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Ranchers.net

Novel test for mad cow disease fuels patent dispute
Local firm says inventor signed off on rights

Duncan Thorne, The Edmonton Journal
Published: Friday, July 21, 2006
EDMONTON - An Edmonton company is confident it has a cheap, ground-breaking test for mad cow disease.

But the test's British inventor -- who claims to have first made the link between BSE and the disease's human form -- insists he still holds the rights.

Edmonton's BSE Prion Solutions Inc. is just as firm that inventor Harash Narang, from Newcastle, England, signed away those rights three years ago.

"We've talked with patent attorneys in London and also in Newcastle," Ron Arnold of BSE Prion said. "Everyone agrees that the documents and the transfer of ownership of the patents was done judiciously and was extremely well put together by the solicitors."

Narang, speaking from Newcastle, acknowledged signing papers, but said it was not clear what he was signing. He said he's the one who continues to pay the patent renewal fees.

Despite their differences, Narang and BSE Prion agree the test holds amazing potential to quickly and inexpensively test live cattle for bovine spongiform encephalopathy -- better known as mad cow disease.

The only approved tests so far for mad cow and its human equivalent depend on removing brain samples after death. A test on live animals would open the way to guaranteeing disease-free herds.

Narang, a former British government scientist who went public about human risks from BSE in 1990, started developing tests for detecting the disease in the late 1980s while at a public health laboratory.

He had been studying cases of a fatal but rare human brain illness, Creutzfeldt-Jakob disease or CJD, when he started noticing some cases were different.

He has said he was well on the way to establishing a link between BSE and the unusual CJD cases when he was ordered to stop his research. He has also claimed officials rejected his calls for increased testing for BSE and the new form of CJD, now known as variant CJD.

He developed three diagnostic tests, including an early version of the urine test that BSE Prion Solutions intends to bring to market.

A wide-ranging 1998 inquiry into Britain's response to the mad cow crisis found problems with Narang's claims. It cited evidence that fellow scientists could not get his test to work.

Even so, Narang continued development of the urine test. A British company, Biotec Global, sponsored much of his work. He is no longer part of the research, but work on it continues, at the United States National Prion Disease Pathology Surveillance Center at Case Western Reserve University in Cleveland, Ohio.

Edmonton's Arnold, a partner in Biotec, said Harang gave Biotec the patent rights in 2003 and it in turn gave Edmonton's BSE Prion the licence for the Americas and Europe.

Biotec has sunk more than $2 million into the research but BSE Prion has not had to pay a licence fee, Arnold said. That's because the project is humanitarian, with plans to hand over any earnings for research purposes, in the form of grants and scholarships.

Narang, who holds shares in Biotec Global despite the ownership dispute, also said he also wants any profits to go into further research. Meanwhile, he added, he's owed back pay and expenses for work he did over the past five years -- a claim Arnold rejects.



The key issue is whether the test is effective.

"We have a test that not only works, but works each and every time," Arnold said. All it needs is formal validation, which may take up to two years, and the acceptance of regulators.

Narang and Case Western researchers reported in 2005 that the urine test could reliably detect a harmless form of the prion protein that is blamed for BSE and variant CJD. It could also detect the bad form -- if the prion was first added directly to the urine.

They said their findings "may lay the foundation for a future technique," if in fact the bad prion can turn up naturally in urine.

"It needs a lot of work still," Ayuna Dagdanova, one of the test's researchers at the U.S. prion surveillance centre, said from Cleveland.

Without solid data it's not possible to say if they are close to detecting BSE in urine, she said.

"No one actually knows.

"But preliminary experiments show the possibility."

[email protected]





http://www.canada.com/edmontonjournal/news/story.html?id=80a7bf7e-0a9c-4f10-9f4b-87fc639c1f5c&k=17840



http://www.canada.com/edmontonjournal/news/story.html?id=80a7bf7e-0a9c-4f10-9f4b-87fc639c1f5c&k=17840&p=2



Date: Sun, 9 Mar 2003 11:26:21 -0600
Reply-To: Bovine Spongiform Encephalopathy
Sender: Bovine Spongiform Encephalopathy
From: "Terry S. Singeltary Sr."
Subject: NARANG TO WORK FOR CASE WESTERN UNIVERSITY USA ???


