Prusiner group hits bottom
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Published results don't support press conference claims
The press releases -- unbelievable fulltext:
... Disgraceful university participation
... New Test for Mad Cow Disease Touted
... Relevent literature reviewed by Roland Heynkes
Highlights of PNAS article
AMA endorses SunBeam products
Backgrounder on porterhouse steaks
...Conflicting earlier Prusiner statement on mad cows in US
NEJM editor: we "didn't know" he worked for WR Grace
...No apology yet to author, no expungement of online archive
...Full text of dirty book review
NEJM: review of TSEs from virologist's perspective
Conflicts plague medical journals: the calcium blocker doctors

Prusiner group hits bottom

Commentary 27 Dec 97 opinion webmaster
This article is the 8th Prusiner paper in PNAS in the last 12 months, or 28th article for the year, ie, one every 13 days. [The 'legal' limit for member self-submissions is reportedly 5.] It is a variation on familiar material on shorter incubation times in overproducing mice.

At the press conferences they talked about having 120 day mice and maybe 40 day mice, although the actual PNAS paper only achieves a reduction from 320 to 250 days. The 200 day mice mentioned in the abstract don't appear again in the text. Prior media discussion of unpublished work rules out conventional publication, so the 120 day mice and "40 day or less" mice are restricted to a subsequent PNAS.

Recall the Irish and Swiss tests take just hours, are far cheaper and presumably much more sensitive. RNA aptamers might ultimately offer even greater specificity. The PNAS paper has no data whatsoever on sensitivity thresholds -- a single massive inoculum titre is used. They told the press that the test was sensitive enough to detect infectious agent in "human foods, cosmetics and drugs made from cattle bones, and the mice could be used make sure that tainted material isn't used to make such products."

The essential point is that the PNAS paper was submitted on November 6, within 24 hours of receiving Oesch's publication of the 15B3 monoclonal antibody and one week after the aptamer report. Prusiner's group had failed earlier in their search for similar discriminatory antibodies and had plowed a huge amount of monetary and human resources into second-best transgenic mouse detectors. They apparently scrambled to pull together obsoleted material that could be quickly placed in PNAS, knowing full well no journalist would critically read the actual text.

Darn those Swiss -- first they find the gene and show the it is encoded by the host, then they are first with the 3D structure, and now first with [published] sensitive detection methodology. Plus they have a near-monopoly on immune system role in transmission. Caughey at Rocky Mt. Labs has been on a tremendous roll. And German, Brazilian, and Chicago groups had the nerve to first report binding partners and before that there was Raymond et al. Press conference hype was apparently needed to achieve public perceptual parity.

While the lab does still do important work, the work is accompanied by a gratuitous program of bash (laminin receptor), exaggerate (this paper and press release), expropriate (Griffiths, Merz, Weissmann), flood (semiweekly journal articles), and follow (hamster nmr). (So BEEFF.)

"If the normal protein does not contain the precise amino acid sequence of this region, known as an epitope, transmission of the infectious protein will not occur."
I could find zero support for this statement in the actual article. They looked at only one triple-variant and a subset of phylogenetic sequences, but not previous species barrier literature. There are no applicable epitopes even mentioned in this article, no data localizing the species barrier to a particular surface patch, only circumstantial consistency that does not allow for action-at-a-distance effects [despite 7,486 Medline papers on allostery]. With 12 authors, someone should be aware of allosteric effects. The authors note 100% variation in overexpression levels within the same mouse strain; perhaps differing transcriptional or translational efficiencies explain their results, e.g., changes in mRNA sequence affect the amount of protein produced which in turn affects incubation times, perhaps changes in amino acid sequence aren't at issue. No controls were reported.
"Despite widespread concern that prion-contaminated beef causes a human form of mad cow disease, Prusiner ate a [porterhouse] steak on the day the Nobel Prize was announced..."
Note this is a quotation from a University press release conjecturally written or approved by the Prusiner -- it is not just a newspaper story seeded with industry PR. Mentioning porterhouse steak again is highly signficant because subsequent to the original dinner on October 6, the English banned beef-on-the-bone; 'porterhouse steak' is a code word for marrow/B cells progenitors and spinal cord/dorsal ganglia. Public health appears to be taking a back seat here to cultivating industry. Waving the porterhouse steak again in advance of any testing sends a message to industry that he can and will provide invaluable public relations. He is not a loose cannon like RF Marsh or those other scientists, quite the contrary.

The T-bone found in a porterhouse steak is a lumbar vertebra sawed in half. The bone is split down the center when a carcass is halved into two sides of beef making the spinal cord available for removal. One ends up with two T-bones from each lumbar vertebrate when the wholesale cuts of meat are finished. The concern with the T-bone in the UK is that it may contain the dorsal root ganglia now known to contain detectable infectivity in cattle which were orally dosed (experimental) with BSE agent. Where does the spinal cord goes when the carcass is halved? An experienced renderer replies:

"Most packers remove it from the carcass just after splitting for several reasons. 1) They don't want it hanging from the carcass as it will act like a wick for microbiological contamination, ie they don't want it hanging on the floor. 2) Must be removed anyway if bones are to be sent to an advanced meat recovery machine... USDA zero tolerance.

