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All About Prions and Food


slkinsey

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Doc, I don't think viruses can be cultured in a nutrient media.  Think about it:  viruses don't have a metabolism and replicate by using the machinery of a living host cell.  If there is no living host cell, the viruses cannot replicate.  Since a nutrient medium is not a living host, no replication.  Right?

Sam, the medium may be different, but viruses are indeed "cultured. There is no regulation that I know of that specifies that culture media may not be "living". As I intimated I believe the issue is a semantic one.

John Sconzo, M.D. aka "docsconz"

"Remember that a very good sardine is always preferable to a not that good lobster."

- Ferran Adria on eGullet 12/16/2004.

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Regarding (2), if prions really are protein-only, do not self-replicate,  there is no way they can be cultured (i.e. grown in a petri dish on nutrient media). Viruses also can not be cultured.

Maybe I am missing something, Patrick, but I am very much under the impression that viruses can be and are cultured. Perhaps there is a semantic misunderstanding?

If you go back and look at postulate #2, I specified "pure culture." Pure culture refers to " A nutrient medium containing the growth of a single strain of an organism free from other living species or strains." Of course viruses can be cultured, for instance using tissue culture (which is how viruses are usually cultured) or even innoculating a living organism, but not in a pure culture, and I don't imagine that is how Koch understood his own postulate. I haven't read Koch, so I could be wrong, but if he did in fact require growth in a pure culture as his 2nd postulate, then viruses could not fufill that posutulate.

"If you hear a voice within you say 'you cannot paint,' then by all means paint, and that voice will be silenced" - Vincent Van Gogh
 

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Regarding the state of the debate over vCJD today, I think its fair to say that there is little disagreement as to whether there is some type of infectious agent in cows with BSE that causes vCJD in humans.

There was little disagreement last week that low-fat diets would reduce heart disease. Nonetheless, the few people who disagreed turned out to be right, at least according to the most comprehensive study ever done on the issue. Part of the reason there was so little disagreement was that it was so hard to get funding to conduct the studies that would disprove the conventional wisdom.

In the BSE/vCJD/TSE arena, it's also difficult to get funding for any research that isn't targeted at supporting the prion theory. When Alan Ebringer was trying to get funding to pursue the theory that BSE was an autoimmune disease triggered by bacteria, he had great difficulty being heard above the "prion noise."

In addition, that there is probably something in BSE-infected cows that relates to vCJD in humans is one link in a chain of causation, but it doesn't necessarily mean that anybody is getting vCJD from eating beef. Pharmaceutical gels and many other possible mechanisms of conveyance are still in many ways more compelling as suspects (though not nearly as dramatic or media friendly).

There have also been a couple of papers over the past couple of years that seem to provide fairly strong support for the protein-only position. Legname et al (2004) induced "BSE" in mice using purified proteins generated by transgenic bacteria that were engineered to produce PrP.

The basic argument against these findings was summarized in the CIDRAP News article on the study (though the study is often cited as Legname et al, which gives the impression of diverse groups of scientists making independent findings in support of Prusiner's theories, the senior author on that study was actually Prusiner):

The news article in Science cites some doubts about the validity of Prusiner's findings. For example, John Collinge, director of the Medical Research Council Prion Unit at University College London, speculated that the mice might have gotten sick even without any injection of prion protein. He said his group had worked with rodents having 10 times the normal level of prion protein but stopped using them after finding signs of prion-like disease in animals that hadn't been inoculated with anything.

According to the article, Collinge said Prusiner's mice might be primed to suffer brain disease without any prion injection. Inoculating them with synthetic prions might trigger disease, but other stresses might have the same effect, he said.

Steven A. Shaw aka "Fat Guy"
Co-founder, Society for Culinary Arts & Letters, sshaw@egstaff.org
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Director, New Media Studies, International Culinary Center (take my food-blogging course)

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God, I really wish I understood what the hell everyone was talking about.

Jason Perlow, Co-Founder eGullet Society for Culinary Arts & Letters

Foodies who Review South Florida (Facebook) | offthebroiler.com - Food Blog (archived) | View my food photos on Instagram

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Regarding (2), if prions really are protein-only, do not self-replicate,  there is no way they can be cultured (i.e. grown in a petri dish on nutrient media). Viruses also can not be cultured.

Maybe I am missing something, Patrick, but I am very much under the impression that viruses can be and are cultured. Perhaps there is a semantic misunderstanding?

If you go back and look at postulate #2, I specified "pure culture." Pure culture refers to " A nutrient medium containing the growth of a single strain of an organism free from other living species or strains." Of course viruses can be cultured, for instance using tissue culture (which is how viruses are usually cultured) or even innoculating a living organism, but not in a pure culture, and I don't imagine that is how Koch understood his own postulate. I haven't read Koch, so I could be wrong, but if he did in fact require growth in a pure culture as his 2nd postulate, then viruses could not fufill that posutulate.