######## Bovine Spongiform Encephalopathy #########


CJD doc jets off


Mar 9 2003


By Phil Doherty, Sunday Sun


The North scientist who first established a link between mad cow disease
and its human form is quitting Britain.


Harash Narang has been head-hunted by a top US university to continue
his research into variant Creutzfeldt-Jakob disease.


He was working for the Government's Public Health Laboratory Service in
Newcastle when he revealed the link and later lost his job.


Dr Narang claimed he was made redundant because he went public with his
findings, an allegation which has always been denied. He said: "I now
have a job at the United States CJD Surveillance Centre based in Case
Western Reserve University, Cleveland, Ohio.


"I'm very excited because it has excellent facilities and is one of the
best CJD surveillance centres in the world.


The university is examining a urine test pioneered by Dr Narang which
can show whether someone has CJD.


Currently only a post-mortem diagnosis can be made.


Dr Narang said: "Early indications show that my test has performed even
better than anticipated. It is expected to be validated very shortly."


And he revealed: "I do not regret telling the truth all those years ago.
If I had to do it again then I would."


Ken Bell, a financial backer of Dr Narang's work, claimed he had been
forced to go abroad because he cannot get laboratory time in the UK.


He said: "Harash has been blackballed in the UK because he told the
public the truth.


"The establishment will try anything to stop him working here. It's a
disgrace."


Noel Baldwin, of the CJD Foundation charity, said: "He has been proved
right about so many things . . . that CJD can be transmitted through
blood, that BSE can cause both variant and sporadic CJD and that you can
test for the disease through urine samples."


Dr Narang starts work at Case University later this month. Shu Chen, one
of his future colleagues, said: "He will be a great asset to our CJD
research."


http://icnewcastle.icnetwork.co.uk/0100news/0100local/page.cfm?objectid=12716797&method=full&siteid=50081


Dr. Narang starts spouting off about sporadic CJD being
tied to beef products, he will not be at Case Western
too long. the first thing i wish he would do is convince
Gambetti et al how important it is to have a CJD Questionnaire
that ask real questions pertaining to route and source,
not the opposite, only asking how agent was diagnosed,
so it can be undiagnosed, that is the first thing Dr. Narang
should do. i will wait to jump for joy about this. Dick
Marsh was blackballed by the CDC and NIH here, it would
not surprise me if Dr. Narang was too if he does not
become yes man like a good many of others...just my 2 cents

worth...TSS


########### http://mailhost.rz.uni-karlsruhe.de/warc/bse-l.html ############
Date: Sun, 9 Mar 2003 23:11:10 +0000
Reply-To: Bovine Spongiform Encephalopathy
Sender: Bovine Spongiform Encephalopathy
From: Steve Dealler
Organization: Netscape Online member
Subject: Re: NARANG TO WORK FOR CASE WESTERN UNIVERSITY USA ???

######## Bovine Spongiform Encephalopathy #########

As far as I know this is correct. Narang is going to be working for Case Western for a while. Apparently they repeated some of his methods and found that they worked concerning diagnostics. Anyway, I cant help feeling that he deserves a lot more backing than he has got so far if only for preventing the big cheeses from wiping out the small guys Steve Dealler

"Terry S. Singeltary Sr." wrote:

snip...

Date: Sun, 30 Mar 2003 14:40:57 -0600
Reply-To: Bovine Spongiform Encephalopathy
Sender: Bovine Spongiform Encephalopathy
From: "Terry S. Singeltary Sr."
Subject: Re: NARANG TO WORK FOR CASE WESTERN UNIVERSITY USA ???


