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Feb. 13, 2007 — Laura Manuelidis's
lab at Yale recently found virus-like particules in
the brain tissue of animals infected with so-called
prion disease, a finding that calls into question a
controversial theory that the diseases are caused by
rogue proteins devoid of genetic materials. Can a scientist
who works on prions comment on this?
—A student at Massasoit Community College in Massachusetts
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Response
by Andrew Steele (shown here with
cows in Switzerland)
MIT graduate student |
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The following is reflective of my opinion only and
not that of Whitehead Institute:
The prion protein (PrP) is normally produced in our
bodies, with particularly high levels of this protein
in our brains. The prion hypothesis dictates that when
a misfolded form of PrP (usually ingested by eating
contaminated meat or directly put into the brains of
surgical patients or experimental animals) comes in
contact with normally folded PrP, it initiates a self-perpetuating
change in conformation. This means that a small amount
of misfolded PrP (called PrP-Sc, or PrP Scrapie) is
capable of causing a lot of trouble because it can set
off a "chain reaction" of misfolding of all
the normal PrP in our brains. No one knows why the misfolding
of PrP is so toxic to cells that make up our brain (neurons)
but there are plenty of ideas.
There is a wealth of experimental evidence supporting
what I have described above, but still some questions
remain. Historically speaking, 30 to 50 years ago everyone
thought that prion disease (e.g., Crutzfelt-Jakob disease,
fatal familial insomnia and scrapie of sheet) was caused
by a virus. In fact, a Nobel prize was awarded to Baruch
Blumberg and Carleton Gajdusek in 1976 for work on the
first prion disease discovered, and at the time, most
people still suspected that an elusive virus was involved.
Stanley Prusiner and others searched very hard for a
virus or other infectious agent. Finally, it became
clear that one defining feature of virtually every prion
disease examined was that there was a misfolded version
of a normal host protein (PrP). When Prusiner postulated
this new model he was widely derided and written off
by many scientists. However, over time this model fit
very well with the experimental data and in 1997, Prusiner
was the sole recipient of the Nobel prize for his pioneering
work.
A few researchers, the most famous is Dr. Manuelidis,
believe that a virus is the culprit in prion disease
and that misfolded PrP is really not a causal force
in disease. The arguments against the prion hypothesis
are often circumstantial and are generally a never-ending
creativity contest, but it’s important to keep
an open mind in science. Also, it is quite a difficult
thing to fight against the orthodoxy and keep a lab
funded, so I respect the courage of those who argue
against the prion hypothesis.
However, to fight against the prevailing model, one
should bring solid data to the argument. The evidence
put forth in a recent publication by Manuelidis and
colleagues in the Proceedings of the National Academy
of Science (communicated by Sheldon Penman) boils
down to one finding: they see something by electron
microscopy (EM) that is round and they only see it in
prion-infected cells. It's quite a leap to move from
this morphological observation to claim that a virus
(or virus-like) species is the causative agent in prion
disease. But this is exactly the claim of the paper.
To prove such an argument it would be essential to demonstrate
that the round spheres seen by EM are indeed viruses!
The authors could have attempted some additional experiments
to do this. For example, they could have amplified viral
RNA or DNA or treated to alleviate the virus infection
or attempted to isolate these spheres. They could also
have tried to infect cells that do not contain prion
protein (these are called PrP knockout cells).
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