- In a breakthrough that could offer new ways to combat
mad cow disease and related human brain disorders like vCJD, the infectious
prions which trigger these diseases may have been synthesised in a laboratory
for the first time.
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- Researchers have been trying - unsuccessfully - to create
mammalian prions in a test tube every since Stanley Prusiner, a biochemist
at the University of California, San Francisco, first theorised in 1982
that prions were infectious particles composed entirely of protein.
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- Now Prusiner's team reports tantalising evidence that
they have been able to build a mammalian prion from scratch. When these
synthetic prions were injected into the brains of mice, they triggered
a prion disease that could be passed to other animals.
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- "The implications are huge and open up many new
ways to study prions and gain new insights about prion disease," says
Giuseppe Legname, a senior scientist in Prusiner's lab and one of the lead
authors of the study.
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- "This is an exciting and fascinating initial experiment,"
says Byron Caughey, a prion researcher at the Rocky Mountain Laboratories
in Hamilton, Montana. "But we're on new ground here. There are details
that need to be worked out before it's clear this is definitive proof."
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- Corrupted shape
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- According to Prusiner's protein-only prion theory, BSE
and related diseases occur when a protein called PrP found in healthy brains
assumes a corrupted "prion" shape. The prion can then perform
an odd sort of replication by coaxing healthy copies of PrP to flip into
the diseased shape.
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- Folding purified PrP into the prion form in a test tube
has been the holy grail of prion science because it seemed like the only
way to silence all doubt that protein - and not some contaminating brain
virus, for example - were actually responsible for BSE. Furthermore, being
able to study prions in isolation would give new insights into how PrP
folds into a prion and how to prevent or reverse the process to treat prion
diseases.
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- The protein-only theory received a boost in 2000 with
the discovery of other proteins from yeast that seem to form prions in
a test tube (New Scientist print edition, 5 August 2000). But despite exhaustive
efforts by many labs, no one had managed to perform the same trick with
ordinary PrP.
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- Instead, Legname says his team used a smaller fragment
of PrP that was believed to form prions more easily. And rather than inject
the synthetic prion into ordinary mice, the researchers used animals that
were genetically modified to produce the same PrP fragment at a level 16
times higher than normal, making them more susceptible to prion infection.
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- The PrP fragment was produced in bacteria, purified and
then encouraged to form prion containing fibres known as amyloid.
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- Rigid tails
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- Control mice that received a brain injection without
the lab-made prions did not develop prion disease after 670 days. But animals
that received the synthetic prions started showing the wobbly gait, ungroomed
fur and rigid tails that are the clinical signs of rodent prion disease
after 380 days.
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- Extracts from the brains of those diseased animals were
injected into normal mice which started getting sick after, on average,
only 154 days. That suggested the starting number of synthetic prions was
low, but improved after one cycle of replication in a mouse brain, says
Legname.
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- The data suggests that PrP did form a prion in the test
tube. But Caughey points out an alternative, though he admits, less likely
explanation: the prions weren't created in the test tubes, but in brains
of mice overproducing the protein.
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- If that is true, those prions must have replicated so
slowly they do not normally kill the mouse, but the additional injection
of PrP accelerated their replication. To eliminate this possibility, it
will be necessary to show that brain extracts from uninjected mice never
trigger prion disease even when injected into a new animal.
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- Legname says those experiments are already under way.
Prusiner's team is also busy testing many PrP folding conditions to find
ways to make prion formation in the laboratory much more efficient.
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- Journal reference: Science (vol 305, p 673)
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- © Copyright Reed Business Information Ltd.
- http://www.newscientist.com/news/news.jsp?id=ns99996219
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