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From: TSS (
Date: August 11, 2004 at 7:37 am PST

-------- Original Message --------
Date: Wed, 11 Aug 2004 09:40:11 -0500
From: "Terry S. Singeltary Sr."
To: Bovine Spongiform Encephalopathy

American nightmare

New Scientist vol 183 issue 2459 - 07 August 2004, page 32

The US has so far found only one mad cow, but experts say there's no
such thing as an isolated case. So where are the rest and will they ever
be found, asks Debora MacKenzie

AT VERN'S Slaughterhouse in Moses Lake, Washington, Tuesday 9 December
2003 was a busy day. "We were swamped," recalls slaughterman Dave
Louthan - especially with "downers", sickly cows too weak to stand.

Amid the rush, one cow caught Louthan's attention - a white, 6-year-old
Holstein standing in a truck at the downers' entrance. She was causing
trouble, and Louthan admits he should have taken her round to the pens
where cattle that could walk awaited slaughter. "But I was in a hurry,"
he says, "and she didn't want to step down off the trailer." Before she
could trample the other cattle, "I put a hole in her forehead".

At that time the US Department of Agriculture was paying slaughterhouses
for brain samples from downers, to test for BSE. The Holstein was
officially among the downers, so Louthan took a sample. Two weeks later,
the USDA announced that the cow was the first case of BSE detected in
the US.

This was the moment that USDA officials had hoped - perhaps even
believed - would never come. Despite years of warnings from the European
Union that the US herd was probably infected, they had always maintained
that the country was BSE-free - even after Canada declared its first
home-grown case in May 2003.

It was devastating news. Overnight, beef exports plummeted, at a
predicted cost to the industry of $2 billion for 2004 alone. The USDA
immediately implemented measures to protect consumers, most importantly
by banning human consumption of brain, spinal cord and intestines from
any cow over 30 months - also known as specified risk material (SRM)
because it is known to carry the highest risk of infection. It also
appointed an international panel of scientists to assess its measures
and advise it what to do next, based on Europe's hard-won experience of BSE.

In February the panel reported back. It praised many of the actions the
USDA had already taken - in particular for facing up to the fact that
BSE had arrived in the US. The infected cow had been born in Canada, so
it would have been possible to claim that the US was still BSE free,
though the lack of any real separation between the two countries' herds
would have made this little more than a technicality. But the report
also found shortcomings, many of which have yet to be rectified. And so,
as millions of North Americans barbecue beef this summer, the disease
may still be spreading among cattle, people are still at risk, and no
one knows how many mad cows there are.

It was back in 2000 that scientists working for the European Commission
predicted that the US herd might have BSE (New Scientist, 10 June 2000,
page 4)
Their reasoning was based largely on two facts: first, prior to 1996,
the US imported British cattle, some of which were certainly infected.
Secondly, it also imported 44 tonnes of British meat and bonemeal (MBM)
feed made from infected cattle, before the UK stopped selling it in
1996. It doesn't take much infected MBM to get an epidemic going: only
20 tonnes of British MBM sparked Switzerland's sizeable epidemic. What's
more, after 1996, the US imported more than 800 cattle from other
European countries that subsequently discovered they had BSE.

In 1997, under pressure from trading partners and worried scientists,
the US banned cattle feed containing material from the carcasses of
other cattle. But as late as 2002, the US Congress's General Accounting
Office found that, just as in the UK in the early days of BSE, the ban
was not being properly enforced.

Easy to miss

Officials continued to point to the lack of any reported instance of BSE
in the US herd, though experience from mainland Europe should have
warned them how easy it is to miss the disease if you rely on finding
sick animals. Calculations by epidemiologist Virginie Supervie of the
University of Paris VI have shown that between 1991 and 1997 there must
have been at least 1725 clinically obvious mad cows in France, and
possibly thousands more, New Scientist has learned. Yet only some two
dozen cases were reported over that period, and Supervie calculates that
another 350 went unreported between 1997 and 2001, despite intense
publicity about BSE. Mainland Europe only really discovered how much BSE
it had when it started testing large numbers of cattle brains in abattoirs.

Some USDA scientists fought for years for such testing in the US, if
only to confirm the country's BSE-free status. The response was
grudging: the US tested 5000 cows in 2002, and 20,000 last year. One of
them was the Holstein that showed up at Vern's in December.