Thanks for clarifying your statement. I knew it was a question of semantics :wink:

John Sconzo, M.D. aka "docsconz"

"Remember that a very good sardine is always preferable to a not that good lobster."

- Ferran Adria on eGullet 12/16/2004.

Docsconz - Musings on Food and Life

Slow Food Saratoga Region - Co-Founder

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God, I really wish I understood what the hell everyone was talking about.

That's the way I fell when reading about computer intricacies :laugh:

John Sconzo, M.D. aka "docsconz"

"Remember that a very good sardine is always preferable to a not that good lobster."

- Ferran Adria on eGullet 12/16/2004.

Docsconz - Musings on Food and Life

Slow Food Saratoga Region - Co-Founder

Twitter - @docsconz

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Regarding the state of the debate over vCJD today, I think its fair to say that there is little disagreement as to whether there is some type of infectious agent in cows with BSE that causes vCJD in humans.

There was little disagreement last week that low-fat diets would reduce heart disease. Nonetheless, the few people who disagreed turned out to be right, at least according to the most comprehensive study ever done on the issue. Part of the reason there was so little disagreement was that it was so hard to get funding to conduct the studies that would disprove the conventional wisdom.

Steven, if it was so difficult to get funding how did this "most comprehensive study" ever get done? That it got done and published is testament that a well designed study will get funded. The difficulty with getting funding is that the team looking for it has to be able to show a reasonable track record and a reasonable approach to the problem. Pie in the sky approaches rarely come off as sound or reasonable. The finite amount of money available is (or should be) most likely to go to the studies with the greatest chance of proving a point. I will admit that it is a bit of a conundrum as an interesting idea without a track record is less likely to fit into that category. It is not, however, impossible.

In the BSE/vCJD/TSE arena, it's also difficult to get funding for any research that isn't targeted at supporting the prion theory. When Alan Ebringer was trying to get funding to pursue the theory that BSE was an autoimmune disease triggered by bacteria, he had great difficulty being heard above the "prion noise."

See above. That may very well be because the likelihood that his theory is correct is low or at least less likely than the "prion noise" that stems from a lot of cumulative data.

In addition, that there is probably something in BSE-infected cows that relates to vCJD in humans is one link in a chain of causation, but it doesn't necessarily mean that anybody is getting vCJD from eating beef. Pharmaceutical gels and many other possible mechanisms of conveyance are still in many ways more compelling as suspects (though not nearly as dramatic or media friendly).

The mindset that these diseases stem from eating infected tissue amongst other possible modalities is supported by the very apparent mode of transmission for kuru. While that certainly doesn't prove that vCJD is transmitted to humans by eating beef from infected cows, it is certainly suggestive. Until proven otherwise, likely a very difficult task, it is probably prudent to assume that that mode of transmission may be potentially causative. As a result, at this time it is IMO prudent for people to abstain from eating beef from infected cattle and venison from infected deer. I do not believe the relatively low risk justifies the recommendation to abstain from all beef or venison, though.

There have also been a couple of papers over the past couple of years that seem to provide fairly strong support for the protein-only position. Legname et al (2004) induced "BSE" in mice using purified proteins generated by transgenic bacteria that were engineered to produce PrP.

The basic argument against these findings was summarized in the CIDRAP News article on the study (though the study is often cited as Legname et al, which gives the impression of diverse groups of scientists making independent findings in support of Prusiner's theories, the senior author on that study was actually Prusiner):

The news article in Science cites some doubts about the validity of Prusiner's findings. For example, John Collinge, director of the Medical Research Council Prion Unit at University College London, speculated that the mice might have gotten sick even without any injection of prion protein. He said his group had worked with rodents having 10 times the normal level of prion protein but stopped using them after finding signs of prion-like disease in animals that hadn't been inoculated with anything.

According to the article, Collinge said Prusiner's mice might be primed to suffer brain disease without any prion injection. Inoculating them with synthetic prions might trigger disease, but other stresses might have the same effect, he said.

No scientific theory should be assumed to be the absolute truth, however, best evidence allows for people to make certain rational choices. The doubt you quoted is an interesting one and suggestive that the results are somewhat uncertain. This certainly allows and calls for further study, which is a good thing, although it hardly disproves the prevailing theory.

John Sconzo, M.D. aka "docsconz"

"Remember that a very good sardine is always preferable to a not that good lobster."

- Ferran Adria on eGullet 12/16/2004.

Docsconz - Musings on Food and Life

Slow Food Saratoga Region - Co-Founder

Twitter - @docsconz

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]Regarding the state of the debate over vCJD today, I think its fair to say that there is little disagreement as to whether there is some type of infectious agent in cows with BSE that causes vCJD in humans.