The spinal cord is like a bunge cord, very elastic. Since the cut is parallel to the spinal cord, the cord is generally not cut but removed intact. However, if a "mis-split" occurs (saw is off center of vertebra) the cord would be cut across. The mis-split section of vertebra would retain that section of spinal cord. Some facilities get this out using suction removal systems in place. If suction techniques are not used, the mis-split sections are removed manually: spinal cord can't enter AMR systems.

FDA recommendations, which are followed by the gelatin industry, don't allow spinal cord, brain or eyes in material sent to gelatin bone operations. If there is any remaining it is very little when proper procedures are followed. The question is does everyone follow them?

Spinal cord is not considered edible in the US. Some spinal cord may be exported (allowed by law) to Middle Eastern countries where human consumption occurs. No document support of this, only hearsay."

Note that at a Congressional caucus luncheon on May 30, 1996, Prusiner "suggested that mad cow disease must be present in US cows at low levels...the longer animals live, the more likely they are to develop the disease...he agreed with a Wisconsin researcher [Prof. R.F. Marsh], who believes mad cow disease was linked to US cows in the mid-1980's...took the opportunity to urge Congress to step up funding..."

Industry is perfectly capable of reading the PNAS paper for themselves -- they know the method isn't sensitive enough to detect didley-squat, especially if USDA is careful to deliver just the rabid downer cows.

If industry can lobby grant money Prusiner's way, they get the best of both worlds: cutting off regular scientists while putting control into safe hands with impeccable PR credentials and proclivities. The nation's ability to test would be restricted to a single, slow, insensitive, expensive facility -- a much more attractive scenario to industry than a fast and highly sensitive antibody test that anybody could do.

The only danger for industry is that he might double-cross them if a publicity opportunity arose to announce the first case of BSE in the US. Can they ever really trust an MD, even one from Des Moines [meat-packing center of US]?

However, the issue is ultimately driven by the best available science. The Europeans are running around out of control. American industry would have to go to a double standard: the Swiss antibody test in private, the PNAS test for public consumption. Then public health groups in the US will ask why the fastest-cheapest-most sensitive method isn't being used here. Not a sustainable scenario.

Disgraceful UCSF participation

CONTACT: UCSF News Service
Jennifer O'Brien, 415/476-2557
To: News Editors/Health, Medical and Education Writers

Headline: UCSF Researchers Make Breakthrough in Detecting ...

BW (Business Wire)
 Mon, Dec 22, 1997
SAN FRANCISCO--(BW HealthWire)--Dec. 22, 1997-- University of California San Francisco researchers report that they have made an important advance in the ability to detect the infectious protein that causes "mad cow" disease. The scientists, led by Fred E. Cohen, Ph.D., Stephen J. DeArmond, M.D., Ph.D., and 1997 Nobel Prize winner Stanley B. Prusiner, M.D., have developed a genetically engineered test mouse that responds much more quickly, reliably and sensitively to the infectious protein than current techniques.

The finding, said Cohen, a professor of cellular and molecular pharmacology, could improve the capacity to screen human foodstuffs, cosmetics and medicinal products for the infectious protein, carried by contaminated cows. The researchers also report that they have identified the portion of the protein that allows for the transmission of the diseased protein across species.

This discovery, said DeArmond, a professor of pathology and neurology, could ultimately lead to the development of a test model that is even more sensitive to the infectious protein than the new one. The study is reported in the Dec. 23 issue of Proceedings of the National Academy of Science.

Prusiner, a professor of neurology, biochemistry and biophysics, won the Nobel Prize this year for discovering that the neurodegenerative diseases known as spongiform encephalopathies, which include "mad cow disease," are caused by a protein that exists in all mammals and birds examined, including humans. He proposed that the protein becomes destructive only when its shape is altered, and that this change occurs either through infection by an already infectious protein or through a genetic mutation.

The protein is believed to be the principal, if not sole, component of an infectious particle that Prusiner named "prion" (PREE-on), for proteinaceous infectious particle. The normal protein is referred to as PrP-c. Prusiner's postulation that spongiform encephalopathies are caused by a protein was novel when it was introduced, as scientists have previously believed that all pathogens are composed of nucleic acids (DNA or RNA), which allow for replication of their material. Proteins, composed of amino acids, are devoid of nucleic acids.

Despite widespread concern that prion-contaminated beef causes a human form of mad cow disease, Prusiner ate a steak in the United States the day he learned he had received the Nobel Prize. And he emphasizes that he does not think that the U.S. food supply has been tainted.

However, scientists do believe that 25 people in Great Britain and France have died in recent years as a result of eating prion-protein contaminated beef. The victims developed a new variety of the human form of the disease, Creutzfeldt-Jakob disease. The cattle, in turn, are believed to have developed the disease by being fed meat and bone meal contaminated with prions from the sheep form of the disease, scrapie. ...

"If you inject mice with large enough doses of prion extract you'll often get a response," said Michael R. Scott, Ph.D., a UCSF associate adjunct professor of neurology and an author of the study. "But we're concerned that the number of infectious prion particles it takes to infect wild-type mice is not reflective of the numbers that can transmit to other species -- including humans."
The collaborators, however, have now succeeded in developing a strain of genetically altered mouse that responds within 250 days to infection and reliably develops the disease. Most importantly, it will respond to lower doses of infection.
"This model," said Cohen, "is sensitive enough that it is now possible to make an accurate determination of the amount of BSE prion in brain and other tissues -- muscle, pancreas, liver and intestine -- that are commonly consumed by humans."
This is a particularly critical achievement because nonbrain tissues, such as muscle, contain lower amounts of prions.