In February, the international scientific panel warned that this level
of testing was not nearly enough to assess the scale of the problem. It
is widely believed that cattle are usually infected in their first year
of life, so the Holstein is likely to have been infected about six years
ago - possibly from feed made in the US or Canada from native-born
cattle. The mantra of all the BSE experts New Scientist has contacted is
that "there is no such thing as an isolated case", so it seems likely
that BSE has been circulating in North America for several years. The
infected cow was the tip of an iceberg whose size can only be guessed.

In line with the international panel's recommendation, the USDA is
cranking up its testing programme. The plan is that between June this
year and the end of 2005, between 200,000 and 300,000 "high-risk" cattle
- downers, animals found dead, or animals with symptoms that look like
BSE - will be tested. The USDA claims this will be enough to detect an
incidence of BSE as low as 1 in 10 million - that's just 10 infected
cows in the entire national herd - though experts expect to find a
higher rate. By way of comparison, France, which became infected in the
same way, had a rate of 2 infected animals per 10,000 in 2003.

The testing regime will involve two kinds of test. Initial "quick" tests
will be carried out at a network of 12 laboratories across the country,
and any positives will then be sent for confirmation at the National
Veterinary Services Laboratories in Ames, Iowa. The samples will be
taken only "from establishments that have voluntarily consented to
sampling", as the USDA plan puts it. These will be mainly renderers and
the farms themselves. More than 11,000 brains were tested during June,
the first month of the programme. As New Scientist went to press none
had been confirmed positive.

But there are a number of questions hanging over the scheme. The plan
will only work if the USDA can find enough "high-risk" cattle to test.
Since December, downers have not been allowed into the human food
supply, which means they are no longer being brought to abattoirs where
they might have been tested. The USDA is now asking farmers to volunteer
their downers for testing, but there is a flaw in this approach. If BSE
is found in a downer, the farmer's entire herd will be destroyed. So if
any cow looks suspicious, there is bound to be a temptation to "shoot,
shovel and shut up", US veterinary experts have privately told New
Scientist. "Several big [beef] producers have told me they won't let the
USDA anywhere near their downers," one said.

In Europe, farmers did exactly the same. Switzerland tried to get round
the problem by randomly testing cattle in abattoirs, to deter farmers
from trying to pass off suspect animals as healthy. The USDA is doing
that too. But with only 20,000 of the 35 million animals slaughtered
each year scheduled for a random test, and only 40 abattoirs enlisted,
the deterrence value is uncertain - especially, as those abattoirs have
been named, making it easy for farmers to avoid them.

Testing times

Mo Salman, an epidemiologist at Colorado State University at Fort
Collins, says he is impressed with the number of high-risk cows the
agencies has managed to test so far. But he adds: "I am sceptical about
their ability to obtain all the needed cattle within 18 months." Salman
says the USDA has "given the green light" to his request to monitor the
quality of the surveillance programme as it develops.

Some other aspects of the testing programme are causing concern,
however. For the initial "quick" test, two main types of test are
available: one is based on a technique called ELISA and the other on the
so-called "western blot". ELISA-based BSE tests are known to be prone to
"false positives". Western blots tend not to give false positives.

Last year, in a submission to the Paris-based World Organisation for
Animal Health (OIE) on international testing standards, USDA officials
recommended that countries with low levels of BSE should use the western
blot, so as to avoid a string of false positives that might alarm
consumers. And yet it has gone against its own advice. Five fast BSE
tests were quickly licensed in the US after the infected cow was found
in December, including a western blot made by the Swiss firm Prionics.
But all the USDA's surveillance labs are using an ELISA test made by
California's BioRad. Predictably, by early July two false positives had
been announced, sending beef futures markets reeling.

The USDA has justified its choice by saying that the other tests need
field trials. Yet the Prionics western blot, to take one example, has
been used 20 million times in Europe. Some observers say BioRad's test
was chosen simply because its salesmen were better. Another theory is
that the USDA's choice of test, and its willingness to announce
unconfirmed positive results that later prove false, is aimed at
desensitising beef markets and consumers to such announcements before
real positives start emerging.

Compounding the uncertainty is the fact that all definitive results will
be decided by one lab, Ames. There are no plans to send any samples to
independent reference labs to double-check Ames's decisions, even though
the test it uses is notorious for being a somewhat subjective.

