mutation/recombination events. Second, multiple copies of the Stx gene may lead to an increase in toxin production and consequently increased virulence…. there is considerable scope for Stx integration directed by as yet uncharacterized factors… Clearly, the occurence of multiple lysogens in a single host [cell] is likely to enhance the evolution and dissemination of bacteriophage-encoded genes throughout bacterial populations, with particular applied relevance for Stx-phages responsible for increasing the pathogenic potential of Escherichia coli hosts.”  http://mic.sgmjournals.org/content/153/12/4098.full
SHIGA-BOOM!
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August 11, 2009

MUTATION

Scientists sometimes say the scariest things, especially if one parallels the descriptions of one system (bacterial populations) to another (human populations). In a document about genetic mutation in bacterial populations, Joshua Lederberg wrote, straightforwardly enough in 1951:
“…mutation is the fundamental source of genetic variation, but in view of the smallness of spontaneous mutation rates, it is obvious that the occasional change of a cell from one genetic condition to another can make little impression upon the composition of bacterial populations. The forces that determine which genetic types will predominate in bacterial cultures are the subject of population dynamics. In diploid sexual organisms, population genetics is greatly complicated by recombination and by the concealment of genetic variation in the heterozygous condition, so that the most drastic culling may have to be carried out for a great many generations to have marked effect on the relative frequency of different gene forms.”
Here are excerpts from the link:
 
“The physiological study of mutant characters is known as phenogenetics, in contrast to formal or cryptogenetics which deals directly with the mechanism of hereditary transmission. One would resonably expect that a gene mutation would require a period of time to work its effects on the phenotype or outward behavior of the organism. This lag in bacterial mutation effects (phenotypic or phenomic lag) was first noticed directly with phage-resistance mutations induced by radiations….Phage resistant mutations play such a large part in genetic study because of the ease with which they can be selected out of large populations, simply by adding suspensions of the virus under appropriate conditions. This facility is shared by antibiotics…”
 
“Current interest in drug-resistance mutations is largely motivated by their importance in limiting the effectiveness of chemotherapy….In most cases, resistance may be developed in a series of individually small steps…evidence for this comes primarily from kinetic studies of increasing resistance under selection…”
 
“A more striking oddity is the mutation which over-adapts the cell to streptomycin so that the resistant mutant is dependent upon streptomycin for growth. The function of streptomycin is possibly to regulate an over-expanded enzyme system….Amino acids and vitamins are not commonly thought of as antibiotics but it has long been known that they sometimes interfere with, rather than promote, bacterial growth. The very ubiquity of these compounds imparts a special interest to them as possible natural regulators. Of equal interest is the correlation between sensitivity to amino acids and virulence in Salmonella and Brucella which may reflect a hitherto unsuspected general principle.”
 
“Auxotrophs have been used for the exploration of many biosynthetic pathways which are remarkably similar in bacteria, molds, and mammals….Mutations leading to catabolic defects have been especially useful in bacterial work, both as genetic markers and in the analysis of fermentation pathways….Most mutation rates are so low (of the order of one per million or billion cell divisions) that mutational equilibria would take too long for human observation, even if the necessary constancy of the environment were possible.”
 
“Induced mutations –Since Mullers announcement [Hermann J. Muller] in 1928 that X-rays would induce mutations in fruitflies an extensive segment of genetic research has concerned the discovery of mutagenic agents and the conditions of their effects. Higher organisms like Drosophila [fruitfly] and maize are indispensible in the finer analysis of the cytological
basis of induced genetic alterations, but microorganisms are very useful tools in the screening of new agents for mutagenic activity and in the study of the gross quantitative aspects of such activity….Dose-response data have been published for mutations induced by X-rays and by UV but their interpretation, especially for UV, is far from simple.
   It has been thought that radiations induced mutations by direct photo-chemical processes, i.e. that the gene itself might be activated by the absorption of a quantum of UV, or by collision with a secondary electron following an X-ray quantum absorption. Some revision of this concept is now necessary on the basis of recent research. The effectiveness of X-rays is potentiated by the presence of oxygen, and there may be a ten fold difference between the doses required for a given effect in oxygen, as against an inert atmosphere. This argues for a radiochemical intermediate, possibly some free radical (peroxide?) which depends upon oxygen for its production under the influence of X-radiation.
   Owing to the powerful penetrability of X-radiation, it has been used in Drosophila studies more extensively than UV which penetrates through living material so poorly that there are serious experimental difficulties in its application in the genetics of plants and animals…[but] UV is probably the most convenient and widely used mutagenic treatment in microbial experiments. The analysis of UV effects has been stimulated by the discovery of photoreactivation.”
 
“Chemical mutagens –A byproduct of research on chemical warfare agents during WWII [is] the realization of the possibility of mutagenic activity of chemicals. The nitrogen and sulfur “mustards” (p-chloro-alkylamines and sulfides) have been studied especially extensively and found to be potent mutagens for all organisms studied. In general their effects are similar to those of X-rays and UV….There is a wealth of further literature on this subject and it is likely to remain an active field….substances as diverse as formaldehyde, acriflavine, urethane, caffeine, hydrogen peroxide, and manganous ion are credibly reported as active in one or another system….and in general, the results of ,i.e., X-ray treatment would not be readily distinguishable from that of formaldehyde.”
 
“Spontaneous mutation– Evidence…is especially paradoxical….One interpretation is that spontaneous mutations are due not to intramolecular accidents or reproductive errors, but rather to the action of intracellular chemical mutagens formed by metabolic processes….but in view of the smallness of spontaneous mutation rates, it is obvious that the occasional change of a cell from one genetic condition to another can make little impression upon the composition of bacterial populations. In diploid sexual organisms, population genetics is greatly complicated by the recombination and by concealment of genetic variation in the heterozygous condition, so that the most drastic culling may have to be carried out for a great many generations to have a marked effect on the relative frequency of different gene forms.”
 
“Marker” mutant cells increased in proportion as mutations accumulated, but instead of increasing indefinitely, their ratio was subject to sporadic downward shifts. The same interpretation was independently formulated for each case: an adaptive mutation increasing the fit of the bacteria to their rather artificial in vitro environment. Owing to the overwhelming preponderance of the cells not carrying the marker, the adaptive mutation will usually occur in an unmarked cell, the descendents of which will then displace the rest of the population, markers and all. After the changeover, marker mutations accumulate again until a possible second changeover takes place to complete another cycle….genetic adaptations are often quite specific for the immediate environment….”
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[2004] “Mutation is the ultimate source of genetic novelty. As such, the rate at which new mutations arise is a central issue in genetics, with profound implications for both evolution and human health… The chief difficulty confronting experimentalists was the fact that [natural] mutations occur at a very low rate.
…”Haldane (1927) was the first to develop the formal theory for equilibrium frequencies of alleles in mutation-selection balance… This provided a straightforward way to estimate the mutation rate for deleterious alleles… In subsequent work, Haldane (1947) suggested that more mutations may come from the male germ line than from the female germ line, a result that has since been well supported by molecular studies.
…”single nucleotide substitutions are at least one order of magnitude more common than other types of mutations, such as insertions or deletions.
…”With the completion of the human genome sequence (International Human Genome Sequencing Consortium 2001) we can now estimate..that each individual harbours roughly 100-200 new mutations… most of these mutations will not occur in genes. However, one of the surprises of genomics has been the large numbers of noncoding sites that are conserved between species and therefore presumably have important functions… The mutations that occur in genes may therefore represent only a subset of the important mutations in humans.” http://www.eebweb.arizona.edu/nachman/pdfs/nachman_2004.pdf

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