The model will also allow for the more accurate scrutiny of drugs and other medicinal products derived from cattle, such as collagen for plastic and reconstructive surgery, and gelatin for food and the production of drug capsules.

"Having such a sensitive test also opens up the door for conducting epidemiologic studies on the frequency of bovine spongiform encephalopathies in countries such as the United States and Canada that have been thought to be spared," said DeArmond. "And our findings in this regard will determine whether it will be important to produce transgenic cattle that are resistant to prions."
The mouse model has been genetically engineered to contain a gene composed only of bovine genetic sequences. As a result, it responds to bovine prions with the speed of a mouse's pathological response but with the sensitivity of a cow.

Having the bovine amino acid sequence is the important factor in transmission of the infectious protein to the mouse. Numerous species contain the same protein, but each has a slightly different amino acid sequence, and this variation seems to be at the heart of the "species barrier," the phenomenon that makes transmission between different types of animals the exception, rather than the rule. Prion transmission, it would appear, is a molecular dance that works best when there is a perfect match.

The fatal dance occurs, according to Prusiner, when the flattened prion protein latches on to the normal, corkscrew-shaped protein [???], presumably with the help of an as-yet unidentified "protein X." The abnormal prion protein then acts as a template, it is believed, refolding the normal protein into a new, flattened, diseased conformation.

Just as a stumbling novice can sometimes find synch with an expert dancer, the prion protein of normal, so-called "wild type," mice will sometimes connect successfully with bovine prions. But sometimes it doesn't.

And such leeway goes only so far, anyway, the UCSF scientists report in the Proceedings. They have identified a regulatory region on normal bovine protein that modulates the protein's conversion into the diseased conformation. If the normal protein does not contain the precise amino acid sequence of this region, known as an epitope, transmission of the infectious protein will not occur.

The scientists came upon this finding somewhat serendipitously, while experimenting with mouse models containing prions produced by various mixed-gene sequences. They observed that mice containing bovine and mouse/prion protein were highly resistant to infectious bovine prions, while mice producing human or human/mouse protein were susceptible to human prions.

In scrutinizing the amino acid sequences for an explanation of these different responses, the scientists defined the epitope region. The region, sequentially disparate in the different animal models but spatially proximal, provides the binding interface for normal protein and protein X.

The UCSF researchers' next step is to try to determine why the particular epitope region allows the infectious form of the prion to then bind to the normal form.

The finding, the researchers say, could ultimately enable them to develop a genetically engineered mouse that is even more sensitive to the infectious proteins than their new model -- and thus better at detecting low levels of prion infection.

New Test for Mad Cow Disease Touted

 AP Online Wed, Dec 24, 1997
SAN FRANCISCO (AP) -- Researchers have developed a fast reliable test for mad cow disease, allowing more efficient screening of blood, medicines and other health products derived from cattle. The trick was engineering a strain of laboratory mice especially sensitive to the bovine disease that can cause a similar brain-wasting ailment, Creutzfeldt- Jakob disease, in humans who eat tainted meat.

When cattle are infected, symptoms don't show up for at least three to five years. But the genetically engineered mice, after being injected with cattle tissue, would display the staggered gait and other warning symptoms of the fatal brain disorder within 120 days, researchers said Tuesday. By further manipulating the mice in the lab, the group expects to cut that time down to 40 days or less.

At least 1 million cows in Britain and France have contracted the highly infectious disease that is fatal in cattle. And at least 20 people, mostly in Britain, have contracted Creutzfeldt-Jakob disease from infected meat. The disorder has never been reported in the United States, but earlier this month federal officials banned imports of all cattle, sheep and related products from Europe until the risk of mad cow disease is assessed.

The researchers at the University of California, San Francisco included Dr. Stanley Prusiner, a Nobel prize winner for discovering microscopic particles that can cause brain-wasting illnesses. The "transgenic" mice carry in their cells a mixture of genes for the creation of normal prions -- protein particles that can cause brain-wasting afflictions -- found in humans, cows and mice, according to Tuesday's report in the Proceedings of the National Academy of Sciences.

The researchers also believe they have identified a portion of the prion protein that allows the disease-causing form to cross the species barrier between animals and humans, Prusiner said. Besides meat, some human foods, cosmetics and drugs are made from cattle bones, and the mice could be used make sure that tainted material isn't used to make such products.

A better way of screening for 'mad-cow' disease

December 24, 1997 By LISA M. KRIEGER, San Francisco Examiner
Nobel-winning scientist Stanley Prusiner and his team of University of California-San Francisco researchers have developed a quicker, more reliable and more sensitive way to screen for "mad-cow" disease. It's not yet feasible -- either economically or logistically -- to screen the filet mignon on your dinner table.

But the test permits more efficient screening of the safety of blood, medicines and other products derived from cattle, such as collagen for reconstructive surgery and gelatin for food and drug capsules. It also could help answer research questions.

"Would I use it to ask: Is this bad meat? I could do that. But it would take 200 days, and you wouldn't want to eat it," said Dr. Fred E. Cohen, professor of cellular and molecular pharmacology and part of Prusiner's team. "You could ask: Is the herd in trouble? And you could answer broader policy questions, like ... is there a part of the animal that should be off-limits? Does risk of infection go up as the animal ages?"
The new test is not a test in the conventional sense. Rather, it is a live mouse -- a "furry test tube," of sorts -- that has been genetically altered to carry cow genes. As a blend of two species, it's a perfect "mad cow" model: It is sickened by bovine diseases, and responds to infection by mad cow disease causing protein particles with the lightning speed of a mouse.