Despite its flaws, surveillance is the aspect of the US response that
has won the highest marks from observers with experience of the European
outbreak. They are less satisfied with the other two components of the
US response: stopping the spread of the infection to cattle, and
protecting people.

Beyond the 1997 ban on feeding ruminant remains to other ruminants, the
US has taken no further measures to stop the spread of BSE among cattle.
Europe has learned the hard way that simple ruminant-to-ruminant bans
don't work, and in February the international panel insisted that more
was needed in the US too. Unless you close off every possible avenue to
infection, BSE continues to circulate.

One such avenue is putting cattle MBM into pig and poultry feed.
Cross-contamination in feed mills or accidental feeding to cattle will
guarantee that some cattle eat MBM. What's more, the remains of pigs and
chickens that eat cattle - including their gut contents - can legally go
into cattle feed, as can poultry litter, which contains poultry feed.

The problem is aggravated by the fact that, since December, downers and
SRM have been banned from human food. That may be a good move from the
point of view of the direct risks to human health, but it also means
that all this potentially infected material is going into pig feed,
poultry feed and pet food. And while it is illegal to feed reject
batches of pet food to cattle, it happens, US veterinary experts have
told New Scientist.

The Food and Drug Administration was due to impose new rules last month
banning cattle blood from cattle feed, which is still legal, and banning
cattle SRM being put in pig and chicken feed, thereby removing most
infection from the feed system. It also planned to ban downers in all
feed, and poultry litter in cattle feed. But the rules were postponed
pending "wider consultation".

Even the existing ban will the slow spread of the infection
considerably, says Stuart MacDiarmid of New Zealand's agriculture
ministry, a member of the international panel. But more should still be
done, he says. "They can't really claim that they have an absolute
barrier as long as SRM are still permitted to go into rations for

As for measures to protect people, banning human consumption of SRM
should prevent virtually all transmission of BSE to humans, says Danny
Matthews of the UK's Veterinary Services Laboratories in Weybridge,
Surrey, another panel member. But some scope for infection remains. Meat
removed by advanced meat recovery systems, in which carcasses are ground
and forced through a filter, is commonly contaminated with spinal cord.
Such meat can still be put in beef stock or flavouring, says Peter Lurie
of the Washington-based consumer advocacy group Public Citizen. These
ingredients then find their way into all sorts of product, from soups to

Lurie also points to the potential risk from brains and spinal cords
from cattle younger than 30 months, which can still be eaten even though
there is evidence that infection can surface in these tissues earlier.
Such material is often found in burgers, hot dogs and the like.

Possibly a worse risk is that, as in the UK, the seriousness of the
situation has not yet been brought home to the slaughterers who remove
the SRM. Even after years of restrictions in Europe, with inspections
and penalties - and the knowledge that people have died - spinal cord
still turns up in carcasses. In the US there is as yet no independent
inspection to confirm that SRM is being removed.

Despite these potential hazards, American consumers seem blithely
unconcerned, and sales of beef have been virtually unaffected.

Final comfort, of course, can be had from the fact that it now seems
very hard for a human to catch the disease. In the UK, where millions of
people were exposed to BSE through infected meat, there have so far only
been 142 confirmed cases of variant CJD, the human form of the disease.

But the US still needs to be on its toes. As Europe learned to its cost,
BSE punishes complacency.



It's a mad cow world

It started out as a British disease, but the UK exported it and then its
trading partners spread it even further afield. Now no country can be
sure it has kept BSE out. Mad cows have gone global.

To date, 24 countries have declared cases of BSE (see Map)
and it seems almost certain that many more are affected. BSE spreads
when infected cattle are rendered into meat and bone meal (MBM), and fed
to other cows. In 1991, at the height of its mad cow epidemic, the UK
exported more than 25,000 tonnes of MBM. The stuff it sent to Europe did
not contain brains, spinal cords or intestines (so-called "specified
risk materials", which carry the most infection), but the MBM it sent
outside Europe did. That year alone Thailand bought 6240 tonnes. Other
big buyers were Taiwan, Singapore and Indonesia. They sold some of it on
to other countries, probably including China.

After the UK stopped exporting MBM in 1996, other European countries
took over the market, insisting they had no BSE - until 2000, when BSE
exploded across Europe. Then the US, also denying it was at risk, took
over Europe's markets. Last December the US found its first mad cow.

