Biology Reference
In-Depth Information
more potent and longer-lasting gene silencing effect.
122,123
Another example of a synthetic
biology application requiring transient changes in gene/protein expression is in cellular
reprogramming and the determination of cell lineage fate. Reprogramming of somatic cells
into an embryonic stem-cell-like state (induced pluripotent stem cells) through transfection
of cell-permeable proteins
124
and mRNA
125
without the use of recombinant DNA has
already been achieved. This will be discussed in greater detail below in the section
'
Stem
cells and regenerative medicine.
'
THERAPEUTIC APPLICATIONS OF SYNTHETIC BIOLOGY
Cancer Therapy
Cancer therapy remains a persistent and formidable clinical challenge because common
treatment modalities such as surgical excision, radiotherapy, and chemotherapy inevitably
lead to some destruction of healthy tissues within the patient. Synthetic biology can
potentially allow more selective targeting and destruction of cancer cells while avoiding the
destruction of healthy tissues. Indeed, a number of novel synthetic gene circuits have been
engineered in mammalian cells,
126
viruses,
127
and bacteria
29,128
to achieve this purpose.
Chen and colleagues
126
were able to engineer a ribozyme-based synthetic gene circuit into
tumor-targeting T-cells to enable rapid proliferation in response to small-molecule drugs.
This was achieved by coupling ligand-responsive ribozyme switches to relevant T-cell
growth-promoting cytokine genes such as interleukin-2 and interleukin-15.
126
At the same
time, the synthetic gene circuit incorporated a
in the form of the suicide gene
thymidine kinase, which provides a means of ablating T-cell proliferation once it is no
longer needed.
126
Ramachandra et al.
127
utilized a genetically engineered adenovirus for cancer therapy. These
investigators constructed a synthetic gene circuit that coupled adenoviral replication to the
p53 pathway in human cells. In this circuit, adenoviral replication was inhibited in the
presence of a normal p53 pathway, while an aberrant p53 pathway characteristic of
malignant cells triggered adenoviral replication, leading to cell death.
safety-switch
'
'
168
Besides mammalian cells and viruses, bacteria can also be utilized for cancer therapy. In the
study of Anderson et al.,
29
E. coli
was conferred with the ability to invade and destroy cancer
cells through expression of the invasin protein from
Yersinia pseudotuberculosis
, which was
activated in the presence of a hypoxic environment characteristic of cancerous tissues. This
was achieved by placing expression of the invasin protein under the control of the formate
dehydrogenase promoter that is induced under anaerobic conditions. In another study by
Xiang et al.,
128
invasin-expressing
E. coli
was utilized to target the colon-cancer-causing ß-1
catenin gene (CTNNB1) through RNA interference. Immune-deficient mice subcutaneously
xenografted with colon cancer cells exhibited significant regression of the tumorous
xenograft upon intravenous administration of genetically engineered
E. coli
. This
demonstrated that localized administration was not necessary, and that cancer-invading
bacteria can be utilized for selective targeting of tumorous tissues at distant sites.
Treatment and Prevention of Infectious Diseases
Human populations worldwide are being threatened by newly emerging infectious
diseases,
129,130
as well as from rapidly evolving new strains of old pathogens that exhibit
increasing resistance to antibiotics and other therapeutic drugs. Hence, a major focus in the
field of synthetic biology is the treatment and prevention of infectious diseases.
A persistent challenge in the treatment of bacterial infections is the development of
antibiotic resistance.
121
This may possibly be overcome through the disruption of molecular
networks implicated in antibiotic defense mechanisms. Lu et al.
31
genetically engineered the