There was little disagreement last week that low-fat diets would reduce heart disease.

Of course there was. There have always been plenty of nutrionists arguing that total calories, not proportion of calories from fat, was much more important. This is not the case with the BSE-vCJD theory, where virtually all of the critics of the prion hypothesis agree with the prion proponents that some type of infectious agent in cows with BSE causes vCJD in humans.

In the BSE/vCJD/TSE arena, it's also difficult to get funding for any research that isn't targeted at supporting the prion theory.

Having never applied for a grant to study these diseases, I can't comment on the these difficulties. However, I do know that often when people claim that they can't get a grant to study hypothesis X, their failure to get a grant is not due to irrational bias on the part of the money-people, but rather to the fact that there already exists good evidence that the hypothesis is a dead-end, or that other line of research seems like a much better bargain for the money. In the case of BSE, there has in fact been lots of work done trying to find a nucleic acid sequence associated with the disease pathogen, as there must be if it is a virus or a bacterium, and so far it can't be found.

In addition, that there is probably something in BSE-infected cows that relates to vCJD in humans is one link in a chain of causation, but it doesn't necessarily mean that anybody is getting vCJD from eating beef. Pharmaceutical gels and many other possible mechanisms of conveyance are still in many ways more compelling as suspects (though not nearly as dramatic or media friendly).

I'm perfectly willing to consider these alternative theories, so let's start with some basic observations and see how well the different theories fare. I promise I'll try my best to give your alternate theories evey benefit of the doubt.

1. Brain homogenate can be taken from a BSE-positive cow and injected into primate and other mammals, causing a vCJD like disease. How would, let's say, pharmaceutical gels explain this observation?

2. The strong temporal (allowing for latency period) and geographic association of BSE and vCJD in the UK, and the decline in vCJD in the UK the ban on feeding MBM to cows. Why have virtually all of the vCJD case occurred in the UK? How do pharamaceutical gels explain the observed temporal and geographic paterns better?

(though the study is often cited as Legname et al, which gives the impression of diverse groups of scientists making independent findings . . .

The study is usually cited as Legname et al because that is easier and more convenient than citing it as Legname, Baskakov, Nguyen, Riesner, Cohen, DeArmond, and Prusiner. That's just standard practice for citing journal articles, and anyone who follows research in this area (or just reads the author list), understands that these researchers have collaborated on many other papers in this field.

The news article in Science cites some doubts about the validity of Prusiner's findings. For example, John Collinge, director of the Medical Research Council Prion Unit at University College London, speculated that the mice might have gotten sick even without any injection of prion protein. He said his group had worked with rodents having 10 times the normal level of prion protein but stopped using them after finding signs of prion-like disease in animals that hadn't been inoculated with anything.

According to the article, Collinge said Prusiner's mice might be primed to suffer brain disease without any prion injection. Inoculating them with synthetic prions might trigger disease, but other stresses might have the same effect, he said.

I'll read the study again tomorrow more closely, but my understanding was that the mice in this study that recieved the control injections developed no signs of disease, while those that recieved the synthetic prions developed disease, that, even more interestingly, the diseased mice could then be used to innoculate and cause that same disease in wild-type mice, who did not overexpress PrP. So, if we accept for the sake of argument that the spongiform encephalopathy seen in the mice given synthetic prions was largely due to those mice overexpressing PrP, how was it transmissable to the wild-type mice?

Also, there was another paper published in Cell in 2005 that is significant in this regard. It used wild-type hamsters, not mice that overexpress PrP. I'll include the abstract and maybe we can discuss this some more in a few days. In the meantime, I look forward to seeing you make the case that pharmaceutical gels are playing a causal role in vCJD.

Castilla et al. 2005. In Vitro Generation of Infectious Scrapie Proteins. Cell 121, 195-206.

Prions are unconventional infectious agents responsible for transmissible spongiform encephalopathy (TSE) diseases. They are thought to be composed exclusively of the protease-resistant prion protein (PrPres) that replicates in the body by inducing the misfolding of the cellular prion protein (PrPC). Although compelling evidence supports this hypothesis, generation of infectious prion particles in vitro has not been convincingly demonstrated. Here we show that PrPC/PrPres conversion can be mimicked in vitro by cyclic amplification of protein misfolding, resulting in indefinite amplification of PrPres. The in vitro-generated forms of PrPres share similar biochemical and structural properties with PrPres derived from sick brains. Inoculation of wild-type hamsters with in vitro-produced PrPres led to a scrapie disease identical to the illness produced by brain infectious material. These findings demonstrate that prions can be generated in vitro and provide strong evidence in support of the protein-only hypothesis of prion transmission.
Edited by Patrick S (log)

"If you hear a voice within you say 'you cannot paint,' then by all means paint, and that voice will be silenced" - Vincent Van Gogh
 

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Steven, if it was so difficult to get funding how did this "most comprehensive study" ever get done?