The upshot is that BSE could be incubating in cattle almost anywhere.
"No country can be sure it has kept it out," says Danny Matthews of the
UK's Veterinary Laboratories Agency in Weybridge, Surrey. "It takes only
a gram of material to infect a cow."

The problem is that there is little incentive to search for or report
cases of BSE - quite the contrary, in fact. "The minute a country
declared it had BSE, the US would refuse to buy its beef, and so would
everyone else," says Marcus Doherr of the University of Bern in
Switzerland, who helped develop the European Union's BSE risk
assessment. "When the US found BSE, it got the same treatment." Faced
with this penalty, is a country like China, which exported $55 million
worth of meat from cattle in 2002, likely to find or announce its first
mad cow? Not likely, BSE experts privately admit. Most of the countries
with declared cases resisted admitting they were infected until they had
no choice.

However, the World Organisation for Animal Health (OIE) in Paris is
trying to bring in rules that encourage countries to admit having BSE by
allowing them to continue exporting beef as long as they take the
appropriate safety precautions that stop it spreading. Up to now these
rules have been stymied by US refusals to import beef from countries
with BSE. Now the US has BSE that may change.

In the meantime, there is a prudent method to estimate whether a country
has BSE. Pioneered by the European Commission, this approach assigns
risk based on an analysis of a country's cattle industry, whether it
imported infected material, and how likely it was to re-circulate the
infection. The technique's track record is impressive. In 2000, it found
a high likelihood of BSE in eight supposedly uninfected European
countries, all of which found cases of BSE shortly afterwards. It was
"unable to exclude" the disease from a dozen countries, of which five,
including the US and Canada, have since found BSE.

The commission now believes that BSE is "highly likely" in eight
countries that have not reported a case, and cannot be excluded from
seven others. Unfortunately, many countries where BSE infection is a
possibility have not asked to be assessed.

A glossary of BSE

BSE: Bovine spongiform encephalopathy, the technical name for mad cow

Downer: a cow too sickly to stand.

MBM: Meat and bonemeal. A type of cattle feed made by rendering down the
carcasses of dead cows. Known to have played a key role in spreading the

SRM: Specified risk material. The cow organs known to carry the highest
risk of BSE infection.

Includes brain, spinal cord and intestine.

vCJD: Variant Creutzfeldt-Jakob Disease. The human form of BSE. Can be
contracted by eating infected beef.

Debora MacKenzie

Out of sight, out of mind?

New Scientist vol 183 issue 2459 - 07 August 2004, page 37

No one has ever contracted the human form of mad cow disease in the US.
But does that mean there's nothing to worry about? Andy Coghlan

CHANCES are you've never heard of the Garden State Racetrack in Cherry
Hill, New Jersey, still less actually been there. But for the punters
who frequented the track until it closed in 2001, the name looms large -
especially if they ever ate there. Because according to a local
campaigner, beef served at the racetrack's restaurant is the source of a
cluster of the human form of mad cow disease.

It's a bold claim, and the official response has been scathing: no one
in the US has ever been formally diagnosed with variant CJD, the human
form of BSE. But back in December the US declared its first case of BSE
in cattle, and it now looks as though the disease has been circulating
in the national herd for several years. That means it is possible that
humans have been exposed to infected meat, which is how people are
thought to catch vCJD.

Of course, these facts don't add up to the conclusion that the Garden
State cluster is real. In fact, the best available evidence suggests
racegoers have little cause for alarm. But the "cluster" raises a wider
question: if Americans did start catching vCJD from infected beef, would
it be detected? Perhaps not. Critics say US surveillance systems for the
disease are inadequate - in many states doctors are not obliged to
report suspected cases. And even when they do, those caused by infected
beef could easily go unrecognised. The chilling conclusion is that the
US could already be incubating a human epidemic of BSE without knowing it.

Mad cow disease, caused by "rogue" prion proteins accumulating in the
brain, emerged in the UK in 1986. It stemmed from feeding cattle the
remains of other cattle, allowing each sick cow to infect numerous
others. In the late 1980s the UK banned this practice and took other
measures to eliminate BSE.

It was too late to stop the disease jumping to humans. In 1996 the
national surveillance centre found a new form of Creutzfeldt-Jakob
Disease. This disease had been known for a long time, occurring at a
rate of about one case per million individuals a year. The commonest
form, sporadic CJD, affects only the elderly, and probably results from
chance mutations. Post-mortems reveal characteristic clumps of protein
in the brain.

