Tuesday, May 14, 2013

man-made pandemics


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profvrr wrote on 2013.May.13 in response to DavidS
 
> Animal models are not predictors of what will happen in humans.

somehow they are.That's why we are using them, why you say "it's good science"
You probably meant: are not so good predictors (as most think)
 
> We study infections in animals to obtain mechanistic clues;
 
you say mechanistic clues, I'd say probability estimates
 
> conclusions about what happens in people require further testing. There are dozens
> of examples of this in the literature. Drugs and vaccines are tested in several animal models,
> but are the drugs and vaccines then released for humans? Of course not; clinical
> trials are done.
 
which often however confirm the animal tests. I'd guess in ~70% of cases
 
> We've had a great deal of experience in this laboratory constructing viruses with
> various mutations, and none have ever been more virulent; most are attenuated.
> The same applies for research done in other laboratories. We have little clue how
> to make a more virulent virus.
 
but there are many papers demonstrating just this increase of virulence.
I don't know much outside influenza, but especially with reassorting influenza viruses :
we have 256 possible children, some are usually
more virulent than the parents, some are less virulent. Only ~10% do survive and replicate
and most transmit worse than in nature. But now I feel that we are getting close to successfully
create/detect and filter the potential candidates. We are clearly better than nature here,
which requires a (rare in humans) double-infection and competition (through immunity) with other viruses,
while we can learn and design and select to specifically target and optimize the outcome.
Since above study is not public and already starts with a HP-virus,
let me select this as an example instead, to demonstrate what I mean  Sun et.al., 2011:
[url]http://www.pnas.org/content/early/2011/02/23/1019109108[/url]
[ For an overview of other reassortment studies see
[url]http://www.flutrackers.com/forum/showthread.php?t=203696[/url] ]
While most (46 out of 127) [H9N2+pH1N1)-reassortant viable children had lower pathogenicity
than the parents, there were still 8 out of 127 that had higher pathogenicity in mice than both
parents.Researchers and terrorists will learn how to create higher pathogenicity by reassortment
or passaging or combinations of both. And how to enhance it to ferrets,pigs,...,humans.
 
This was for reassortment experiments, but also for single mutations and passaging
there are many papers how these may increase virulence.
Some keywords that come to mind:: N66S in PB1-F2, E627K in PB2, H5N1 in mouse-brain
after passaging, chicken-adapted,quail-adapted H9N2, D225G in HA of pH1N1 and 1918-H1N1,
search "virulence mutations", "influenza"
 
> Part of the problem is that we focus on amino acid
> changes in isolation; in nature these are accompanied by hundreds of other changes
> which are eventually selected in various hosts to make the final pathogen.

in flu it's often just one mutation. And the mutations usually accumulate one by one.
Each of the viruses in that chain must be viable. We have many influenza sequences
meanwhile, so we can study the chains. And in the labs they can create these mutations
by passaging.

> We don't have a chance at duplicating this and I've never seen any laboratory come close.
 
Palese,Fouchier,Kawaka,...I feel they are pretty close
 
> Just take a look at the scientific literature on viral pathogenesis.
> My beliefs are indeed relevant. They are based on 30+ years of doing research in the
> laboratory on viral pathogenesis, and keeping up with the literature.
 
but things have changed a lot recently. Now we have reverse genetics, better organized
labs with rooms full of ferret-cages, 200000 flu sequences at genbank, 70000 flu-papers at pubmed.
Next Generation Sequencing
 

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profvrr wrote:
> I firmly believe that laboratory-constructed viruses do not have what it
> takes to be a human pathogen: only viral evolution in nature can
> produce the right combination of RNA segments and mutations.
> ... I can find plenty of virologists who would have the same view.
> We are talking about humans, not animal models.
 
laboratory-constructed viruses do have what it takes to be a ferret pathogen ?
Humans are animals. We are not so special from the virus' POV.
Why might it work in different animals but not in humans ?
Presumably only because we can't test it in humans for ethical reasons.
There is no magical difference that separates humans from ferrets
but not ferrets from mice or guinea pigs. We cannot be 100% sure
before we tested it in humans - but maybe 80%, and that's still useful.
So lab-viruses probably often do have "what it takes to be an animal or
human pathogen" but tests to confirm this for humans are rarely available.

.

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