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'Lifeless' prion proteins are 'capable of evolution'
frp, the BBC at <http://news.bbc.co.uk/2/hi/health/8435320.stm>
Abnormal prion proteins cause at least 20 fatal diseases
BBC News
Page last updated at 00:06 GMT, Friday, 1 January 2010
Scientists have shown for the first time that "lifeless" prion
proteins, devoid of all genetic material, can evolve just like
higher forms of life.
The Scripps Research Institute in the US says the prions can
change to suit their environment and go on to develop drug
resistance.
Prions are associated with 20 different brain diseases in humans
and animals.
The scientists say their work suggests new approaches might be
necessary to develop therapies for these diseases.
In the study, published in the journal Science, the scientists
transferred prion populations from brain cells to other cells in
culture and observed the prions that adapted to the new cellular
environment out-competed their brain-adapted counterparts.
When returned to the brain cells, the brain-adapted prions again
took over the population.
Charles Weissmann, head of Scripps Florida's department of
infectology who led the study, said: "On the face of it, you have
exactly the same process of mutation and adaptive change in
prions as you see in viruses.
This is a timely reminder that prion concerns are not going away
and that controls to stop abnormal prions being transmitted to
humans through the food system or through blood transfusions must
be vigorously maintained Professor John Collinge, Medical Research
Council Prion Unit.
"This means that this pattern of Darwinian evolution appears to
be universally active.
"In viruses, mutation is linked to changes in nucleic acid
sequence that leads to resistance.
"Now, this adaptability has moved one level down- to prions and
protein folding - and it's clear that you do not need nucleic
acid (DNA or RNA) for the process of evolution."
Mammalian cells normally produce cellular prion protein or PrPC.
During infections, such as the human form of mad cow disease
known as vCJD, abnormal or misfolded proteins convert the normal
host prion protein into its toxic form by changing its
conformation or shape.
"It was generally thought that once cellular prion protein was
converted into the abnormal form, there was no further change",
Mr Weissmann said.
"But there have been hints that something was happening.
"When you transmit prions from sheep to mice, they become more
virulent over time.
"Now we know that the abnormal prions replicate, and create
variants, perhaps at a low level initially.
"But once they are transferred to a new host, natural selection
will eventually choose the more virulent and aggressive variants."
Professor John Collinge, of the Medical Research Council's (MRC)
Prion Unit, described the research as exciting confirmation of a
hypothesis that he had proposed two years ago, that there could
be a "cloud" or whole array of prion proteins in the body.
He called it the cloud hypothesis.
He said: "The prion protein is not a clone, it is a quasi-species
that can create different protein strains even in the same animal.
"The abnormal prion proteins multiply by converting normal prion
proteins.
"The implication of Charles Weissmann's work is that it would be
better to cut off that supply of normal prion proteins rather
than risk the abnormal prion adapting to a drug and evolving into
a new more virulent form.
"You would do this by trying to block the sites on the normal
prion protein that the abnormal form locks on to to do its
conversion.
"We know there is an antibody that can do this in mice and the
Medical Research Council's Prion Unit have managed to engineer a
human antibody to do this.
Chemical libraries
"It is currently undergoing safety tests and we hope to move to
clinical trials by the end of 2011"
Professor Collinge said the MRC was also trying to find more
conventional chemical compounds to do this and has been
collaborating with the chemical company GlaxoSmithKline (GSK).
He said: "They have given us access to their chemical libraries,
which contain millions of compounds, and we have already
identified some that may work well.
"This is a timely reminder that prion concerns are not going away
and that controls to stop abnormal prions being transmitted to
humans through the food system or through blood transfusions must
be vigorously maintained."
PRION DISEASES
Human prion diseases such as Creutzfeldt Jakob disease (CJD) can
arise sporadically, be acquired by infection or be inherited
because of a mutant gene coding for the prion protein
They are relatively rare but have occurred in epidemic form in
Papua New Guinea as a result of brain cannibalism
Animal prion diseases include scrapie in sheep and goats, chronic
wasting disease in deer and elk and transmissible mink encephalopathy
Bovine spongiform encephalopathy (BSE) first appeared in UK in
mid-1980s
It is estimated that more than two million UK cattle were infected
Variant CJD (vCJD) caused by the same prion strain as BSE was
first recognised in the mid-1990s
***************
'Lifeless' prion proteins are 'capable of evolution'
frp, the BBC at <http://news.bbc.co.uk/2/hi/health/8435320.stm>
Abnormal prion proteins cause at least 20 fatal diseases
BBC News
Page last updated at 00:06 GMT, Friday, 1 January 2010
Scientists have shown for the first time that "lifeless" prion
proteins, devoid of all genetic material, can evolve just like
higher forms of life.