Moreover, infected mice are small, cheap and easy to dispose of in contrast to infected cows.

Until now, the only way to determine if a live cow has the mad cow disease called bovine spongiform encephalopathy, or BSE, is to wait out a lengthy incubation period of four years. Scientists have tried to speed things up by injecting cow tissue into normal mice. But even then it takes nearly a year for the mouse to develop signs of disease. And disease comes only sporadically, and only with high levels of exposure to the protein particles. This new mouse is ultra-sensitive. It is also quick to sicken, showing BSE-like symptoms such as walking backward, only 200 to 250 days after infection.

While eight months is a long time to wait before eating a particular hamburger, it's well within the time frame needed to make safety decisions about drug and blood products.[??? --webmaster]. The United States has 101 million cattle -- one cow for every 2.5 people. With the outbreak of BSE in British cattle, possibly leading to a rare but fatal brain illness called Creutzfeldt-Jakob disease in 21 young people, U.S. public health officials feared a similar epidemic here. The U.S. agricultural industry, like Britain's, until recently recycled animal scraps, turning them into cattle feed and fertilizer. This process, known as animal recycling, causes a low-level infection to become dramatically amplified.

Last June, the Food and Drug Administration banned the practice of adding slaughterhouse scraps to animal feed. U.S. ranchers now feed their cattle an alternative type of supplement, based on soy-based proteins and cottonseed meal. Also, cattle here are slaughtered while still young, before the number of infectious particles has a chance to climb. Perhaps because of these precautions, not a single case of mad cow disease has ever been detected in this country, in tests of more than 3,000 specimens from 43 states. And no U.S. cases of Creutzfeldt-Jakob disease in humans have been linked to beef consumption, say health officials. The United States bans the sale and consumption of meat derived from the animal's central nervous system or lymph system. But the ban does not exclude blood, blood products, gelatin, milk, milk products, pig and horse proteins. Also, there is the fear that cattle can develop the disease spontaneously -- creating an ever-present health risk despite import restrictions and regulations on animal feed. The test could be used to do studies to screen for the prevalence of BSE illnesses in countries such as the United States and Canada, which presumably have been spared.

Review of earlier contributions

Dr. Roland Heynkes Aachen, Germany 22.12.97
Actual press release quote:
"Prusiner's postulation that spongiform encephalopathies are caused by a protein was novel when it was introduced, as scientists have previously believed that all pathogens are composed of nucleic acids (DNA or RNA), which allow for replication of their material. Proteins, composed of amino acids, are devoid of nucleic acids."
Comment: "This is an impertinent lie and manipulation of scientific history!

Tikvah Alper, D.A. Haig and M.C.Clarke published in BBRC1966; 22(3): 283 that a putative scrapie virus could hardly have more than 800 base pairs and that this "suggests that the agent may be able to increase in quantity without itself containing nucleic acid". And they mention an article of I.H. Pattison from 1965 with a similar conclusion.

E.J.Field suggested in the British Medical Journal 1966; ii: 546 that the agent might be a replicating polysaccaride and J.S. Griffith explained how proteins could replicate without nucleic acids in "Self-replication and scrapie - Nature 1967 Sep 2; 215(105): 1043-4.

This was the protein only hypothesis a full year before S.B.Prusiner finished medical school. He started with his prion research 1972, five years later.

"Currently, the only sure-proof way to determine if a live cow has bovine spongiform encephalopathy (BSE) is to wait out its lengthy incubation period -- a minimum of four years."
Comment: The minimum incubation period of BSE is of course not 4 years, but less then two years.

Breakthrough study provides the first method of accurately measuring prions that cause 'mad cow' disease

December 23, 1997 NAS
...
"The [PNAS] article is the first report of genetically engineered mice that are highly susceptible to BSE prions and consistently demonstrate symptoms of the disease in less than 250 days following exposure. Symptoms can sometimes take years to appear in humans. The researchers note that these genetically engineered mice now make possible an accurate determination of BSE prion concentrations in brain and other tissues, as well as the evaluation of drugs and other medicinal products derived from cattle-such as collagen and gelatin for prion contamination.

Moreover, the availability of these mice also will make possible epidemiological studies about the frequency of BSE among cattle in countries that have been thought to be spared from the disease, such as the United States and Canada."

A prion protein epitope modulating transmission of BSE prions to transgenic mice

Proc. Natl. Acad. Sci. USA Vol. 94, pp. 14279-14284, December 1997
Michael R. Scott, Jiri Safar, ...Fred E. Cohen, Stephen J. DeArmond, and Stanley B. Prusiner
Summary (webmaster opinion): Yet another line of transgenic mice, this time with bovine substitutions from residues 97 to 186, injected with 30 microliters of 10% brainstems from histologically positive BSE cows, came down with a BSE-like disease in 250 days, somewhat faster than wildtype mice (320 days). No endpoint titration was reported to measure sensitivity of the test, so its suitability for testing low-titre material is completely unknown. The line expressed a variable [8-16 times] amount of mouse prion per gram of total protein when compared with bovine brain (data not shown).

