Sunday, May 21, 2006

HEALTH SESSION: "Directed evolution of new viruses for gene delivery" - David Schaffer

Overview of Health & Synthetic Biology by Wedell Lim:
The ability to systematically and flexibly manipulate and control cellular systems is the threshold to a new era in medicine, hence the importance of synthetic biology

synthetic organic chemistry -> intellectual capital: understanding of biochemical reactions; tangible benifits: construction of novel molecules

Synthetic biology -> intellectual capital: understanding cellular networks;cells with modified & novel functions;

Schaffer's talk:

Eytemology of virus: essentially "poison" (roots in latin, sanskrit).
serotypes are . Numerous serotypes of Adeno-Associated viruses have been isolated. The require the presence of an adenovirus to replicate, and they're non-pathogenic (90% of human population have already been exposed, and it's highly efficient).

Crosses cell membrane though interaction with heparan sulfate and delivers its genetic payload into the nucleus.

However, "viruses did not evolve in nature to be used as human therapies," and hence we will need to evolve them to our own ends. To re-evolve the virus to have the properties we desire, libraries of the genomes of different serotypes of the virus can be constructed, modified (i.e. introduce point mutations), and then screened.

A large fraction of the human population harbors antibodies and neutralizing antibodies against numerous AAV serotypes, which can signifiantly reduce gene delivery efficiency. How do you get around this? Evolve the virus by selecting for those that can still infect in the presence of a neutralizing antibody. [What were the unexpected effects of injecting AAVs with serum?] Interestingly, the two most important mutations that seem to allow mutants to evade rabbit antiserum are in a region that binds with the target cell receptors. More interestingly, mutations that allow AAVs to evade human serum are not in the same places; one is not exposed, but actually inside the virius at the interface between a receptor spike and other internal machinery.

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