Scripps research study shows infectious prions can arise spontaneously in normal brain tissue

JUPITER, FL, July 26, 2010 — In a startling new study that involved research on both sides of the Atlantic, scientists from The Scripps Research Institute in Florida and the University College London (UCL) Institute of Neurology in England have shown for the first time that abnormal prions, bits of infectious protein devoid of DNA or RNA that can cause fatal neurodegenerative disease, can suddenly erupt from healthy brain tissue.

The catalyst in the study was the metallic surface of simple steel wires. Previous research showed that prions bind readily to these types of surfaces and can initiate infection with remarkable efficiency. Surprisingly, according to the new research, wires coated with uninfected brain homogenate could also initiate prion disease in cell culture, which was transmissible to mice.

The findings are being published the week of July 26, 2010, in an advance, online edition of the journal Proceedings of the National Academy of Sciences (PNAS).

“Prion diseases such as sporadic Creutzfeldt-Jakob disease in humans or atypical bovine spongiform encephalopathy, a form of mad cow disease, occur rarely and at random,” said Charles Weissmann, M.D., Ph.D., chair of Scripps Florida’s Department of Infectology, who led the study with John Collinge, head of the Department of Neurodegenerative Disease at UCL Institute of Neurology. “It has been proposed that these events reflect rare, spontaneous formation of prions in brain. Our study offers experimental proof that prions can in fact originate spontaneously, and shows that this event is promoted by contact with steel surfaces.”

Infectious prions, which are composed solely of protein, are classified by distinct strains, originally characterized by their incubation time and the disease they cause. These toxic prions have the ability to reproduce, despite the fact that they contain no nucleic acid genome.

Mammalian cells normally produce harmless cellular prion protein (PrPC). Following prion infection, the abnormal or misfolded prion protein (PrPSc) converts PrPC into a likeness of itself, by causing it to change its conformation or shape. The end-stage consists of large aggregates of these misfolded proteins, which cause massive tissue and cell damage.

A Highly Sensitive Test

In the new study, the scientists used the Scrapie Cell Assay, a test originally created by Weissmann that is highly sensitive to minute quantities of prions.

Using the Scrapie Cell Assay to measure infectivity of prion-coated wires, the team observed several unexpected instances of infectious prions in control groups where metal wires had been exposed only to uninfected normal mouse brain tissue. In the current study, this phenomenon was investigated in rigorous and exhaustive control experiments specifically designed to exclude prion contamination. Weissmann and his colleagues in London found that when normal prion protein is coated onto steel wires and brought into contact with cultured cells, a small but significant proportion of the coated wires cause prion infection of the cells — and when transferred to mice, they continue to spawn the disease.

Weissmann noted that an alternative interpretation of the results is that infectious prions are naturally present in the brain at levels not detectable by conventional methods, and are normally destroyed at the same rate they are created. If that is the case, he noted, metal surfaces could be acting to concentrate the infectious prions to the extent that they became quantifiable by the team’s testing methods.

The first author of the study, “Spontaneous Generation of Mammalian Prions,” is Julie Edgeworth of the UCL Institute of Neurology. Other authors of the study include Nathalie Gros, Jack Alden, Susan Joiner, Jonathan D.F. Wadsworth, Jackie Linehan, Sebastian Brandner, and Graham S. Jackson, also of the UCL Institute of Neurology.

The study was supported by the U.K. Medical Research Council.

About The Scripps Research Institute

The Scripps Research Institute is one of the world’s largest independent, non-profit biomedical research organizations, at the forefront of basic biomedical science that seeks to comprehend the most fundamental processes of life. Scripps Research is internationally recognized for its discoveries in immunology, molecular and cellular biology, chemistry, neurosciences, autoimmune, cardiovascular, and infectious diseases, and synthetic vaccine development. Established in its current configuration in 1961, it employs approximately 3,000 scientists, postdoctoral fellows, scientific and other technicians, doctoral degree graduate students, and administrative and technical support personnel. Scripps Research is headquartered in La Jolla, California. It also includes Scripps Florida, whose researchers focus on basic biomedical science, drug discovery, and technology development. Scripps Florida is located in Jupiter, Florida. See www.scripps.edu