High copy number mice with more rapid onset have been reported in numerous previous publications. The live-assay method is slow, expensive, and probably less sensitive than monoclonal antibody such as 15B3. And with mice, there is always the issue of special facilities and escape containment, not a vacuous consideration considering the persistence of TSE in wild elk and deer populations..

A mouse strain having human residues 97 to 168 but mouse from 169 to 186 and beyond had different residues at 184, 186, and 203 from the bovine strain and a different incubation time. The amino acids involved are hydrophobic, buried and not expected to present an antigenic determinant, and indeed no antibody described in this paper defines this region as an epitope nor discriminates these regions. By aligning sequences from about half of the known prion genes, the authors identified by an unspecified method other variable residues somewhat nearby that might have also have to do with a species barrier. No explanation was given for excluding other variation tabulated in their earlier articles; the species used were not stated, most have never been tested experimentally.

The claim here requires that protein conformation cannot be influenced 'at-a-distance,' yet there are 7,486 studies at Medline reporting allosteric effects in a huge variety of proteins. Overall, the evidence for the strain-type "epitope" is as flimsy as the "protein" X story; both are starting to take on a life of their own by virtue of repetition.

Five of these same authors published two years ago experiments with very similar transgenic mice that "demonstrate that PrPSc binds to PrPC in a region delimited by codons 96 to 167." Cell 1995 Oct 6;83(1):79-90. Four of the authors had noted even earlier that "transgenic chimeric mice [between residues 96 and 167] developed neurologic disease approximately 200 days after inoculation with brain homogenates." PNAS1994 Oct 11;91(21):9936-9940.

Three of the same authors published very similar experiments last year with shortened incubation times in overexpressing transgenic mice: "Mice overexpressing [eightfold] the wild-type MoPrP-A transgene were highly susceptible to inoculated mouse prions, exhibiting abbreviated scrapie incubation times of 45 days... After crossing the mutant transgene onto a null background, the resulting mice displayed a highly synchronous onset of illness at 145 days of age, which was shortened to 85 days upon breeding to homozygosity." Genes Dev 1996 Jul 15;10(14):1736-1750 Before this, they noted already in 1994 that "the length of the incubation time was inversely related to the number of Prn genes." PNAS1994 Jun 7;91(12):5690-5694.

In other words, chimeric bovine with a 250 day incubation was a bit of bad luck.


Legend: Hamster numbering.
...red: "epitope" formed by residues 184, 186, 203, 205
...green: phylogenetically variable: 138, 139, 143, 145, 148, 155 (unspecified species and method)
...blue:"protein X" 168, 172, 215, and 219

"The complete bovine ORF used was derived from the brain of a Hereford bull afflicted with BSE. Sequencing of the ORF revealed that this version contains six copies of the octarepeat sequence octarepeat, the N-terminal region contains two single base insertions relative to hamster." [Mysterious: no such frameshift anomaly is reported in authors' ref.16: GenBank 2136801, 266112, 130910; J Infect Dis 1993 Mar;167(3):602-613 -- webmaster]

"Interestingly, the ratios of the three glycoforms were similar in bovine and chimeriac mouse brains and in those reported for nvCJD patients, with a predominance of the fully glycosylated fragment....Recent studies have documented the ability of Asn-linked glycosylation to modify the distribution of both PrPC and PrPSc in concert with the particular strain of prion." [DeArmond, S. J., .. Prusiner, S. B. (1997) Neuron, just out: Dec 97 Neuron, 18(6): 1336-48 subscription-only]"

"Moreover, endpoint titrations of BSE prions in cattle suggest much higher titers of prions in bovine brain than those determined by mouse bioassays (J. Wilesmith, personal communication)."

"Some mutations associated with inherited human disease create transmissible disease (178, 200, 210) (J. A. Mastrianni and S.B.P., unpublished data) whereas others create disease in the founder's lineage that are not transmissible to murine hosts expressing wild-type PrP (e.g., 102) (27, 64). Seven point mutations (178, 180, 183, 198, 200, 208, 210) known to cause inherited prion diseases, including those that are known to create a transmissible encephalopathy, map to this region of the structure as well)."

Designing Transgenes.

"The identification of a species-specific 'epitope' that modulates the conversion of PrPC into PrPSc has important implications for the design of PrP transgenes. Whether optimal Bo/Mo chimeric transgenes should contain Mo or Bo residues at positions 184, 186, 203, and 205 remains to be established. Similarly it is unknown whether improved Hu/Mo chimeric transgenes can be constructed by simultaneously mutating human residues at these same positions to mouse residues. Mutagenesis at any or all of these positions may overcome paradoxically long incubation times. "

Implications for Public Health and Monitoring the Food Supply.

"The Tg(BoPrP) mice make possible, for the first time, an accurate determination of BSE prion titers in brain and other tissues. Determining the titers of BSE prions in muscle, pancreas, liver, and intestine that are commonly consumed by humans may be of utmost importance. Because the bioassay for bovine prions in non-Tg mice is so insensitive, the levels of prions in these bovine tissues remain unknown. If the distribution of bovine prions proves to be different from that presumed for sheep, then assumptions about the efficacy of the specified bovine offals ban of November 1989 that prohibited human consumption of CNS and lymphoid tissues from cattle older than 6 months of age may need to be reassessed.