But the new form was a different proposition: it affected young people
and produced distinct protein clumps. It is now generally accepted that
this vCJD is a result of eating BSE-infected beef. So far there have
been 142 confirmed cases in the UK.

Since 1997 the National Prion Disease Pathology Surveillance Center at
Case Western Reserve University in Cleveland, Ohio, has been on the
look-out for vCJD in the US. The centre has had 1277 suspected cases of
CJD referred to it, of which 792 were confirmed as CJD. Only one was
vCJD: a woman who had been brought up in the UK, and is assumed to have
caught the disease there. She died in June.

But the centre can only investigate the cases it knows about. In most
European countries and Canada, CJD is a notifiable disease, which means
doctors are legally obliged to report all cases. In the US only 25
states have a notification policy, so cases in other states could slip
through the net. The surveillance centre has sent out 60,000 letters
nationwide to physicians, neurologists, pathologists and anyone else who
might help, asking them to report suspected CJD cases. "We made a
tremendous effort to increase awareness," says Pierluigi Gambetti, the
centre's director.

The measures have helped. In 2003 there were 284 referrals, compared
with just 94 in 1998. But even now only about 60 per cent of cases where
CJD is listed on the death certificate as a possible cause are referred
to the centre. And some doctors may not even realise CJD is a possible
cause of death.

These concerns that vCJD could, in theory, be overlooked lend at least
some plausibility to the Garden State racetrack claims. Janet Skarbek,
an accountant from New Jersey with no scientific training, took it upon
herself to investigate after a close friend, aged 29, died from a
degenerative brain disease four years ago. Skarbek traced 15 other
individuals who had met a similar fate. The common thread was that they
had all been to the racetrack and eaten at the restaurant between 1988
and 1992. And their deaths had hallmarks of CJD.

After sustained lobbying by Skarbek, the New Jersey Department of Health
and Senior Services and the Centres for Disease Control and Prevention
(CDC) in Atlanta, Georgia, carried out an investigation, which included
autopsies and analysis of stored brain samples from at least half the
cases. In May they announced their findings. Three of the 16 people who
had died, including Skarbek's friend, had not had CJD. Eleven did have
CJD, but the sporadic form. This is no more than would be expected among
the number of people attending the race track over that time. The other
two cases, as well as one possible additional case, are still under

Unfounded fears

"The cases are spread out over 12 years, and that's not a cluster," says
Larry Schonberger, the CDC's coordinator of CJD surveillance. "People
who've been to that racecourse are now unnecessarily fearful about their

But these results cannot rule out a link with BSE. In February,
Salvatore Monaco and his colleagues at the University of Verona in Italy
discovered a new form of BSE in cows that produces brain disease
patterns very similar to those of sporadic CJD (Proceedings of the
National Academy of Sciences, vol 101, p 3065). And in the UK,
researchers led by John Collinge at the Medical Research Council's Prion
Unit in London have carried out studies in mice that are also worrying.
They showed that mice injected with prions that usually cause vCJD can
develop brain abnormalities typical of sporadic CJD (The EMBO Journal,
vol 21, p 6348). Collinge told New Scientist that his more recent
research, still unpublished, suggests it is the strain of the mouse that
determines which disease appears. "The implication is that some people
exposed to BSE might get disease with pathology which we recognise as
sporadic CJD," he says. He warns, however, against jumping to
conclusions. "You must be cautious extrapolating from animal models."

The number of sporadic CJD cases in the UK has risen since surveillance
began, from 28 in 1990, to 50 in 2000. Some of that is no doubt due to
better reporting systems. "The question is whether there's a minority of
cases which have another cause," Collinge says. His team is now trying
to develop molecular probes capable of identifying a subtype of
"sporadic" CJD that may in fact be human BSE.

Perhaps unsurprisingly, Skarbek has jumped on these findings. She has
asked Collinge to analyse some of the brain samples, and is lobbying the
CDC to carry out a full epidemiological investigation that would delve
into the life histories and eating habits of the racetrack goers. The
CDC, however, has no plans to comply and denies any suggestion of a
cover-up. "There's no conspiracy," Gambetti says. "On the contrary,
we're always on the watch for something unusual. If there are cases out
there, we want to detect them."