######## Bovine Spongiform Encephalopathy #########


Greetings list members,


i have heard nothing else about Harash Narang at
Case Western. i would be curious to know what
techniques they may be evaluating and for what
species? it seems (through personal communications
with Harash Narang over the years), the he is not
a big fan of the Prion only theory, and believes
the agent to be a virus.


personal communication with Harash Narang Dec. 2000 and Jan. 2001;


[[Having worked with CJD and other related diseases for over 30
years, my view from the start has been, this is an infectious
disease. Host genes play a minor role if any in incubation
period. Do not consider BSE/CJD in isolation, consider other
virus infections, many have different strains. Each strain
of the same virus produces some different symptoms on the
same host, such as Flu. Polio virus strains can have different
effect on host depending on the age of infection. Those who
get themselves infected by accidental inoculation with old
Type I scrapie, some like polio might develop in 20 to 40
years CJD with dementia type symptoms: this would be classical
CJD. Those who eat the Type II scrapie, all (except those
who have eaten Type I scrapie, which unknown have been
vaccinated) will develop CJD with symptoms like ataxia.
This is being called nvCJD. I hope this gives you some more
information.]]


snip...


[[We have to get the message across that prion is not the agent.
It is a virus.]]


so, is this the route case western reserve university et al
are going to take now?


i see nothing on their site about Harash Narang and what he is
doing? i am most curious about this, as i have followed his
work in the past, and i am most confused about this move?


http://www.cjdsurveillance.com/center.html



Lingering doubts about Bovine Spongiform Encephalopathy (BSE)and Creutzfeldt-Jakob

disease (CJD).

Despite the lack of compelling evidence, the origin of BSE was considered to be due to feeding

cattle with meat and bone meal prepared from the waste remains of sheep infected with the type

scrapie. The "cannibalistic" practice of feeding cattle has resulted in the selection of BSE.

To this day officials have not realised or acknowledged that there are more than 20 different

strains of scrapie in sheep. Based upon clinical signs there are two main types: Type I, "itchy",

and Type 11, the ataxic "trembly" type.

Pattison IH and Millson GC - 196 1. Scrapie produced experimentally in goats with special

reference to the clinical syndrome. Journal of Comparative Pathology 71:2 (April). 101- 108.

Pattison IH and Millson GC - 196 1. Experimental transmission of scrapie to goats and sheep by

the oral route. Journal of Comparative Pathology 71 :2 (April) 17 1 - 176

Type I Scrapie

This type ("itchy") causes sheep to lose their wool and is the common type. When cattle are

experimentally inoculated with Type I scrapie some will develop a clinical disease. This disease

is not clinically similar to BSE. However, Spongiform type changes are seen in the brain. On

the other hand, if cattle are fed with scrapie brain no equivalent clinical disease or lesions have

been observed and the animals remain healthy.

Type I1 Scrapie

This type causes sheep to '?remblell. It was a minor but more virulent strain of the scrapie agent

in sheep, producing trembling ataxia. The BSE strain has shorter incubation periods and appears

very efficient in infecting other species by the oral and intracerebral routes. These clinical signs,

trembling and ataxia, are similar in BSE, vCJD, Kuru, and sheep inoculated with brain tissues

from cows. A single infected BSE cow, whether expressing symptoms or not, entering the human

or animal food chain with the ''agent'' could potentially infect a large number of humans or

animals.

Type I1 scrapie is the disease agent which is most likely to have infected cattle and humans, but

MAFF have not undertaken any experiments to determine whether or not Type I1 scrapie is the

real source of BSE. I consider that cattle developed BSE from eating feed containing cattle

remains from cattle, which had been given contaminated Type I1 scrapie feed.

In the UK one breed of sheep (black faced sheep) is resistant to Type I scrapie (Foster et al.

Studies on restricted transmission of scrapie in sheep and BSE in goats using embryo transfer

European Commission Agriculture Transmissible Spongiform Encephalopathies 14- 15

September 1993 p229 and p 23 1). However, if this resistant breed of sheep is injected or fed

with BSE brain tissue it will develop Type I1 scrapie (Narang - Origin and Implications of Bovine

Spongiform Encephalopathy - Proc SOC Expt Biol and Med - 1996 - 211:306 to 322; Narang HK.

