Molecular Biology of the Cell by Bruce Alberts, Alexander Johnson, Julian Lewis, David Morgan, Martin Raff, Keith Roberts, Peter Walter by by Bruce Alberts, Alexander Johnson, Julian Lewis, David Morg

CELL REPROGRAMMING AND PLURIPOTENT STEM CELLS
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studying
disease
mechanism
treatment
with drugs
disease-specific drugs
screening for
theraputic
compounds
patient
transplantation of genetically
matched healthy cells
cMYC, OCT4,
KLF4, SOX2
healthy cells
in vitro
differentiation
Figure 22–47 Use of iPS cells for
drug discovery and for analysis and
treatment of genetic disease. The
left side of the diagram shows how
differentiated cells that are generated from
iPS cells derived from a patient with a
genetic disease can be used for analysis of
the disease mechanism and for discovery
of therapeutic drugs. The right side of the
diagram shows how the genetic defect
might be repaired in the iPS cells, which
could then be induced to differentiate in an
appropriate way and grafted back into the
patient without danger of immune rejection.
(Based on D.A. Robinton and G.Q. Daley,
Nature 481:295–305, 2012).
skin biopsy
repaired iPS cells
affected cell type
in vitro
differentiation
use gene targeting
to repair diseasecausing
mutation
patient-specific iPS cells
With the advent of iPS cells and direct transdifferentiation, at least one major
hurdle has been surmounted, in principle at least: the problem of immune rejection.
ES cells, because they are created from early embryos that generally come
from unrelated donors, will never MBoC6 be n22.119/22.44
genetically identical to the cells of the patient
receiving the transplant. The transplanted cells and their progeny are therefore
liable to rejection by the immune system. Both iPS and transdifferentiated cells, in
contrast, can be generated from a small sample of the patient’s own tissue and so
should escape immune attack when transplanted back into the same individual.
Tissue repair by transplantation, however, is not the only application for which
ES, iPS, and transdifferentiated cells can be used: there are other ways in which
they promise to be more immediately valuable. In particular, they can be used to
generate large, homogeneous populations of specialized cells of any chosen type
in culture; and these can serve for investigation of disease mechanisms and in the
search for new drugs acting on a specific cell type (Figure 22–47).
Where a disease has a genetic cause, we can derive iPS cells from sufferers and
use these cells to produce the specific cell types that malfunction, to investigate
how the malfunction occurs, and to screen for drugs that might help to put it right.
Timothy syndrome provides an example. In this rare genetic condition, there is a
severe, life-threatening disorder in the rhythm of the heart beat (as well as several
other abnormalities), as a result of a mutation in a specific type of Ca 2+ channel.
To study the underlying pathology, researchers took skin fibroblasts from patients
with the disorder, generated iPS cells from the fibroblasts, and drove the iPS cells
to differentiate into heart muscle cells. These cells, when compared with heart
muscle cells prepared similarly from normal control individuals, showed irregular
contractions and abnormal patterns of Ca 2+ influx and electrical activity that
could be characterized in detail. From this finding, it is a small step to development
of an in vitro assay for drugs that might correct the misbehavior of the heart
muscle cells.
This approach to drug discovery—where iPS cells are prepared from the individual
patient, differentiated into the relevant cell type, and used to test candidate
drugs in vitro—would seem to represent a huge advance on the slow, costly traditional
methods that involve administration of test compounds to large numbers
of people.