Andy Coghlan

Human BSE - why is a cure so elusive?

New Scientist vol 183 issue 2459 - 07 August 2004, page 12

EIGHTEEN years after BSE first emerged in the UK, we still have little
idea how to treat people who have contracted the human version, variant
Creutzfeldt-Jakob Disease (vCJD).

An investigation by New Scientist has revealed that the relatives of
people with vCJD are frustrated by the slow progress being made to find
new treatments. Time and effort are being wasted researching drugs that
simply don't work, they say, while other, radical, treatments are not
being made readily available.

But while researchers privately disagree over which approaches show most
promise, they say there is now a united effort to find a drug best able
to save lives.

Later this month, the UK government's Medical Research Council will
officially launch a trial of potential treatments, after four years of
argument over which to test. Called the "PRION-1" trial it will focus on
quinacrine, an anti-malarial drug that showed early promise in treating
various forms of CJD. The National Prion Disease Clinic at St Mary's
Hospital in London has already given the drug to around 20 patients, but
the results are not yet in.

Quinacrine first came to prominence in 2001, when Nobel prizewinner
Stanley Prusiner of the University of California at San Francisco used
it to treat Rachel Forber, a Briton who contracted vCJD. Forber's
condition initially improved, but she died, apparently from liver
complications triggered by the drug. Prusiner's team is now trying to
improve quinacrine's efficacy while limiting its side effects. The
researchers say that by fusing two quinacrine molecules together they
have made the drug 10 times more effective in laboratory tests.

But others think quinacrine is unreliable. Markus Otto leads a team at
the University of Göttingen in Germany that has been investigating
treatments for CJD since 1996, when the variant form of the disease was
discovered. He says that patients given quinacrine develop yellow skin,
vomit and have dangerously high levels of toxic liver enzymes. "With
quinacrine, we only saw side effects, so we won't use it."

Don Simms, the father of Belfast vCJD patient Jonathan Simms, agrees
that quinacrine has few benefits. "To put quinacrine in a trial is a
waste of public money. In its current form it doesn't work," he says.

Simms would rather see the PRION-1 trial test another drug called
pentosan polysulphate (PPS), which is used to treat infections of the
urinary tract. When infused directly into the brains of CJD patients,
PPS appears to stop abnormal prion proteins from forming clumps and
killing neurons. Jonathan Simms was the first to be given the drug in
January 2003, and is still alive 18 months later, even though at one
point before his treatment began he had been given just hours to live.
"He's not got better, but he has remained stable, and I believe that in
the absence of anything else PPS should be tried," Don Simms told New

At least eight surviving patients have received PPS. Although the law in
England and Wales prevents the media reporting details of individual
cases, New Scientist understands that four of the recipients have vCJD,
one has sporadic CJD (the most common form), and three have an inherited
form of CJD called Gerstmann-Sträussler-Scheinker syndrome.

At least three of the patients have been treated with PPS at the
National CJD Surveillance Unit in Edinburgh. "This is not because we
think intraventricular PPS is a good treatment or should be done," says
Richard Knight, consultant neurologist at the unit. "But we recognise
that some individuals insist on this treatment, and if they want it, we
think it's unreasonable not to offer it."

He backs the position of the UK government's Committee on Safety of
Medicines, which says that PPS may halt or delay the progress of CJD,
but should not be given to patients in the latter stages of the disease
as it prolongs life without improving health.

Don Simms agrees that his son has shown little signs of genuine
recovery, but says that he has improved in some ways. "Jonathan's
suffered no adverse side effects, his blood pressure and his pulse are
back to normal, and he's able now to clear his own airway and swallow
his own saliva. I don't think it's a cure, but it has slowed down or
stopped the disease."

But Simms says that, despite the drug's early promise, it is not readily
available. In England and Wales, for instance, relatives of CJD patients
who can't decide for themselves must ask the courts to sanction the
treatment. Otto says he would like to prescribe PPS to people with CJD
and has found a neurosurgeon willing to administer it. But ethical
review boards and insurers have reservations over the treatment and have
not yet given it the go-ahead.

An MRC spokeswoman says that the PRION-1 trial will monitor patients
given PPS, although it will not officially test the drug. And the trial
has been designed so that new treatments can be evaluated as and when
they emerge.