Lingering Doubts about Spongiform Encephalopathy and Creutzfeldt-Jakob disease. Proc Soc

7

Exp Biol Med 226:640-652,2001; Narang HK. A Critical Review of Atypical cerebellum type

Creutzfeldt-Jakob disease: Its Relationship to "new variant" CJD and Bovine Spongiform

Encephalopathy. Proc SOC Exp Biol Med 226:629-639,2001; Narang HK. A Critical Review of

the Nature of the Spongiform Encephalopathy Agent: Protein theory versus Virus Theory Proc

SOC Exp Biol Med 227 xxx-xxx Jan, 2002; and Fraser et a1 - Transmission to mice, sheep and

goats and Bioassay of Bovine Tissues - European Commission Agriculture Transmissible

Spongiform Encephalopathies 14- 1 5 September 1993 p 145 and p 15 5).

Thus, allelic complexity in the sheep PrP gene which was considered to control the susceptibility

and incubation periods and was used as one of the strongest points in evidence for support of the

protein-only hypothesis group, also failed to identify any genotype resistance to the BSE agent. It

appears that the strain differences of the agent have an upper hand in controlling susceptibility

and the incubation period rather than the PrP gene.

Following the meat and bone-meal ban in relation to cattle in July 1988 sheep have been

extensively fed with BSE-contaminated meat and bone-meal. This has caused Type I1 scrapie in

sheep, including sheep breeds, which were resistant to Type I scrapie (see Fraser et a1 above).

Type I1 scrapie is therefore changing from being a minor strain to a major strain. In 1995 I spoke

to a farmer who had lost all of his sheep from Type I1 scrapie about a year earlier. He had fed his

sheep with meat and bone-meal. MAFF have been aware of the fact that BSE transmits to all

breeds of sheep since at least 1993 (see Transmissible Spongifonn Encephalopathies - European

Commission Agriculture Brussels 14-15 September 1993 p. 155).

Nature of the BSE/CJD agent

Several hypotheses seriously addressed the possibility that the replicating agent was a piece of

cell membrane, a complex glycolipid or protein. Depending upon which hypothesis an author

favors, references are selected to support a chosen hypothesis and completely ignore references,

which do not fit a particular way of thinking. This group of slow viruses "stand-out" as being

entirely different from all other known viruses, and the apparent lack of specific antigenicity

make it an unconventional replicating agent. This again is not unique to the BSE/CJD agent,

AIDS virus neither produces an inflammatory response nor the antibody can neutralize the virus.

All the direct evidence demonstrates that the BSE/CJD agent is a virus for details see Narang

HK. A Critical Review of the Nature of the Spongiform Encephalopathy Agent: Protein theory

versus Virus Theory Proc SOC Exp Biol Med 227 xxx-xxx Jan, 2002.

In primary transmission fi-om one species to another, the BSE/CJD agent affects most of the new

host species animals inoculated. However, in some cases the clinical disease develops only after

a prolonged incubation period. This species barrier may disappear on one further passage in the

new host, and the incubation period is usually shortened.

Identification of PrPSC in the brain and other tissues or body fluids is often taken as a definitive

marker of the disease. Lasmezas et a1 (Transmission of the BSE agent to mice in the absence of

detectable abnormal prion protein. Science 275402-405, 1997) study has further implications

particularly in relation to transmission studies from one species to another. Fraser et a1

(Transmission to mice, sheep and goats and bioassay of bovine tissues. In: Bradley R and B

8

Marchant, Eds. EEC Meeting 1993. Brussels, Proc Consultation BSE Scientific Vet Committee

Commission European Communities pp145-159, 1994) used RI11 mice to bioassay non-neuronal

tissues from BSE-affected cattle, although mice died with incubation periods ranging from 222 to

over 86 1 days. As histopathological examination revealed no vacuoles, the authors concluded

that the tissue samples tested did not contain the agent. There is no hisopathological details given

and how many brains from each group were examined. Samples of tissues included lymph node,

semen and fat (Table 1). It is obvious from the data given in Table 1 for each type of tissue

sample that the pattern in the incubation periods observed for the different tissue samples tested

strongly suggests transmission with the BSE agent. Lasmkzas et a1 (1998) were to use Fraser et a1

