364 17 Synthetic Biology in Immunotherapy and Stem Cell Therapy Engineering
Finally, as synthetic biologists build increasingly complex systems, the twin
issues of scaling and implementation must be addressed. Current strategies in
circuit design generally result in a roughly linear relationship between part num-
ber/size and functionality. For example, an RNAi-based cancer-cell identifier has
been demonstrated to distinguish HeLa cells from a number of other cancer cell
lines by sensing the levels of six distinct microRNAs (miRNAs) through a net-
work of constitutive and inducible promoters linked to genes encoding various
inducer proteins and miRNA target sites [123]. This work provided an elegant
example of a synthetic, multi-input system in mammalian cells applicable to cel-
lular therapeutics engineering. However, adding each new miRNA input would
require a significant increase in the footprint and complexity of the computation
network without the benefit of economy of scale, leading to problems of parts
shortage (i.e., there are limited numbers of inducible promoters available) and
low integration efficiency (i.e., the system will eventually be too large to be deliv-
ered and stably integrated in the cell). This challenge of scalability will have to be
resolved before a broad range of cellular therapeutics with the necessary level of
functional complexity can be developed through synthetic biology.
Cellular therapeutics has generated a tremendous amount of excitement in
recent years, particularly in cancer immunotherapy. The cell engineering tech-
niques and circuit design expertise being developed through synthetic biology
are poised to make timely and significant contributions to the continuing
improvement of cellular therapeutics. Important challenges remain to be
addressed in biological system design and implementation methods, and the
accumulating knowledge from ongoing efforts in synthetic biology will be criti-
cal in the construction of synthetic biological systems with real-world applica-
tions in health and medicine.Acknowledgment
This material is based in part upon work supported by the National Institutes of
Health (DP5OD012133-01 and P50CA092131) and the National Science
Foundation (CBET 1533767). P.H. is supported by the NIH Biotechnology
Training in Biomedical Sciences and Engineering Program (T32 GM067555).Definitions
Cellular therapy The use of living cells, as distinct from chemical pharmaceuti-
cals or biologics, as therapeutic agents in the treatment of diseases
Immunotherapy Disease treatment that modulates the immune system to
enhance immune responses against disease agents or diseased cells
Adoptive T-cell therapy A type of cellular immunotherapy in which autolo-
gous T cells with specificity toward disease targets, including cancerous and
virally infected cells, are expanded ex vivo and reinfused into the patient.
T cells harvested from the patient may have endogenous disease-specific