4 COMMENTS

  1. BSE is more political than health orientated; see “Meat Trade News Daily”(13 Sep 2010)
    (http://www.meattradenewsdaily.co.uk/news/130910/neterlands___bse_is_more_political_than_health_orientated_.aspx);
    A 10-year-old cow in the Netherlands has tested positive for BSE, the first such result in more than two years. BSE first emerged in Britain in the 1980s and has been found in herds in several European and other countries. Here are some key facts:
    THE ORIGINS: The disease first diagnosed as BSE in November 1986. Known formally as BSE, the disease swept through Britain in the 1980s and early 1990s, leading to millions of animals being slaughtered and burnt. Scientists blamed the disease’s spread on waste produced in slaughterhouses and used to make animal feed. Cattle feed usually contained waste from the slaughter of other cows, so BSE is transmitted. and it is thought to cause vCJD in humans.
    THE COST: Britain destroyed 3.7 million cattle in the 1980s and 1990s because of BSE. Between 1986 and 2002, 181,376 cases were confirmed in Britain. During that time Britain spent more than $6 billion, excluding job losses, in sorting out the crisis. The worldwide ban on British beef exports imposed after the emergence of BSE in 1980s was partially lifted in 1999. In March 2006, EU experts agreed to a complete lifting of the embargo, nearly 10 years to the day after it was imposed….

  2. Neurodegeneration- as a loss of parasympathetic function?
    A team of researchers, led by Iowa State University, found that the retinas of infected sheep with scrapie emitted a characteristic “glow”. The study appears in the journal Analytical Chemistry ( http://esciencenews.com/articles/2010/09/08/eyes.cattle.may.become.new.windows.detect.mad.cow.disease).
    Most cases of BSE in Great Britain have occurred in dairy cows between 3 and 6 years of
    age… There were variations in the frequency with which some signs were recorded in
    animals observed at different times during the epidemic (WILESMITH et al., 1992). These
    „different variations“ in older animals; it seems are in connection with the neurovegetative
    disorders… Cows affected by BSE show a reduced time spent ruminating, although eating time is maintained at normal levels. This reduction can be marked and rumination can cease (AUSTIN and SIMMONSON, 1993).
    The loss of parasympathetic function unmasks the baseline syphathetic bias inherent
    in the end-organs, resulting in the familiar signs of aging including tachycardia,
    constipation, insomnia, erectile dysfunction, fluid retention, and systemic inflamantion. These consequences in turn may contribute to many of the common diseases associated with aging including type-2 diabetes, Alzheimer´s, atherosclerosis, and cancer. Maintenance and resoration of the parasympathetic function may enable upstream control over the deleterious aspects of inherent end-organ adrenergic bias (LEE et al., 2004).
    In the eye, the thin layer of tissue that lies between the sclera and the retina is the choroid. This is rich in blood vessels that nourish the retina, and the dark pigments of the choroid absorb light rays so that they are not reflected back out of the eye. STEINLE et al. (2000) concluded that sympathetic -noradrenergic vasoconstriction occurs throughout the choroid, whereas parasympathetic nitrergic vasodilation plays a selective role in modulating blood flow in anterior tissues of the eye. Choroidal blood flow in eyes is light driven and controlled by a parasympathetic input from ciliary ganglion (KIMBLE et al., 2006). In addition, CUTHBERTSON et al. (2003) about the retina parasympathetic control found that with the FG (fluorochrome) labeling is evident a strong white glow in the choroid and sclera. Now researchers found that the retinas of infected sheep emitted a distinct “glow”; the scrapie-positive retinas fluoresce a lot – they gave a lot of light back, and this light was very structured….
    . Transmissible spongiform encephalopathies are commonly propagated by extracerebral
    inoculation of the infectious agent. Indirect evidence suggests that entry into the central
    nervous system occurs via the peripheral nervous system. GLATZEL et al. (2001) concluded that sympathetic innervation of lymphoid organs is rate limiting for prion neuroinvasion and that splenic sympathetic nerves may act as extracerebral prion reservoirs.
    The autonomic nervous system (ANS) regulates bodily functions and the activity of
    specific organs. As example, the ANS plays a role in the diameter of the pupils. The
    mechanism of mydriasis usually involve either a disruption of the parasympathetic nerve
    which causes contraction of the pupil, or over- activity of the sympathetic nervous system
    (SNS). LEGGETT et al (1990) reported that a cat which developed a change of temperament, with muscle tremors, ataxia and pupillary dilatation was suspected and later confirmed histopathologically to have a spongiform encephalopathy.
    So we can conclude that the loss of parasympatetic function can be found when the SNS
    prevails and sympathetic vasoconstriction occurs throughout the choroid- in spongiform encephalopathies.
    In addition, calcium and magnesium regulate the sympathetic nervous system (SNS) which controls our “fight or flight” reaction. SNS is stimulated by calcium, and inhibited by magnesium.
    Some of the theories established by ongoing research. According to alternative “BSE ammonia- magnesium ”theory, the origins of the neurodegenerative diseases may lie in chronic magnesium deficiency (coupled with a high protein intake in ruminants).