Because the study was supposed to show the opposite: it was supposed to quantify the benefit of low-fat diets once and for all. Nobody thought it was going to quantify the benefit at zero; the results were a complete surprise to everyone except for a minuscule minority of skeptics who were never taken seriously.

Steven A. Shaw aka "Fat Guy"
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Steven, if it was so difficult to get funding how did this "most comprehensive study" ever get done?

Because the study was supposed to show the opposite: it was supposed to quantify the benefit of low-fat diets once and for all. Nobody thought it was going to quantify the benefit at zero; the results were a complete surprise to everyone except for a minuscule minority of skeptics who were never taken seriously.

But Steven, that is the whole point of doing the studies. While the results obtained were not those expected, the hypothesis had not previously been irrefutably proven.If it was a proven fact, save the money. By all means if reasonable studies testing the prion hypothesis can be designed they should be undertaken, but they need to be well designed and willing to show whichever conclusion the results demand.

John Sconzo, M.D. aka "docsconz"

"Remember that a very good sardine is always preferable to a not that good lobster."

- Ferran Adria on eGullet 12/16/2004.

Docsconz - Musings on Food and Life

Slow Food Saratoga Region - Co-Founder

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1. Brain homogenate can be taken from a BSE-positive cow and injected into primate and other mammals, causing a vCJD like disease. How would, let's say, pharmaceutical gels explain this observation?

Because the gels are (or were during the relevant time period) made from cattle byproducts. People were getting cattle byproducts into their systems in many ways, not just by eating beef. So even if it's true that BSE can jump the species barrier and cause vCJD it's not clear that eating beef is the method of transmission (and it almost surely wasn't in the case of the vegetarians who got it). Pharmaceutical gels are just one example. We were talking about cultures above. Apropos of that, fetal calf serum from England was used as a growth medium for many vaccines during the relevant time period. Bone meal was popular as a fertilizer among organic farmers. The water supply may even contain some of this stuff. Yet all the attention has been focused on beef.

2. The strong temporal (allowing for latency period) and geographic association of BSE and vCJD in the UK, and the decline in vCJD in the UK the ban on feeding MBM to cows. Why have virtually all of the vCJD case occurred in the UK? How do pharamaceutical gels explain the observed temporal and geographic paterns better?

In addition to the simple explanation that all these other sources would be affected the same way, there's also the possibility that cows and humans could be getting the disease from a common source, like a waterborne bacterium. Sometimes we never find out why a particular disease shows up and then goes away. In addition, detection tends to be a self-fulfilling prophecy. When people die in Zimbabwe and El Salvador, nobody tests them for vCJD.

Steven A. Shaw aka "Fat Guy"
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Director, New Media Studies, International Culinary Center (take my food-blogging course)

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Because the study was supposed to show the opposite: it was supposed to quantify the benefit of low-fat diets once and for all. Nobody thought it was going to quantify the benefit at zero; the results were a complete surprise to everyone except for a minuscule minority of skeptics who were never taken seriously.

I don't think it's entirely accurate to say that there existed only a "minuscule minority ... who were never taken seriously" in the scientific/medical community who were were skeptical of the premise that dietary fat was the end-all, be-all with respect to heart disease, cancer, etc. -- although this may be true of the popular media.

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they need to be well designed and willing to show whichever conclusion the results demand.

The low-fat study was a great example of a well-designed study, and the researchers who performed it deserve a lot of praise for being real scientists and just coming out with the results despite their probable disappointment.

But some of Prusiner's prion studies are just too reminiscent of the studies they do to prove that every substance in the world causes cancer: "We bred a bunch of mice with the special ability to get cancer if you look at them funny. Then we injected them fifty times a day with the human equivalent of a million portions of pure polysorbate 60. And guess what? All the special cancer-prone mice got cancer! Therefore, newspapers should immediately report that polysorbate 60 causes cancer and parents everywhere should chase down their children's schoolbuses this morning and reclaim their lunches."

Steven A. Shaw aka "Fat Guy"
Co-founder, Society for Culinary Arts & Letters, sshaw@egstaff.org
Proud signatory to the eG Ethics code
Director, New Media Studies, International Culinary Center (take my food-blogging course)

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they need to be well designed and willing to show whichever conclusion the results demand.

The low-fat study was a great example of a well-designed study, and the researchers who performed it deserve a lot of praise for being real scientists and just coming out with the results despite their probable disappointment.

Not to be a killjoy, but a fat study applies to prions how?

The long and the short of it is that there is a lot of study going on in the realm of protein folding. There are several leading hypotheses that explain some interesting parts of protein folding. But these also leave a lot to be desired. So, specifically how PrP or others fold into the pathological form, is unsure.

