An experimental therapy has dramatically extended the lives of mice infected with prions, which cause conditions like Creutzfeldtā€“Jakob disease (CJD). The news, announced by Sangamo Therapeutics, boosts hopes of developing treatments for these conditions.

ā€œMice die very rapidly if they are not treated. The average lifespan of the mice that are treated is starting to extend over 500 days, which is kind of the normal lifespan,ā€ says at Sangamo Therapeutics. ā€œItā€™s very effective.ā€

Prion diseases are unusual in that they are caused by a misfolded protein that makes other proteins of the same kind misfold too and join up to form damaging strand-like fibrils in cells. Fragments of fibrils spread the problem to other cells.

This causes serious damage to the brain, with death usually occurring within a year of the first symptoms. ā€œItā€™s a devastating disease,ā€ says Fontenot.

Some forms of CJD are caused by eating contaminated food such as meat from cattle with BSE (bovine spongiform encephalopathy), also known as mad cow disease, or by surgical instruments or blood contaminated by prions. Others are due to mutations that make misfolding more likely. But with most cases of CJD, there is no clear cause ā€“ they may be a result of spontaneous misfolding.

In almost every prion disease, the protein that misfolds is one called PrP. Its normal function isnā€™t clear, but mice and cows engineered so they canā€™t make PrP donā€™t seem to have any serious ill effects and they are immune to prion diseases because there is no PrP in their bodies to misfold.

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So, efforts to develop treatments for CJD are focused on PrP. To do this, researchers at Sangamo Therapeutics created a protein that binds to a specific sequence of DNA near the gene that produces PrP and switches it off, preventing the protein from being made. A gene to make this turn-off-PrP protein can be delivered into brain cells using viruses selected for their ability to target neurons.

To test the treatment, the researchers infected mice with prions. Untreated mice developed symptoms about 120 days later and all died after around 160 days.

But mice lived much longer if they were given a single dose of the virus carrying the gene for the turn-off-PrP protein, with this treatment coming either 60 or 120 days after infection. Ten of these 19 mice were still alive 360 days post-infection, and five survived for 500 days, Sangamo Therapeutics revealed at a in Los Angeles in May.

ā€œThe work is encouraging,ā€ says at the Institute of Prion Diseases at University College London, whose team has developed another potential treatment based on antibodies that target PrP.

Sangamo Therapeutics is now tweaking the turn-off-PrP protein to target the human gene for PrP, and hopes to begin human trials soon, says Fontenot. In people, the viruses carrying the gene for the turn-off-PrP protein may need to be injected into spinal fluid or directly into the brain.

LOCALS were startled last week when thousands of Skittles were found on a road in Wisconsin. But they were even more startled when the fruity sweets turned out to have fallen off a truck .

It matters what we feed our livestock. A small change in UK cattle-feeding practices in the 1980s led to ā€œmad cow diseaseā€, and then to horrendous illness and killed some people who ate affected meat. Now we know that many more people may have been infected than originally thought ā€“ and a new wave of vCJD may be on its way (see ā€œMany more people could still die from mad cow disease in the UKā€œ).

That the number of cases is likely to remain fairly small is dumb luck. But it was not luck that contained the epidemic in the first place, it was strict food safety rules ā€“ which protected beef-eaters worldwide. Between 1980 and 1996, the UK exported animal feed to more than 80 countries, much of it likely to have been infected with BSE. Regulations stopping this, and changing the handling of cattle, eventually stopped the disease spreading among animals.

Now, with Brexit likely to be triggered imminently, those controls ā€“ along with others carefully enacted over decades ā€“ are back up for debate. This is especially notable as the UK looks for new trade agreements with the US, with agriculture first in line for negotiation.

In this new world order, the temptation will be to wave aside rules that safeguard the food chain if they present barriers to striking deals. But such regulations are not just needless bureaucracy, despite political caricatures. The BSE epidemic demonstrates that they offer real protection: they cannot simply be cast off, no matter how vehemently industry claims they stifle sales and profitability.

Whenever regulatory regimes meet, gaps appear through which new risks emerge. We know there are other food-borne illnesses out there. Skittles-fed beef may (or may not) be innocuous in terms of human health. But we need to be sure what else weā€™re eating.

