Engineering Synthetic Genetic Systems to Manufacture Biologic ...

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Dec 12, 2012 (4 years and 6 months ago)

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Engineering Synthetic Genetic Systems to Manufacture Biologic Therapeutics


Howard M. Salis

Pennsylvania State University


Our Interpretation of the FMM Program

Using synthetic biology techniques, bacteria and yeast can be engineered to manufacture a
broad range of biologic therapeutics. These include small molecule metabolites (alkaloids,
terpenoids), modified proteins (monoclonal antibodies, thiopeptide antibiot
ics), or nucleic acids
(siRNAs, DNA vaccines) that bind to cellular targets to treat or prevent disease. Our goal is to
engineer microbes to dynamically switch between the production of two or more biologic
therapeutics in response to human
-
controlled, ext
racellular signals within a large
-
scale
bioreactor environment. This program would enable microbial engineers to manufacture
diverse chemical products while utilizing a single, engineered microbial strain.


This overall goal has two clear challenges. Firs
t, to reliably engineer metabolic pathways to
manufacture therapeutics. Second, to develop genetic regulators to control the activation of
these pathways. The current approach for engineering metabolic pathways relies primarily on
trial
-
and
-
error procedure
s


the successful artemesinin drug pathway (JD Keasling and
colleagues) required 150 person
-
years of development to achieve economic viability. Thus, to
carry out the first goal in a timely fashion, advanced techniques will be required to optimize
multipl
e metabolic pathways. To carry out the second goal, new genetic regulators are required
to rapidly and precisely control the gene expression of the pathways' components.


Our Capabilities:

Design & Optimization of Synthetic Genetic Systems


Our Capabili
ties:

Construction and Assembly of Synthetic DNA


Our Capabilities:


Dynamic Control of Gene and Protein Expression


We are experts in the rational design, construction, and optimization of synthetic DNA for
bioenergy and biomedical applications (Salis
et. al.,
Nature Biotechnology
, 2009; Tabor, Salis, et.
al.,
Cell
, 2009). We develop predictive biophysical methods that allow you to experimentally
control protein expression across a 100,000
-
fold scale. We employ our techniques to tune
recombinant protein

expression and to systematically optimize long metabolic pathways (6+
enzymes) in the lab. We use advanced genetic engineering techniques to construct large
genetic systems (10,000 bp +) and to perform combinatorial cloning with 6+ DNA parts. Finally,
we
employ our biophysical models to engineer regulatory RNAs that control protein expression
in response to extracellular signals. Our expertise spans the interface between molecular
biology, biomolecular engineering, and synthetic biology.


We are building
a genetic compiler for synthetic microbes:


http://salis.psu.edu/software