(1 994) criteria, where negative pathology and PrPSC- pattern was observed, 55% of mice could

have been classified as negative transmission with the BSE agent. It is more than possible that

negative pathology and PrPsc- pattern is the likely outcome when transmitting the disease from

non-neuronal tissues and, therefore, would be misdiagnosed. It is also well-established fact that

in some hosts infected with a low dose of the BSE agent, both clinical disease and vacuoles may

not appear in the life span of the host. The disease remains subclinical. Under these

circumstances, it is common practice to make a second and third pass with negative brains.

However, it appears that no attempt was made by Fraser et a1 (1994) to inoculate a second series

of mice with brains of mice. This revealed no spongiform changes, which would have

conclusively demonstrated presence or absence of the agent in the non-neuronal tissues. It is

quite possible that the PrPSC negative pattern property is unique in transmission of the BSE

agent.

Someone should ask a serious question: Why Fraser et a1 (1994) did not follow the golden rule of

second passage?

Urine test

(1)

(2)

(3)

Tubulofilamentous particles/scrapie-associated fibrils (SAF) are ultrastructural

markers, whilst protease-resistant protein (PrP) is a protein marker.

Post-translational modifications of PrPC into PrPSC starts soon after the animals

are infected.

The PrPC found in normal and infected host tissue differs from PrPSC in its

physical properties and its susceptibility to PK.

To test for BSE and CJD involves demonstration of PrPSC in the urine specimen.

Patent application NO GB98/00374 and 9601045.8 I purposed this test for many

years. MAFF and Department of Health for one or other reason never supported my

work. However, now in 2001 Dr M Gideon et al, from Israel have confirmed my

findings of PrPSC in urine samples, both in BSE cattle, humans and other animals

infected with scrapie.

9

Vaccine

There are some 20 different strains of the scrapie agents. Infection with one strain blocks the

others. On the other hand, since we know that infection with one strain of scrapie blocks

other strains (Bruce & Dickinson 1987. J Gen Vird 68,78439).

Comparative mink experiments using scrapie and BSE strains demonstrated that mink fed

with scrapie brains did not develop the clinical disease and only between 10% and 15% of

those injected developed the clinical disease. However, all mink fed or injected with BSE

brain tissues developed the clinical disease. Similar results appear to have been coming out of

cattle experiments.

For a number of years, the phenomenon of interference between the two strains of the agent

has been known. Based on this phenomenon, I proposed that the Type I strain of scrapie acts

as vaccine against BSE, Type I1 scrapie. Many people have eaten Type I strain unknown to

them and, therefore, will have a natural protection. In summer 2000, at Birmingham, Dr. S.

Prusiner stated that his colleague, Dr. Mike Scott, believed that sheep carry two strains of the

agent: scrapie strain and the BSE strain. The agent has always been in sheep and probably

always will be. Now Dr Stanley Prusiner has openly admitted the phenomena of interference

between the two strains of the agent. He believes that the scrapie strain is somewhat

dominant, preventing the BSE strain from infecting cattle and people when both are present.

In other words, the scrapie strain acts as a vaccine against the BSE strain.

I therefore consider that it is important to feed and inject with BSE brain tissue mink which

have been fed on scrapie brains to demonstrate that the scrapie strain would block the up take

of the BSE agent. This could be used in cattle to produce a vaccine and protect environmental

infection of cattle. If this phenomenon is true for humans, many of us will have eaten scrapieinfected

tissues and will therefore be naturally protected from BSE, which would be a great

comfort to know.

The phenomena of interference will only be effective if the agent causing the disease is a

virus. Therefore it must be a virus.



http://www.royalsoc.ac.uk/inquiry/index/288.pdf



TSS
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