  3. Until recent time in the scientific literature we have read, seen, heard… ; scientists believe mad cow disease (BSE) spreads when farmers feed cattle recycled meat and bone meal (MBM) from infected animals. The disease is also believed to be linked to the rare but fatal human variant, Creutzfeldt-Jakob disease (vCJD).
    But a few weeks ago, we were able to read; Infectious agents of the sort believed to cause mad cow disease in humans can appear “as if from nowhere” when healthy brain tissue comes into contact with steel when scientists observed several unexpected instances of infectious prions in control groups where metal wires had been exposed only to uninfected normal mouse brain tissue…
    The catalyst used in their study was a simple steel wire (or stainless steel?). Steel is an alloy that consists mostly of iron and has a carbon content between 0.2% and 2.1% by weight, depending on the grade. Carbon is the most common alloying material for iron, but various other alloying elements are used, such as manganese (Mn)… Varying the amount of alloying elements and the form of their presence in the steel (solute elements, precipitated phase) controls qualities of the resulting steel

    According to some researchers, the deformed prions would become more prone to binding with manganese (Mn), and it is this combination that makes them dangerous. It is postulated that Mn -bound prions then become rogue prions that have the ability to deform other normal prions in a chain reaction that eventually destroys the brain. This hypothesis contends that TSEs are likely linked to environmental conditions rather than prion-contaminated feed. The researchers discovered that prions require copper (Cu) to develop properly. If Cu is low and exposure to high levels of Mn occurs, the prion may bind to Mn and turn into the fatal form that eventually burns holes in the brain.

    It is almost universally accepted that the normal protein (PrPc) is a metal binding protein. PrPc was first suggested to be a copper (Cu) binding protein in the early 1990’s and confirmed by David Brown and colleagues in 1997 (BROWN,D.R., 2001). Recently the team of professor BROWN repeatedly pointed out that elevated manganese (Mn) was associated with prion infection – in field cases and experimentally infected animals (BSE and scrapie). So sheep infected with scrapie and cows infected with BSE have elevated levels of Mn in their tissues before clinical symptoms appear, according to new research. These findings were published by the Brown´s team in the Journal of Animal Science (HESKETH et al., 2007)

    However, there could be a possibility; increased the Mn absorption and retention
    can be found in the longer-term Mg deficiency. Mn2+ is very similar to Mg2+ in terms of its chemical properties, including inner and outer shell complexation. In biological systems, only Mn2+ is readily capable of replacing Mg2+, and only in a limited
    set of circumstances. The body can replace Mn with Mg with similar efficiency in Mn-activated proteins (WAPNIR, 1990). Similarly, Mn can occupy Mg allosteric sites in Mg-activated proteins, such as the sarcoplasmic reticulum Ca- ATPase (CHIESI and INESI,1981). Mn2+ effectively binds ATP and allows hydrolysis of the energy molecule by most ATPases.
    Investigated the relationship between Mg deficiency and Mn metabolism, YASUI et al
    (1995) found that Mn content in central nervous system tissues and visceral organs was highest in rats fed a low Ca-Mg diet. SANCHEZ- MORITO et al. (1999) found that feeding rats a diet deficient in Mg decreased urinary and fecal Mn excretion. They also observed greater Mn retention in skeletal muscle, heart and kidney in Mg-deficient rats as compared to control. They concluded that under experimental conditions, Mg deficiency increased Mn absorption, which was reflected as increased Mn deposits in all soft and hard tissues studied except the sternum and liver