Even beyond that,it took a lot of work to get enough pathological PrP to get to the stage where its structure could be studied either via NMR or X-Ray crystallography (both of which have their individual problems with structure determination).

We've looked at prions from the Koch's postulates side, but what about turning the inspection around and looking at it from the side of what can you find (or not find) to lead you to a pathogen from the standpoint of the sufferer of CWD, BSE, CJD, scrapie, kuru, etc?

I always attempt to have the ratio of my intelligence to weight ratio be greater than one. But, I am from the midwest. I am sure you can now understand my life's conundrum.

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Not to be a killjoy, but a fat study applies to prions how?

As one of many examples of cautionary tales about scientific overconfidence.

Steven A. Shaw aka "Fat Guy"
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Proud signatory to the eG Ethics code
Director, New Media Studies, International Culinary Center (take my food-blogging course)

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they need to be well designed and willing to show whichever conclusion the results demand.

The low-fat study was a great example of a well-designed study, and the researchers who performed it deserve a lot of praise for being real scientists and just coming out with the results despite their probable disappointment.

But some of Prusiner's prion studies are just too reminiscent of the studies they do to prove that every substance in the world causes cancer: "We bred a bunch of mice with the special ability to get cancer if you look at them funny. Then we injected them fifty times a day with the human equivalent of a million portions of pure polysorbate 60. And guess what? All the special cancer-prone mice got cancer! Therefore, newspapers should immediately report that polysorbate 60 causes cancer and parents everywhere should chase down their children's schoolbuses this morning and reclaim their lunches."

Media reaction is a separate issue from the underlying scientific hypotheses. As for the prion studies that is the point of doing the studies with good controls. it may turn out that prions are a red herring with this disease, but I am not aware of a better hypothesis at this time, nor have you offered one based on anything more than the thought that the prion hypothesis may not ultimately be correct.

John Sconzo, M.D. aka "docsconz"

"Remember that a very good sardine is always preferable to a not that good lobster."

- Ferran Adria on eGullet 12/16/2004.

Docsconz - Musings on Food and Life

Slow Food Saratoga Region - Co-Founder

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they need to be well designed and willing to show whichever conclusion the results demand.

The low-fat study was a great example of a well-designed study, and the researchers who performed it deserve a lot of praise for being real scientists and just coming out with the results despite their probable disappointment.[...]

I think most of us are happy with the results they got, but those of us who aren't scientists need to ask ourselves whether we might not view the study differently if by following all the same procedures they had gotten results we didn't like. Science has to operate without respect to popularity, and let the chips fall where they may. And if that results in not implicating dietary fat in heart disease but implicating beef and venison in prion-borne diseases, so be it.

Michael aka "Pan"

 

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I am not aware of a better hypothesis at this time, nor have you offered one based on anything more than the thought that the prion hypothesis may not ultimately be correct.

I (and, much more importantly, several esteemed scientists whose expertise is in this area) have offered several competing hypotheses, chief among them that the agent is an as-yet-undiscovered virus or bacterium with extraordinary resilience. It can take ages to find the viral or bacterial infectious agent responsible for a disease, and right now we're not even looking for one. Instead nearly the whole relevant scientific community, minus several strong detractors who can't get their work funded, is obsessed with prion research that may eventually turn out to be a wild goose chase. Gary Taubes has made a compelling (to me at least) case that this is not happening for good scientific reasons but is, rather, the result of Prusiner's charismatic and relentless campaign to drive all competing theories out of the TSE ecosystem.

Steven A. Shaw aka "Fat Guy"
Co-founder, Society for Culinary Arts & Letters, sshaw@egstaff.org
Proud signatory to the eG Ethics code
Director, New Media Studies, International Culinary Center (take my food-blogging course)

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I (and, much more importantly, several esteemed scientists whose expertise is in this area) have offered several competing hypotheses, chief among them that the agent is an as-yet-undiscovered virus or bacterium with extraordinary resilience.

But, where is the bacterium when you look at a histological slice of the affected area? Do you posit that the bacterium crosses the blood-brain barrier, or does it make some chemical that does?

I'm not saying that it isn't possible, but what you're saying is 3 steps from blaming "little people" of stealing infected folks' neurons. I think it is really, really unlikely that a bacterium can survive the whole transport chain from beef bone meal to infecting a cow or a human.

I always attempt to have the ratio of my intelligence to weight ratio be greater than one. But, I am from the midwest. I am sure you can now understand my life's conundrum.

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But, where is the bacterium when you look at a histological slice of the affected area?  Do you posit that the bacterium crosses the blood-brain barrier, or does it make some chemical that does? 