This article appeared in print under the headline ā€œNo beef with bureaucracyā€

Second wave

Unfortunate few

Could microbes be to blame for a host of diseases we thought they had nothing to do with? Researchers have found that bacteria in the blood of healthy people may help trigger strokes and heart attacks, and perhaps also contribute to conditions like Alzheimerā€™s disease, diabetes and arthritis.

All of these disorders involve inflammation ā€“ a general activation of the immune system that normally serves to fight infection, but that can get out of control and cause damage. These conditions are also all linked to overactive blood clotting, excessive levels of iron in the blood, and sheets of abnormally folded proteins.

No one knows why these traits are linked to so many diseases, but finding out could help us stop them. To see if bacteria could be playing a role in all this, at the University of Manchester, UK, and , at the University of Pretoria in South Africa, have been looking at their ability to disrupt clotting.

Blood has always been considered free from microbes, because bacteria donā€™t grow when it is put in a culture dish. But recent DNA sequencing methods reveal that each millilitre of blood in fact contains around 1000 bacterial cells.

These bacteria are usually dormant. But they can be revived when iron becomes available in the blood, and begin secreting lipopolysaccharides (LPS) ā€“ molecules on their cell walls that are recognised by the immune system and stimulate inflammation.

Clotting catalyst

Kell and Pretorius wondered if LPS might also directly affect clotting. Most dormant bacteria in our blood comes from our gut. They mixed LPS from the common gut bacteria Escherichia coli with fibrinogen, a small protein in the blood that normally forms the fibrin scaffolds of clots. The LPS changed the fibrinogen, encouraging it to form abnormal clots that look a lot like those involved in heart attacks, strokes and deep vein thrombosis.

ā€œIn all inflammatory conditions we have noted a matted, denser fibrin structure, without the typical ā€˜spaghetti structureā€™ found in healthy individuals,ā€ says Pretorius. Just one molecule of LPS in a mixture of a hundred million fibrinogen molecules was enough to encourage the formation of these misformed clots.

This means LPS must act as a catalyst, says Kell. They think LPS bends fibrinogen out of shape, and this shape-change spreads from protein to protein in a similar way to the deformation associated with prion proteins that cause BSE.

And since LPS triggers inflammation, it increases levels of fibrinogen in the blood, further raising the risk of the aberrant disease-linked clots. Because of their weird structure, these clots are also resistant to being broken down by blood enzymes. Together, these effects could be raising the risk of aberrant clotting, leading to heart attacks and strokes.

Fighting inflammation

Overactive clotting is also a feature of inflammatory conditions like rheumatoid arthritis and Alzheimerā€™s. These conditions involve excess levels of iron. The body normally keeps levels of free iron in the blood low to keep bacteria dormant and block their growth.

ā€œWe think bugs are involved in all these diseases,ā€ says Kell. Their observation that LPS causes fibrin to form mats, and the fact that LPS also binds to many other proteins, could implicate it in forming the amyloid mats seen in other inflammatory diseases, such as those in in the brains of people with Alzheimerā€™s and Parkinsonā€™s disease. Earlier this year, other researchers found that injecting bacteria into the brains of mice prompted them to form amyloid plaques overnight.

What does this all mean for these diseases? Further research could open up several new approaches for tackling them, from removing dormant microbes from our blood, to blocking the inflammatory proteins that they shed.

(Image: Picnic at Glyndebourne by Tony Ray-Jones, 1967. National Media Museum/Science & Society Picture Library/courtesy Arts Council Collection, Southbank Centre. Part of Roger Hiornsā€™s curated section)

History is Now: 7 Artists Take on Britain is at the Hayward Gallery, London, from 10 February to 26 April 2015

ā€œYes, of course, I ate loads of burgers,ā€ laughs Roger Hiorns.

Hiorns is one of seven contemporary British artists to curate and Hiornsā€™s own contribution reprises one of the darkest sagas in the history of world agriculture, the rise and fall of mad cow disease or BSE.