    Some other of the BSE- alternative theories established by ongoing research. Also alternative „BSE ammonia- magnesium theory“ is well known in the world from 2002 (http://www.agriworld.nl/feedmix/headlines.asp?issue=3), see the full text. “Lone voices in the BSE debate” (www.warmwell.com/lone_voices_in_the_bse_debate[…). According to this theory, the origins of the diseases may lie in chronic magnesium deficiency coupled with a high protein intake. So defective prions are markers of the diseases rather than the cause and BSE can be a naturally occurring disease, not an infectious disease. See also other relationships (WHY great progress about BSE eradicating within the EU…?) , according to my web http://www.bse-expert.cz and recent presentation at 29th World Veterinary Congress in Vancouver; Neurodegenerative Diseases and Schizophrenia as a Hyper or Hypofunction of the NMDA Receptors (www.bse-expert.cz/pdf/Veter_kongres.pdf)

  4. You wrote; Infectious prions can arise spontaneously in normal brain tissue…. WHY? Because mad cow disease (BSE) can be a naturally occurring disease, so not an infectious disease, so beef is safe in the all world. WHY? Because, about the BSE/ vCJD diseases; this was never justified scientifically. In 1996, a variant form of Creutzfeldt-Jakob disease (vCJD) was discovered in small clusters in Britain. It was immediately suspected that the outbreak of BSE could be connected to the clusters of vCJD in humans. Because of the 100%mortality rate of both diseases, the British government issued a “Mad Cow Warning.” People were cautioned not to eat beef that may come from diseased cattle, for fear the disease could be transmitted to humans via the meat products they consumed. However, WHY the number of vCJD cases peaked in 2000 and is now declining ? There are my responses; Over the next few years, researchers desperately searched for the cause of BSE and any possible connection to the human variant (vCJD). The first theory that appeared to make sense was that British cattle were being fed meat and bone meal (MBM) feed that included potentially contaminated brain and spinal cord matter that could the source of the disease in cows. Theoretically, eating contaminated meat could transfer the disease to the human population.
    Upon further research, the connection to the human vCJD, was thought to exist because an abnormal prion protein (PrPsc) that was found in both diseased cattle and infected human brain and spinal cord cells. This abnormal prion protein causes the normal prion proteins to convert to abnormal prion proteins. Once enough prion proteins are converted, they cause the death of neurons (brain cells) in both cattle and humans.
    Over a 14 year period, there were 115 confirmed cases of variant CJD that were closely examined. None of them could establish a clear connection to beef consumption. By this time, scientific theories had become fact in the minds of the general public. No additions, corrections or retractions to the previous information given to the public were printed by either the media, or government officials. There is still very little evidence to support the idea that BSE (mad cow disease) can be transmitted to humans by any means other than perhaps eating brain and spinal cord tissue (even that is not certain).
    Several experts have continued to research BSE and vCJD trying to uncover causes and possible connections despite the lack of funding. Funding is extremely difficult to obtain because there is already an “acceptable theory” out there and no one seems to care whether it is accurate or not.
    Some of the theories established by ongoing research. According to my theory, the origins of the diseases may lie in chronic magnesium deficiency coupled with a high protein intake. So defective prions are markers of the diseases rather than the cause and BSE can be a naturally occurring disease, not an infectious disease. WHY?
    Because, about the BSE/ vCJD diseases; this was never justified scientifically! It was pure, math-model-driven science fiction. But it was pushed very vigorously by the British science establishment, which has never confessed to its errors… See more about the; BSE/ vCJD mathematical- models, see recent large three comments in Telegraph.co.uk (www.telegraph.co.uk/health/healthnews/7168326/D oes-vCJD-still-pose-a-major-public-health-threat .html). See also other relationships (WHY great progress about BSE eradicating within the EU…?) , according to my web http://www.bse-expert.cz and recent presentation at 29th World Veterinary Congress in Vancouver; Neurodegenerative Diseases and Schizophrenia as a Hyper or Hypofunction of the NMDA Receptors (www.bse-expert.cz/pdf/Veter_kongres.pdf)

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