These mice also make possible for the first time the evaluation of drugs and other medicinal products derived from cattle for prion contamination. For example, collagen from cattle is used widely in plastic and reconstructive surgery, and gelatin is used in foods and in the production of a wide variety of drug capsules. The availability of Tg(BoPrP) mice will also make possible epidemiologic studies on the frequency of BSE in countries such as the United States and Canada that have been thought to be spared. With these mice, it is now possible to determine the frequency of sporadic BSE, particularly in older cattle.

Such studies will determine whether or not it will be important to produce Tg cattle that are resistant to prions either through PrP transgenes that bind tightly to protein X and act as dominant negatives or by genetic ablation of the PrP gene. "

The ability of Asn-linked glycosylation to modify the distribution of both PrPC and PrPSc in concert with the particular strain of prion

DeArmond, S. J., .. Prusiner, S. B. (1997) 
Dec 97 Neuron 18(6): 1336-48 subscription-only
The same issue of Neuron contains articles by:
Peter T. Lansbury
Structural Neurology: Are Seeds at the Root of Neuronal Degeneration?
1151-1154

CA. Ross
Intranuclear Neuronal Inclusions: A Common Pathogenic Mechanism for Glutamine-Repeat Neurodegenerative Diseases?
1147-50.

Mad cow disease must be found in US cows in low levels, says researcher

Food Chemical News  ... 3 June 1996
After more than two decades of research on prions, Stanley Prusiner of UCSF suggested that mad cow disease must be present in US cows at low levels.

Prusiner, who spoke at a May 30 congressional caucus luncheon, said the longer animals live, the more likely they are to develop the disease. He said he agreed with a Wisconsin researcher [Prof. R.F. Marsh], who believes mad cow disease was linked to US cows in the mid-1980's.

Prusiner criticized the British government for setting up an expert panel with members chosen by the government, rather than by an independent body such as the National Academy of Sciences. He stopped short of recommending measures to halt the potential spread of the disease in the US, citing the complex chain of economic, political, and scientific variables affecting policy decisions.

Many factors conspired to cause mad cow disease in Britain, including the deregulation of the rendering industry, he said. The fat content increased in meat and bone meal fed to cows. While more than 160,000 cattle have come down with the disease, the numbers peaked in 1992 and are beginning to drop off there. The practises that led to the disease's spread stopped in the late 1980's, he said. Today, there are an estimated 1,000 cows dying of the disease every month.

The California researcher said scientists still don't know whether diseased cows can affect humans. He said it's still unclear what route exposes cows to the disease, whether through cuts in their mouths or [infectious agent] carrried by white blood cells.

He took the opportunity to urge Congress to step up funding of biomedical research.

Backgrounder on porterhouse steaks

Web sites containing information on porterhouse steaks:
Porterhouse: n (1758) 1 archaic: a house where malt liquor (as porter) is sold
2: a large steak cut from the thick end of the short loin to contain a T-shaped bone and a large piece of tenderloin

"We sell only Premium Lean Limousin Beef. All our steak selections, except for T-Bones & Porterhouse are certified by the American Heart Association."

Buy a porterhouse steak online:

 Box of 4 16 oz. ea. $95    Place in cart 
 Box of 4 20 oz. ea. $109   Place in cart 
Porterhouse steaks, popularly known as T-Bones, are really two steaks in one; the bone divides the rich, flavorful strip and the tender filet. And remember, true porterhouse steaks like ours have much larger filets than most T-bones.

Medical journal criticized for poor verification method

December 27, 1997  The Associated Press 
BOSTON -- The New England Journal of Medicine allowed a chemical company official to write an unfavorable review of a book that claims chemicals in the environment are responsible for an epidemic of cancers. The journal, which has been drawing criticism since the review was published last month, apologized for not informing readers that the author was the medical director of W.R. Grace -- a company that has been accused of polluting the environment.
"We should have recognized that W.R. Grace was a conflict of interest, but unfortunately the person who handled it didn't recognize that," the journal's editor-in-chief, Dr. Jerome P. Kassirer, said in Saturday editions of The Boston Globe.
Kassirer said the journal, which has had similar problems in the past, would print a complete explanation of its gaffe within four weeks.
"Our conflict-of-interest policy is pretty tight, the tightest in the business," he said. "It was a simple oversight."
In 1989, an article in the journal downplayed the dangers of exposure to asbestos but did not inform its readers that the author had ties to the asbestos industry. After that, the journal changed its policy to refuse reviews or editorials whose authors were connected to firms with a financial interest in the topic.

But last year, the journal ran an editorial claiming the benefits of diet drugs outweigh the risks. It failed to note that the authors were paid consultants for companies that made or marketed one of those drugs, Redux -- recently pulled off the shelves due to safety woes.

"I think there's an infection at the New England Journal of Medicine that is badly in need of treatment," said Paul Brodeur -- a journalist who has written about chemical pollution.
The author of last month's book review, Dr. Jerry H. Berke, said he had signed a conflict-of-interest statement spelling out his affiliation with W.R. Grace. Berke said his first drafts of the review mentioned his connection to Grace, but that he decided "at the very last minute" to identify himself as independent. "The folks at Grace wanted to make certain that I was writing my own opinion," he said. "I wasn't trying to be cute or duplicitous or anything." In the book and upcoming movie "A Civil Action" -- Grace is blamed for polluting the drinking water in a Boston suburb, sickening several children. "It's laughable that Berke would think that he could write an objective review of the book given that he was an employee of W.R. Grace," Kassirer said.