I'm not positing anything. I'm a writer not a medical researcher. So I can only answer your question by giving examples of what real researchers have posited. For example, Alan Ebringer, professor of immunology at King's College London, posited that vCJD, BSE, etc. could be autoimmune diseases or similar to autoimmune diseases and that the damage could be caused by the body's reaction to an infectious agent. Specifically, the agent he identified was Acinetobacter calcoaceticus. He found that cows with BSE also had high levels of the antibodies that attack Acinetobacter, and that these same antibodies might attack brain cells. So he theorized that "Prions are not infectious particles. Instead they are the breakdown products of damaged nervous tissue."

I think George Venters summarized the contrarian position well in his paper "New variant Creutzfeldt-Jakob disease: the epidemic that never was":

Summary points

    The causal link between the bovine spongiform encephalopathy prion and new variant Creutzfeldt-Jakob disease is open to question

    Assessment of the evidence against relevant epidemiological criteria reveals the weakness of the case for a link

    The rate of growth in the number of cases is very much less than would be expected from a foodborne source

    The rate of growth is consistent with a previously misdiagnosed but extremely rare disease being found---this could have resulted from the improved ascertainment of all possible cases of Creutzfeldt-Jakob disease that has been achieved in recent years by the United Kingdom Creutzfeldt-Jakob Disease Surveillance Unit

For all I know -- I don't have access to the really comprehensive databases of medical research unless I'm on assignment for a journal that can get me access -- there are newer studies that are more definitive. But the ones I hear about from time to time seem to have all the same old problems.

I'm also not invested in the prion theory being right or wrong. Primarily, my concern is that the levels of proof we had at the relevant times were not sufficient to justify the extreme policy responses. Were we to treat every theory that way, we'd be in big trouble. If the theory turns out to be right in 2010, it doesn't change the prematureness of the overreaction in the 1990s. If it turns out to be wrong, well, that's just going to be embarrassing for a lot of people. And once scientists get so rhetorically and politically involved in their theories that their missions become to advance those theories at all costs they stop, in my opinion, being scientists.

Speaking of theories that sound like they rely on "little people" or gremlins or whatever, has anybody stopped to think about how weird the prion theory sounds? All this folding and these inert infectious agents sound a lot more science-fictiony than the much simpler claim that "we haven't found the virus yet." Some observers have likened the prion theory to the "Ice Nine" substance in Kurt Vonnegut's novel Cat's Cradle. For years we've believed that all infections come from either bacteria or viruses. It's pretty reasonable to say that when a new infection comes along and it proves hard to understand that we should still devote some serious effort to finding the responsible bacterium or virus, rather than abandon the whole theory in favor of a cool-sounding word like "prion."

Steven A. Shaw aka "Fat Guy"
Co-founder, Society for Culinary Arts & Letters, sshaw@egstaff.org
Proud signatory to the eG Ethics code
Director, New Media Studies, International Culinary Center (take my food-blogging course)

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I'm not positing anything. I'm a writer not a medical researcher. So I can only answer your question by giving examples of what real researchers have posited. For example, Alan Ebringer, professor of immunology at King's College London, posited that vCJD, BSE, etc. could be autoimmune diseases or similar to autoimmune diseases and that the damage could be caused by the body's reaction to an infectious agent. Specifically, the agent he identified was Acinetobacter calcoaceticus. He found that cows with BSE also had high levels of the antibodies that attack Acinetobacter, and that these same antibodies might attack brain cells. So he theorized that "Prions are not infectious particles. Instead they are the breakdown products of damaged nervous tissue."

I have seen some of this, and I find it to be certainly intriguing and worthy of further study. I have unfortunately been too busy to spend the time to read more than the abstract, but I plan on perusing the paper this weekend.

I'm also not invested in the prion theory being right or wrong. Primarily, my concern is that the levels of proof we had at the relevant times were not sufficient to justify the extreme policy responses. Were we to treat every theory that way, we'd be in big trouble. If the theory turns out to be right in 2010, it doesn't change the prematureness of the overreaction in the 1990s.

I am in 100% agreement with you here. No matter how you slice it, there are common diseases, influenza, hepatitis, tetanus, heart disease... that kill many more people a year that simply don't get the press requisite of their "pathology fraction", to coin a term.

On the other hand, is it really bad to get the beef out of beef feed? These critters have been evolving for millions of years into ruminants, and in the course of 30 or 40 beef generations, we're trying to work against that. Aesthetically, it goes against the grain of my animal husbandry background.

If it turns out to be wrong, well, that's just going to be embarrassing for a lot of people. And once scientists get so rhetorically and politically involved in their theories that their missions become to advance those theories at all costs they stop, in my opinion, being scientists.

Scientists certainly have their cross to bear in this, but don't forget the journalists who sensationalized it, and the politicians to capitalized on it.

Speaking of theories that sound like they rely on "little people" or gremlins or whatever, has anybody stopped to think about how weird the prion theory sounds? All this folding and these inert infectious agents sound a lot more science-fictiony than the much simpler claim that "we haven't found the virus yet."