One of those could be flupirtine, a painkiller being investigated by
Otto's team. In a clinical trial it appeared to slow the decline in
mental sharpness in CJD patients compared with those given a placebo.
But, like PPS, it could not reverse the disease or stop it progressing.
As a result, Otto's team is treating patients who are still only mildly
affected by the disease.

Andy Coghlan

When proteins attack

New Scientist vol 183 issue 2459 - 07 August 2004, page 39

Humans are supposed to be protected from animal diseases by something
called the species barrier. So what went wrong with BSE? Philip Cohen

THE BSE epidemic in the UK was an unmitigated disaster. It devastated
the beef industry, destroyed peoples' livelihoods, unleashed a terrible
disease upon the population and cost billions of pounds of public money.

But to a small group of biochemists there was a silver lining. BSE and
its human equivalent, vCJD, belong to an obscure group of diseases
called prion diseases, transmitted through an implausible mechanism
involving shape-shifting proteins that formed clumps in the brain.
Without BSE, prion science would probably have remained a backwater.
Once the disease struck, however, it went mainstream.

Now, as the US ramps up its BSE testing programme and the threat of a
global epidemic becomes ever more real (see "American nightmare")
prion science has come of age. At the time of the UK outbreak there were
multiple unknowns and controversies - not least over the very nature of
prions themselves. Today, new insights are settling these questions and
could accelerate efforts to grapple with the big challenges, such as how
to prevent transmission to humans and, perhaps most importantly,
discover how to prevent a similar disaster from ever happening again.

It was 22 years ago that Stanley Prusiner of the University of
California at San Francisco presented the world with an unlikely and
controversial proposition. Prusiner's "prions" were pure proteins -
devoid of DNA, RNA or genes - that were supposedly able to transmit
infectious brain disease such as BSE. It was a highly unorthodox idea
and, not surprisingly, took a while to catch on: even Prusiner's 1997
Nobel prize for the discovery didn't quite silence the sceptics.

This year, though, prion biologists got their proof, showing shown that
a single protein can exhibit all of the prions' mysterious abilities.
For all but a few die-hard sceptics, this has established once and for
all the existence of protein-only infectious agents.

As a result, the stage is set for scientists to tackle the next big
question of prion biology: how can the same infectious protein exist as
several different "strains", each causing a different disease? This is
more than an academic question. It holds the key to explaining why some
prions spread from one species to another - as BSE does from cattle to
humans - while others apparently do not. It will also tell us how great
a risk humans face from emerging prion diseases, such as chronic wasting
disease in elk and deer.

Even to prion proponents the existence of different strains seemed hard
to reconcile with the most popular prion model, in which prions have a
dual personality, a sort of Dr Jekyll and Mr Hyde. Prusiner's hypothesis
concerned the mammalian brain protein PrP - the one involved in BSE, CJD
and scrapie. In its good (Jekyll) form, molecules of the protein sit
innocuously on the surface of brain cells. But when the protein switches
shape to become the Mr Hyde prion form, PrP clumps together and forms
fibres called amyloids, which choke nerve cells to death. What's more,
each Mr Hyde can convert any Jekyll it meets into another Hyde, in a
deadly chain reaction.

Nothing in this model gave any reason to think that the prions could
exist in multiple forms - yet that's exactly what they seemed to do.
Researchers discovered, for instance, that when scrapie prions from
sheep were passed from mouse to mouse, they separated into about 20
different strains, each with a distinct incubation period and pattern of
brain damage. Yeast biologists have found something similar. Yeast prion
strains are designated "weak" or "strong" based on how efficiently they
convert their Jekyll counterparts to the Mr Hyde form.

There seemed no way that a single protein, made of an invariant sequence
of amino acids, could produce such variety. And so sceptics maintained
that prions must contain some sort of concealed genetic material that
encoded instructions for strain behaviour. Prions might play a role in
disease, they said, but only genetic information could display the type
of diversity seen in different strains.

Now prion proponents have the evidence they say should silence the
doubters. Part of the proof comes from studies in yeast by two
independent research teams, Chih-Yen King and Ruben Diaz-Avalos at
Florida State University in Tallahassee and a group led by Jonathan
Weissman at the University of California, San Francisco.