The Hayward Gallery asked each of the seven to chart the evolution of specific strands of the UKā€™s social history since the war. Timed to coincide with the run-up to the general election in May, topics picked by the other six artists for the exhibition include controversial themes such as the development and influence of cinema, the impact of protest since the war, and the growth of consumerism as a measure of wellbeing.

Hiornsā€™s project is the one that most firmly embraces science. And at a time between 1980 and 2000 when eating beef was considered a highly risky business in the UK, his dietary admission adds a personal touch to his artistic contribution.

There he reveals meticulously and engagingly, the rise and fall of BSE. For me, it was like zooming back in time, revisiting in one manic flurry the multitude of twists and turns in the tale I covered as a journalist for New Scientist.

By 1996 confirmation came that the disease had flipped over into people, causing a harrowing equivalent of mad cow disease called variant Creutzfeldt-Jakob Disease (vCJD). To date as well as 52 citizens of other countries, .

Can we expect more cases of vCJD in Britons who for 20 years consumed beef potentially infected with ā€œprionsā€? The mutated brain protein can destroy the central nervous system and brain, leaving it a spongy mass of holes, characteristic of BSE.

So far, as Hiorns points out all the people who died except one have had just one of the three possible genetic profiles that may affect their vulnerability to the disease, and almost all succumbed at an incredibly young age, typically between the late teens and late 20s.

But 60 per cent of the UK population have one or other of the other two genetic variants. Could they too be infected, but not succumb until later in life? ā€œThis thing may not be over yet,ā€ says Hiorns.

Whether it is or not, the exhibition is a masterpiece of historical, fact-based presentation, and a timely reminder of a crisis that gripped the UK, and later much of Europe, for two decades. ā€œItā€™s a terrifying subject that created a sense of dread in our generation,ā€ says Hiorns.

Aided by some stunning artworks and artefacts, including cowsā€™ heads preserved in formaldehyde by British artist Damien Hirst, and a 3D model of the prion protein, Hiorns set out to deliver what he calls ā€œa slice of truthā€, a warts-and-all account of what happened from start to finish of the crisis.

As his exhibition shows, the saga severely undermined public faith in the ability and desire of politicians to protect them from harm, and the extent to which the interests of farmers, butchers and food retailers overrode those of ordinary people.

BSE showed up for the first time in 1984 and scientists promptly worked out, as early as 1987, that animal carcasses turned into cattle feed were spreading the contagion.

The government banned the feeding of animal protein to cows in June 1988, although this didnā€™t stop the epidemic of BSE that peaked in 1992 with 37,280 cases.

Few suspected that the disease would ever cross into people, but as a precaution in 1989, the government banned cow tissues most likely to harbour prions from the human food chain. These included offal, brains, spinal cord material, the spleen and the intestines. This move alone may have saved millions of lives.

But beef remained on sale. Hiornsā€™s exhibition includes footage of the now-famous incident in 1990 when agriculture minister, John Gummer, tried and failed to convince the public that beef was safe by unsuccessfully trying to persuade his daughter Cordelia to take a bite of his burger. That, Hiorns believes, was the turning point when the public lost faith in the government.

As the BSE epidemic ploughed on through its peak in 1992, the government stuck fervently to its line that the disease couldnā€™t cross over into people, even after reports of unusual deaths in farmers beginning as early as 1993.

The dam finally broke in 1996 when scientists demonstrated that a handful of young patients had died from a new disease that was unequivocally the human equivalent of BSE. One of the major exhibits is the ā€œwestern blotā€ test of human brain proteins produced in May 1996 by John Collinge of University College London that proved BSE and vCJD were the same disease. ā€œFor me, itā€™s the icon of the show,ā€ says Hiorns.

On 20 March 1996, health secretary Stephen Dorrell officially announced a ā€œprobable linkā€ between BSE and vCJD. The news was catastrophic and traumatised the nation. A week later, there was a global ban on British beef exports, and ā€œmechanically recovered meatā€ was excluded from the food chain. This concoction of meat fragments obtained by high pressure spraying of carcasses, was suspected of carrying prions from infected animals.

New fears surfaced that vCJD could spread in incompletely sterilised surgical equipment, or in blood donations .