Given current molecular biologists' understand of enzymes catalytic properties, cellular signal cascades, and protein folding, it doesn't seem all that farfetched to me. Many proteins fold on their own. Many do not. The ones that don't, have other proteins to help them. So, the stage has already been set for protein-protein folding interactions. The stage has been set with enzyme catalysis for decades. Signal cascade studies are relatively new, also, but becoming well understood.

On the other hand, I can't point to a reaction pathway that prions participate in. I also can't point to a signal that they induce. But, it was only within the past two years that we figured out how nitroglycerin helps to mediate muscle tension in arteries. So, it may be science fiction-y, but it's "alternate universe" not "super science" science fiction.

Furthermore, based on the understanding it is helping to give us in protein structure and function, I think that prions should still be studied.

I always attempt to have the ratio of my intelligence to weight ratio be greater than one. But, I am from the midwest. I am sure you can now understand my life's conundrum.

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Venter's paper cited by Steven is interesting and I certainly agree with his main point that alternative approaches should not be ignored as the case for BSE prions as the causative source for vCJD in humans is by no means proven. There are a number of important elements in this paper though. First, is that Venter is not refuting prions as the source of the disease. He is simply questioning whether they are truly related to BSE prions - a legitimate question.Another good point he made is that studies have been down to "prove" the theory rather than test it. Clearly the theory needs to be tested. While the causal relationship between BSE and vCJD has yet to be proven beyond a shadow of a doubt, neither has it been disproven. Until that is the case, it is my opinion that given the potential ramifications of the association if true, BSE infected cattle should be considered unsafe for human consumption even if the majority of humans may not be susceptible to it. Personally, I would like nothing better than to know that interspecies infectivity of prions (or any other potential source of this disease) is impossible or at least highly improbable and of extremely low risk. While that may indeed be the case the evidence for this so far as I am aware is still less strong than the evidence that it is possible.

John Sconzo, M.D. aka "docsconz"

"Remember that a very good sardine is always preferable to a not that good lobster."

- Ferran Adria on eGullet 12/16/2004.

Docsconz - Musings on Food and Life

Slow Food Saratoga Region - Co-Founder

Twitter - @docsconz

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1. Brain homogenate can be taken from a BSE-positive cow and injected into primate and other mammals, causing a vCJD like disease. How would, let's say, pharmaceutical gels explain this observation?

Because the gels are (or were during the relevant time period) made from cattle byproducts. People were getting cattle byproducts into their systems in many ways, not just by eating beef. So even if it's true that BSE can jump the species barrier and cause vCJD it's not clear that eating beef is the method of transmission (and it almost surely wasn't in the case of the vegetarians who got it).

Thank you for the clarification.

First, let me point out that there is no doubt whatsoever that the agent that causes BSE in cows can "jump the species barrier" and cause spongiform encephalopathy in other species. You appear to be conceding this point, so forgive me if I beat a dead horse, but I do want to make this clear. For ethical reasons you cannot take material from a BSE-positive cow and feed it to a human, but you can literally take a little bit of brain from a BSE cow, feed it to primates in a single oral dose, and see the primate develop vCJD-like spongiform encephalopathy a few years later. This has been shown with macaques (Lasmezas et al, 2005) and lemurs (Bons et al, 1999) and other species.

And further, these animals not only develop spongiform encephalopathy, they develop spongiform encephalopathies that are basically identical to vCJD but different from other spongiform encephalopathies such as scrapies (e.g. Collinge et al, 1996; Hill et al, 1997; Bruce et al, 1997).

Even more compelling is the study by Scott et al (1999). As I said above, you can't give a healthy human a dose of brain from a BSE cow. But what you can do, and what Scott et al did do, is take brain from a deceased human that died of vCJD, and brain from a cow that had BSE, administer both materials to genetically identical mice, and compare the effects. When they did this, they found that "The incubation times (approx 250 days), neuropathology, and disease-causing PrP isoforms in Tg(BoPrP)Prnp0/0 mice inoculated with nvCJD and BSE brain extracts were indistinguishable."

Second, if gels were contaminated with the BSE agent, wouldn't western blots detect this? If so, were is the evidence for this? It is estimated that hundreds of thousands of BSE positive cows entered the food chain in the UK, now where is the evidence that the BSE agent entered the pharmaceutical chain? Can you show a single example of tranmission of spongiform encephalopathy via a pharmaceutical gel? It may well be the case that some of the vCJD cases were spread by a mode other than food, I'm just curious to see what the evidence is for this. For the record, let me clarify that I don't think that steaks were responsible for transmitting the BSE agent to humans. I would think it much more likely that ground beef with bits of high-risk materials is much more likely.