Author of the book responds:

Washington Post  Saturday, January 10, 1998; Page A17-- Sandra Steingraber 
News to Me:
"I am the author of the book "Living Downstream: an Ecologist Looks at Cancer and the Environment," which was criticized harshly in a review published in the November issue of the New England Journal of Medicine [1997: 337: 337 (21):1562 - Book Review Berke JH.] As your paper reported in a Dec. 28 Associated Press news story, the reviewer, Jerry H. Berke, is a senior official at W. R. Grace & Co., a multinational chemical manufacturer. His professional identity was not revealed in the review itself.

The headline of your paper's story, "Medical Journal Apologizes for Ethics Blunder," however, was news to me. I have received no apologies from the New England Journal of Medicine nor even a phone call of explanation.

The question of what the journal editors knew about Berke's corporate affiliation and when they knew it is not a trivial one. If his employment was not known to the journal, why not? If it was, then why was he assigned my book to review in the first place?

Berke's conflict of interest is more than philosophical. Receiving my direct attention in the book are the cluster of childhood cancers in Woburn, Mass., which formed the basis of a famous lawsuit involving W. R. Grace & Co., now the subject of a forthcoming movie."

[It is impossible that an eminent journal could send a book out to a total stranger for review, improbable that a Massachusetts-based medical journal could be unaware of a highly publicized Massachusetts-based cancer cluster, not believable that the editors could allow outside reviewers to make determinations of their ethical conflicts of interest. All this while NEJM makes pious criticism of arch-rival JAMA and the Sunbeam endorsements!

Then there is the issue of unstated annual dollar value of advertising placed by WR Grace, affiliates, and industry associations in the NEJM. And finally, will the NEJM put the book out for independent review and publish that as a replacement? Right now there is no notice whatsoever at the online archive of the book review that anything has gone amiss. -- webmaster]

Code of Ethics not applicable to NEJM editors?

"II. A physician shall deal honestly with patients and colleagues, and strive to expose those physicians deficient in character or competence, or who engage in fraud or deception."
Book Review: full text of Berke's broadside
Jerry H. Berke, M.D., M.P.H. 
49 Windsor Ave. 
Acton, MA 01720
"An older colleague of mine once suggested that the work product of an environmentalist is controversy. Fear and the threat of unseen, unchosen hazards enhance fund-raising for environmental political organizations and fund environmental research, he suggested. Though his view may be cynical, it was my introduction to the "politics" of the environment. Living Downstream is an environmental polemic and an unapologetic call to arms. Dr. Sandra Steingraber has analyzed an enormous volume of data with which she attempts to convince us first, that we are in the midst of a cancer epidemic and second, that chemical residues and pesticides in the environment are the cause of this deadly scourge.

Steingraber's first premise has not been supported by serious scientific analysis. In the February 1, 1995, Journal of the National Cancer Institute, Susan Devesa and colleagues reviewed cancer epidemiology in the United States extensively, comparing the five-year periods 1975 through 1979 and 1987 through 1991 ("Recent Cancer Trends in the United States." 1995;87:175-82). Although they note that age-adjusted incidence rates for all cancers increased by 18.6 percent among males and 12.4 percent among females, they conclude that these increases in cancer incidence are entirely explained by known factors. Early and improved detection of breast and prostate cancers, cigarette smoking as a determinant of lung cancer among women, and increases in non-Hodgkin's lymphoma and Kaposi's sarcoma as a result of acquired immunodeficiency account for the increases. Philip Cole and Warren Sateren, in an accompanying editorial, warn that causal interpretation of cancer statistics can "leave the unwary to see a rise in cancer where none has occurred." They go on to say that "it is only a small jump to the idea that this rise was due to environmental contamination." The ease with which such hypotheses may be developed, and their emotional charge, lead to "the prediction of an impending disaster of ever-increasing cancer rates." "In reality," they go on to say, "the disaster has remained impending for more than twenty years, and Devesa's findings suggest that it will not occur."

So obsessed is Steingraber with environmental pollution as the cause of cancer that she dedicates little more than a paragraph to dismissing high-fat diets and obesity as causes of breast cancer, despite the contention of the American Cancer Society that a 50 percent reduction in fat intake will help prevent breast and other cancers. She writes with indignation about environmental chemicals with estrogenic effects on the order of 1/10,000 the potency of estradiol but makes no mention of the possible contribution of estrogen-replacement therapy to the risk of breast cancer. She quotes data from in vitro studies suggesting dramatic synergistic effects of environmental estrogens that were originally published in Science but have since been withdrawn by the authors because the results could not be repeated. She casually applies the word "carcinogen" to a wide variety of industrial and agricultural chemicals, and although she speaks with authority about theoretical mechanisms of cancer, she fails to make mechanistic distinctions that would distinguish those few chemicals that cause genotoxic injury from those whose effects in animal models are clearly dose related. These are just a few examples of oversights and simplifications that can be found throughout her book.

Steingraber is otherwise a marvelous writer who combines the discipline of a scientist with the skill of a poet. She personalizes mundane statistics, and her book shifts easily from personal recollections and vivid descriptions of formerly pristine settings to the statistics of environmental pollution and the disease burden that she perceives is borne by the populace. In one chapter, she traces the MCF-7 cell line, widely used in cancer research, to a woman who died in Michigan in 1970 and from whom these cells originated. It is this human face that she places on cancer that gives her writing its poignancy and sense of urgency. Steingraber is a survivor of cancer diagnosed in her mid-twenties. In addition to making her passionate, her own cancer diagnosis seems to have resulted in her study of the field of cancer epidemiology from the perspective of a victim.