In 2000 a two-year inquiry into the whole saga was finally published, and by this time BSE had spread to Europe, and to the US by 2003. Based on detecting prions in appendixes at post-mortems, epidemiologists predicted that ā€œthousands would dieā€ of vCJD.

The sense of panic, ably captured in Hiornsā€™s choice of news cuttings, video footage, official documents and artefacts, lasted for at least another decade until the BSE epidemic began to peter out ā€“ and then almost vanish globally.

The doomsday scenarios of mass dementia didnā€™t materialise, and the visceral impact of the saga began to fade away.

Hiorns expresses great admiration for the scientists who rapidly discovered the source of vCJD and recommended the most prudent steps to tackle it. ā€œCredit goes to the scientists ā€“ they were on the ball and understood the situation very quickly,ā€ says Hiorns. ā€œIt was when politicians got involved that things became cloudy and vested interests came into the equation. Essentially, they promoted business interests over public health,ā€ he says.

If there is a lesson at all from the crisis, itā€™s that protection of public health should always take precedence, says Hiorns. ā€œYou should never feel youā€™re somehow just an expendable node in a causal system,ā€ he says. ā€œYou get this feeling that governments see the population as a mass, not as a group of individual people.ā€

Whether or not we see a new wave of cases in the future, Hiorns pays tribute to those who have already died, including in his exhibits an image of a plaque to their memory on Londonā€™s Albert Embankment. Soberingly, he points to recent research again on appendixes suggesting that as many as 1 in every 2000 Britons may be infected. Who is to blame? Hiorns invites viewers to make up their own minds.

ā€œWe were all supposed to die of mad cow disease!ā€ People who accuse public health agencies of crying wolf are fond of citing the discovery, in 1996, that a cattle disease widespread in the UK causes the deadly disease vCJD in people. Despite widespread dismay at the time, there have been only 177 cases of vCJD in the country ā€“ and 51 elsewhere ā€“ to date.

The biggest survey yet, however, shows the UK did not really dodge that bullet ā€“ it just hasnā€™t killed many of the people it hit. What we donā€™t know is how many might still die.

A study of 32,000 appendixes removed between 2000 and 2012 from British people born between 1941 and 1985 suggests that 1 in every 2000 people in the UK is carrying the abnormal protein, or prion, that causes the disease. This means as many as 31,000 people may carry the prion ā€“ twice the previous best estimate.

The researchers, mostly from the UKā€™s national human and animal health labs and led by of University College London, warn that we do not know what further damage those infections may cause. In particular, there seems to have been less transmission of the prion via blood transfusions than would have been expected. The researchers are calling for development of a reliable blood test for the prion so we can make sure it is not spreading undetected.

Silver lining

Half the people infected are at particular risk: they carry the genetic form of the protein that has been found in all cases of vCJD to date. However, the researchers warn that they do not know whether such people will simply be lifelong carriers, or may one day develop vCJD. Meanwhile, other genetic forms of the prion could be affecting people in unrecognised ways.

The silver lining, says Richard Salmon, a retired neurologist who wrote an editorial accompanying the research, is that recent research shows that the vCJD prion behaves much like the pathological proteins behind a number of other diseases involving brain degeneration, including Alzheimerā€™s and Parkinsonā€™s diseases. These are huge threats to ageing populations.

ā€œWe have developed, of necessity, a huge body of expertise in studying prion diseases in Britain,ā€ says Salmon. This knowledge could be used to study treatments for such things as Alzheimerā€™s. However, he fears as worries about vCJD wane, funding to maintain that expertise is waning too.

How it happened

Bovine spongiform encephalopathy (BSE) is caused by a misfolded protein ā€“ a prion ā€“ which accumulates in brain tissue, causing death. It is spread when susceptible animals eat tissues from infected animals that contain the prion. BSE was discovered in British cattle in 1987 and has been blamed on the widespread use of cattle remains as cattle fodder in the UK. The UK government initially claimed the prion could not spread to humans ā€“ but it was found to do so in 1996.

By that time inadequate controls meant infected beef had been in the human food chain for years, and there were fears of a mass plague of agonising, invariably fatal vCJD. Fortunately, they did not materialise, but it was unclear whether that was because the prion had not infected people or because for some reason it didnā€™t make them sick.