Third, obviously you are right that someone who hasn't eat beef can't have been exposed to the BSE agent by beef. I've only read about one vegetarian who developed vCJD, and this person is said to have worked for years in a pet shop that sold feed made with higher-risk cow materials, and thus almost certainly could have been orally exposed to the BSE agent, perhaps by inhaling small feed particles. Further, there are at least a couple of cases where the vCJD agent appears to have been transmitted person to person by blood. So, I agree with you that eating beef is not necessarily the only mode of transmission.

In addition to the simple explanation that all these other sources would be affected the same way, there's also the possibility that cows and humans could be getting the disease from a common source, like a waterborne bacterium.

Again, where is the evidence? What kind of a bacterium could be so good at evading detection? How could even the bacterium's nucleic acids be so good at evading detection? As I already pointed out, we know that you can take the material from a BSE infected cow, subject it to chemical or physical insults that are known to decompose nucleic acids, and yet the the material retains its infectivity. How is that consistent with a bacterium being the causal agent? I have read that you can take the original infectious material from a cow, purify it until nothing is detectable but the PrP-res, and it is still infectious.

"If you hear a voice within you say 'you cannot paint,' then by all means paint, and that voice will be silenced" - Vincent Van Gogh
 

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Speaking of theories that sound like they rely on "little people" or gremlins or whatever, has anybody stopped to think about how weird the prion theory sounds?

Well, anyone who has even a passing familiarity with the history of science will recognize immediately that just about every single well-established theory today was originally thought to be counterintuitive. As it turns out, the universe is very, very weird. Geocentrism was weird. Germ theory of disease is weird. Genetics is weird. Plate tectonics is weird. General relativity is weird, and certainly science-fictiony. Quantum mechanics is weird. Stellar mechanics is weird. The expansion of the universe is weird. If you'll pardon me for saying so, I don't find the fact that Fat Guy or any other person finds the prion theory "weird" to be a strike against it.

All this folding and these inert infectious agents sound a lot more science-fictiony than the much simpler claim that "we haven't found the virus yet."

See what I mean? If you think that protein folding and protein misfolding is "science-fictiony," you might want to read an introductory text on molecular biology. Its a fairly well-understood phenomenon and is fundamental to all sorts of cellular processes. And if you think that inert infectious agents sound science-fictiony, I'm puzzled as to why you would think viruses are any less so. Just like prions, they are inert until they can interact with other biological materials.

It's pretty reasonable to say that when a new infection comes along and it proves hard to understand that we should still devote some serious effort to finding the responsible bacterium or virus, rather than abandon the whole theory in favor of a cool-sounding word like "prion."

You continue to imply that little or no effort has been devoted to finding a bacterium or virus associated with BSE/vCJD. Not only is this simply incorrect, you have yet to explain how a virus or bacterium could survive treatment with nucleic-acid decomposing chemicals. Maybe there is a good explanation and I just haven't heard of it. If so, I'd love to hear about it.

ETA: Fat Guy's saying that prion theory sounds weird and science-fictiony reminded me of a quote, but it took me a minute to recall what it was. It was this quote from Richard Dawkins:

""Never say, and never take seriously anyone who says, 'I cannot believe that so-and-so could have evolved by gradual selection.' I have dubbed this kind of fallacy 'the Argument from Personal Incredulity.' Time and again, it has proven the prelude to an intellectual banana-skin experience." Richard Dawkins - River out of Eden

Edited by Patrick S (log)

"If you hear a voice within you say 'you cannot paint,' then by all means paint, and that voice will be silenced" - Vincent Van Gogh
 

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But, where is the bacterium when you look at a histological slice of the affected area?  Do you posit that the bacterium crosses the blood-brain barrier, or does it make some chemical that does? 

I'm not positing anything. I'm a writer not a medical researcher. So I can only answer your question by giving examples of what real researchers have posited. For example, Alan Ebringer, professor of immunology at King's College London, posited that vCJD, BSE, etc. could be autoimmune diseases or similar to autoimmune diseases and that the damage could be caused by the body's reaction to an infectious agent. Specifically, the agent he identified was Acinetobacter calcoaceticus. He found that cows with BSE also had high levels of the antibodies that attack Acinetobacter, and that these same antibodies might attack brain cells. So he theorized that "Prions are not infectious particles. Instead they are the breakdown products of damaged nervous tissue."

I'm not a writer or a medical researcher either, or even a college graduate for that matter, but a couple of obvious questions about this theory leap to mind immediately. First, is Acinetobacter calcoaceticus limited to, or enormously more prevalent in the UK compared to surrounding countries? Second, and this one is really obvious, do cows given doses of Acinetobacter calcoaceticus develop BSE?

"If you hear a voice within you say 'you cannot paint,' then by all means paint, and that voice will be silenced" - Vincent Van Gogh
 

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