Weissman's group had already shown that they could synthesise prion
forms of the yeast protein Sup35 in a test tube and cause them to form
clumps. And when inserted into yeast cells, the prions converted normal
Sup35 molecules into new prions. This remains the best direct evidence
so far for the protein-only hypothesis (New Scientist, 5 August 2000, p

However, that experiment didn't address the issue of strains. Now the
two groups have shown that Sup35 can also form different strains of
prion. Both groups worked with purified Sup35 made in bacteria to
eliminate the possibility that another molecule could be involved in
strain formation. Previous work showed that changing the temperature at
which the clumps formed led to slightly different properties. On a hunch
that these different forms may also act as different strains, the
researchers purified Sup35 and let it clump at different temperatures.

As hoped, this led to clumps with different properties. Structural
studies revealed subtle differences in how the atoms were arranged in
clumps formed at 4 °C versus 37 °C. Similarly, the clumps showed
different resistance to degradation by heat and enzymes. And crucially,
the different clumps acted as different strains when put back into yeast
cells. Those formed at 37 °C behaved as weak prions generation after
generation, and those born at 4 °C behaved as strong prions. Just as
intriguingly, when later removed from yeast cells, the prions descended
from 4 °C ancestors maintained their physical properties even if they
replicated for generations at higher temperatures (Nature, vol 428, p
319 and p 323).

Here was clinching proof that the same protein could form different
strains of prion. "There is no wiggle room around that fact," says Weissman.

Final proof

"This is the final proof of the protein-only theory," says Mick Tuite of
the University of Kent in Canterbury, UK. "It will take a while for
other people to replicate and verify these experiments. But I think
these will emerge as the most important papers in this field in the last
10 years."

Not everyone agrees. Laura Manuelidis of Yale University, one of the
most outspoken critics of Prusiner's protein-only idea, argues that
experiments in yeast will never address all the issues of human prion
diseases. "These results are very relevant for understanding how
proteins form amyloids," she says. "But they say very little about how
infectious agents cause BSE or vCJD." To silence all doubt, she says,
mammalian biologists need to catch up to their yeast colleagues and
provide better evidence of protein-only mammalian prions.

As New Scientist went to press, Prusiner's team reported significant
progress towards this goal. They made amyloid from PrP produced in
bacteria, then injected these synthetic prions into the brains of mice.
The result: a prion disease that can be passed to other animals
(Science, vol 305, p 673). What is more, prions made in slightly
different ways caused different types of brain damage, suggesting they
behave as different strains. Prion researchers will be scrutinising the
results to determine whether they are final proof of the protein-only

Clearly, a better understanding of strains could have big practical
pay-offs, since they have emerged as an important public health issue.
For example, there are hints that a second form of prion disease has
recently emerged in cattle (see "Out of sight, out of mind")
Presumably this is caused by a different strain of prion, but as yet no
one knows whether it is a threat to human health.

Another big issue is the so-called "species barrier", which apparently
prevents some prion diseases such as scrapie from jumping into humans
but allows others, notably BSE, to do so, albeit at a low rate. The
assumption has always been that there is some fundamental difference
between certain species' prion proteins that stops one from transforming
the other into an infectious form.

But research into strains has shed new light on this question. Fred
Cohen, a long-time collaborator of Prusiner's at UCSF, has found prion
strains that cause disease in mice so slowly the animals usually die
from other causes first. But if you give the strain a whole extra
lifetime in which to develop, by grinding up the brains of infected
animals and injecting them into other mice, the second generation
develops a prion disease. "If you only looked at one generation, you'd
say there must be a powerful species barrier operating here. But the
difference is much more subtle," he says.

In other words there is no absolute species barrier - it's just that
some strains of prion are so slow to act you never see them.
Back-of-the-envelope calculations suggest that even a fairly small
difference in the energy required for a prion strain to transmit its
shape can alter transformation rates 100-fold. This might explain the
incredibly wide range of disease progression rates among prion diseases,
ranging from a few months in a mouse to decades-long incubation in humans.

The implications of this are somewhat worrying. If some strains can jump
the species barrier more readily than others, could we one day face a
new strain of BSE, chronic wasting disease or even scrapie that easily
converts human PrP to prions? For now, there is no evidence that any
such strain has emerged. "However," cautions Byron Caughey, who studies
prions at the Rocky Mountain Laboratories in Hamilton, Montana, "it's
something we should be concerned about and stay vigilant for."

Philip Cohen


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