A decade ago it was discovered that the prion lodges in the appendix, offering a way to search for it in living people who have their appendix removed. Early studies suggested widespread infection was possible, but the samples were too small to be sure.

Where we are now

Now it is clear that people of all ages and across the country were widely infected, regardless of whether they had the genetic form of the prion protein associated with the disease. In fact, more people with the alternate, resistant forms were found to be carrying the prion than would be expected if its distribution was random, for reasons unknown.

ā€œThis shows we need to understand more about the natural history of the prion,ā€ says Salmon. ā€œInfections donā€™t lead to disease as readily as we originally feared, but we donā€™t know why, or whether these infections have a sting in their tail.ā€

Models suggest infected people could still develop vCJD in coming decades. Salmon worries that the prion might cause diseases in people with the resistant genotypes that do not look like classic vCJD and so could be missed. This is especially likely in older people, in whom dementia is more common and not often investigated after death.

Meanwhile we could soon discover even more precisely who was infected during the days of BSE in the UK. Tests for prions in blood are almost ready. Markus Moser, CEO of , a BSE test manufacturer in Zurich, Switzerland, says his company and the National Institutes of ĪēŅ¹ø£Ąū1000¼ÆŗĻ in the US have developed the , which detects prions at low enough levels that ā€œin hamster and sheep, it works as a blood testā€.

It has not been validated on blood samples from people with vCJD, because these have not been made available, says Moser ā€“ but the test .

Journal references: ;

ROGUE proteins responsible for mad cow disease have been discovered in the saliva of cows infected as part of an experiment. The finding might pave the way for a simple test for BSE before the symptoms are apparent.

The result from a team led by at the National Institute of Animal ĪēŅ¹ø£Ąū1000¼ÆŗĻ in Tsukuba, Japan, also suggests, not for the first time, that saliva may be one way some prion diseases can spread. This group of diseases includes scrapie, chronic wasting disease and variant Creutzfeldt-Jakob Disease (vCJD), the human form of mad cow disease.

However, all available evidence suggests this method of transmission is highly unlikely. So far, the team stress there is no epidemiological evidence that saliva, milk, blood or spinal fluid from BSE-infected animals is infectious.

ā€œData from sheep with scrapie and deer with chronic wasting disease suggest the infectivity levels are likely to be very low,ā€ says of the Roslin Institute in Edinburgh, UK, who investigates infectious disease.

At present, diagnosing BSE is only possible by examining brain tissue after death, when the prions are visible as plaques. To find out if the disease could be detected in live animals, the Japanese team deliberately infected three cows. Then every four months, they screened samples of the cowsā€™ saliva using PMC, or protein misfolding cyclic amplification, which ramps up tiny amounts of prion to measurable levels.

In one cow, they detected prions two months before typical symptoms of mad cow disease would be expected to emerge. In the other two, prions were detectable just as the first symptoms began to appear.

ā€œOnce the infectious agent reaches the central nervous system, it may spread [away] from the brain to the salivary glands,ā€ the researchers wrote in their report (Emerging Infectious Diseases, ).

When BSE spiralled out of control in the UK 20 years ago, the source was incontrovertibly traced to cattle feed contaminated with brain tissue from infected cows. The Japanese research raises the possibility that it could also spread in body fluids through licking ā€“ a theoretical possibility that canā€™t be ruled out by their current data.

The crux of the matter, says at Colorado State University in Fort Collins, who is evaluating an alternative test for prion detection, is whether thereā€™s enough infective material in saliva to spread the disease. ā€œSure, it may occur in unusual cases, but it is probably not a major pathway for BSE transmission,ā€ he says.

ā€œEpidemiological data indicate that in cattle, spread of BSE from animal to animal is very limited or absent, and so any shedding of BSE prions from cattle is very unlikely to spread the disease environmentally,ā€ says , a pathologist at the University of Nottingham, UK.

Although BSE is now practically extinct globally, it still crops up unexpectedly. All researchers contacted by New Scientist said that a test to detect the disease in live animals before they developed symptoms would be invaluable to keep the disease in check.

Ā“A test to detect mad cow disease in live animals before symptoms develop would be invaluableĀ”