The Scripps Research Institute in the US says the prions can
change to suit their environment and go on to develop drug
resistance.
Prions are associated with 20 different brain diseases in humans
and animals.
The scientists say their work suggests new approaches might be
necessary to develop therapies for these diseases.
In the study, published in the journal Science, the scientists
transferred prion populations from brain cells to other cells in
culture and observed the prions that adapted to the new cellular
environment out-competed their brain-adapted counterparts.
When returned to the brain cells, the brain-adapted prions again
took over the population.
Charles Weissmann, head of Scripps Florida's department of
infectology who led the study, said: "On the face of it, you have
exactly the same process of mutation and adaptive change in
prions as you see in viruses.
This is a timely reminder that prion concerns are not going away
and that controls to stop abnormal prions being transmitted to
humans through the food system or through blood transfusions must
be vigorously maintained Professor John Collinge, Medical Research
Council Prion Unit.
"This means that this pattern of Darwinian evolution appears to
be universally active.
"In viruses, mutation is linked to changes in nucleic acid
sequence that leads to resistance.
"Now, this adaptability has moved one level down- to prions and
protein folding - and it's clear that you do not need nucleic
acid (DNA or RNA) for the process of evolution."
Mammalian cells normally produce cellular prion protein or PrPC.
During infections, such as the human form of mad cow disease
known as vCJD, abnormal or misfolded proteins convert the normal
host prion protein into its toxic form by changing its
conformation or shape.
"It was generally thought that once cellular prion protein was
converted into the abnormal form, there was no further change",
Mr Weissmann said.
"But there have been hints that something was happening.
"When you transmit prions from sheep to mice, they become more
virulent over time.
"Now we know that the abnormal prions replicate, and create
variants, perhaps at a low level initially.
"But once they are transferred to a new host, natural selection
will eventually choose the more virulent and aggressive variants."
Professor John Collinge, of the Medical Research Council's (MRC)
Prion Unit, described the research as exciting confirmation of a
hypothesis that he had proposed two years ago, that there could
be a "cloud" or whole array of prion proteins in the body.
He called it the cloud hypothesis.
He said: "The prion protein is not a clone, it is a quasi-species
that can create different protein strains even in the same animal.
"The abnormal prion proteins multiply by converting normal prion
proteins.
"The implication of Charles Weissmann's work is that it would be
better to cut off that supply of normal prion proteins rather
than risk the abnormal prion adapting to a drug and evolving into
a new more virulent form.
"You would do this by trying to block the sites on the normal
prion protein that the abnormal form locks on to to do its
conversion.
"We know there is an antibody that can do this in mice and the
Medical Research Council's Prion Unit have managed to engineer a
human antibody to do this.
Chemical libraries
"It is currently undergoing safety tests and we hope to move to
clinical trials by the end of 2011"
Professor Collinge said the MRC was also trying to find more
conventional chemical compounds to do this and has been
collaborating with the chemical company GlaxoSmithKline (GSK).
He said: "They have given us access to their chemical libraries,
which contain millions of compounds, and we have already
identified some that may work well.
"This is a timely reminder that prion concerns are not going away
and that controls to stop abnormal prions being transmitted to
humans through the food system or through blood transfusions must
be vigorously maintained."
PRION DISEASES
Human prion diseases such as Creutzfeldt Jakob disease (CJD) can
arise sporadically, be acquired by infection or be inherited
because of a mutant gene coding for the prion protein
They are relatively rare but have occurred in epidemic form in
Papua New Guinea as a result of brain cannibalism
Animal prion diseases include scrapie in sheep and goats, chronic
wasting disease in deer and elk and transmissible mink encephalopathy
Bovine spongiform encephalopathy (BSE) first appeared in UK in
mid-1980s
It is estimated that more than two million UK cattle were infected
Variant CJD (vCJD) caused by the same prion strain as BSE was
first recognised in the mid-1990s
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