I read Living Downstream with a sense of sadness that this otherwise talented writer should have produced such a biased work. She has obviously put forth an enormous effort of scholarship in compiling this work; however, scholarship designed to prove a preconceived notion is notoriously poor scholarship. As Edward Campion in his July 3, 1997, editorial in the New England Journal of Medicine (1997;337:44), titled "Power Lines, Cancer, and Fear," concluded, "The 18 years of research [on the link between electromagnetic fields and cancer] have produced considerable paranoia, but little insight and no prevention. It is time to stop wasting our research resources." The focus on environmental pollution and agricultural chemicals to explain human cancer has simply not been fruitful nor given rise to useful preventive strategies.

None of us consciously wish for a contaminated environment, and many of Steingraber's calls for a new paradigm having to do with less chemical dependency in agriculture are unassailable. Nonetheless, Living Downstream frightens, at times misinforms, and then scorns genuine efforts at cancer prevention through lifestyle change. The objective of Living Downstream appears ultimately to be controversy."

Mechanisms of Disease: Transmissible Spongiform Encephalopathies

NEJM 337 1821-28 1997
Anne M. Haywood
Commentary (webmaster): The NEJM and Medline offer nothing online, no abstract even, but a fax of the article can be obtained for $10 credit card charge.

Haywood AM in Medline: mimimal, virus-related, nothing previously published in TSEs or related fields, dementia, or infectious disease. Possibly this is a viral advocacy theory article prompted by a personal relationship with Manuelidis-Rohwer-Diringer.

I have now read the 8 page text without learning anything -- this is a well reviewed subject already. The piece is rather curious in its blandness, better suited for a Republican doctor's waiting room than office or lab. The level of technical detail would work for a newspaper or magazine, though it is not up to Rhodes' writing. From the odd list of citations (little molecular biology, 3-4 1997 citations out of 69 total), the article was basically completed in 1996. Some things (prions) are dealt with very cautiously and critically, others (speculative epidemiological predictions for nvCJD) are taken at face value and quoted from their abstract.

It is puzzling what motivates an outsider to submit a non-expert review article unrelated to professional interests to an eminant journal. NEJM readers would presumbably be more interested in risk from blood and blood products or in familial or iatrogenic CJD but the account here is inadequate for a working physician. The story of how and why NEJM came to run this article is a greater curiosity, surely 8 pages of space is not given out to such an article without some serious outside considerations.

Conflicts of interest plague American medical journals, medical journal says

January 7, 1998 Reuters 
BOSTON - Virtually all the doctors who defended a class of drugs widely used to treat heart disease had hidden links to the makers of the drugs, the New England Journal of Medicine said in its Thursday issue. The Journal said a team of researchers found that almost all the doctors who rushed to defend the safety of calcium channel blockers in 1995 had financial links to the drug companies that make them. "We wonder how the public would interpret the debate over calcium-channel antagonists if it knew that most of the authors participating in the debate had undisclosed financial ties with pharmaceutical manufacturers," said the study team, who argued that "the medical profession needs to develop a strong policy governing conflict of interest." Calcium channel blockers are used mainly to treat heart diseases marked by spasms in the organ's artery. The drugs prevent calcium from entering smooth muscle cells and cause the smooth muscles to relax and reduce muscle spasms.

The National Heart, Lung and Blood Institute warned physicians in 1995 that one particular drug -- short-acting nifedipine -- should be prescribed "with great caution, if at all." It said short-acting calcium channel blockers were linked with an increased risk of death from heart attack. The warning kicked off a major debate. The authors of the new study, led by Dr. Henry Thomas Stelfox of the University of Toronto, tried to gauge the involvement of industry-supported doctors in the calcium channel controversy by identifying articles published between March 10, 1995, and September 30, 1996, and categorizing them as supportive of the medicines, critical of them, or neutral.

Then they sent surveys to the authors of the 70 articles asking about their financial links to drug companies in general, and calcium channel blocker makers in particular. They discovered that "96 percent of the supportive authors had financial relationships with manufacturers of calcium-channel antagonists, as compared with 60 percent of the neutral authors and 37 percent of the critical authors." The researchers also wondered if the authors who were critical of calcium channel blockers had financial ties to companies making competing types of heart medicines. "The answer was no. In fact, supportive and neutral authors were more likely than critical authors to have financial interactions with manufacturers of competing products," they concluded. Only in two of the articles had the editors disclosed any potential conflict of interest for the writer.

Although the Stelfox group acknowledged that the supportive authors may have ties to drug companies because the companies seek relationships with doctors who already support their products, the researchers concluded, "The results demonstrate a strong association between authors' opinions about the safety of calcium-channel antagonists and their financial relationships with pharmaceutical manufacturers."

There are many ways for doctors to get support from pharmaceutical firms. Drug companies sponsor ongoing medical education programs and hire physicians to serve as consultants, perform research, or speak at symposia. Often those financial ties are not disclosed, although the editors of medical journals say they are working harder to unearth potential conflicts of interest when doctors publish in their magazines. Whether support from the pharmaceutical industry is actually swaying the opinions of doctors "cannot be determined by the results of our study," the Stelfox team said.

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