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A new, innovative, and insightful way for scientists to study mental illnesses has
been developed using induced pluripotent stem cells. Researchers take simple skin cell
samples from people with dispositions towards particular mental diseases and
“reprogram” them to become induced pluripotent stem cells. These iPS cells are used to
grow neurons that are used to model illnesses ranging from schizophrenia to bipolar
disorder. The once misunderstood and unknown biological processes that result in mental
illnesses can now be observed in laboratories. Not only does this breakthrough open
doors for a better understanding of how and why these disorders affect the brains of
individuals, but it also provides a platform for the testing of potential psychiatric drug
treatments.
To grasp the immensity of this breakthrough, it is important to understand the
ethical issues associated with stem cell research, the significance of being able to create
pluripotent stem cells from existing human cells, and the inherent difficulty of studying
the brain. Embryonic stem cells are the “gold standard” for all cells. That is, they are
capable of developing any of the body’s cell types. Actual human embryonic stem cells
are by no means easy to obtain, as the ethical debate over the damaging of embryos to
harvest stem cells rages on. Though it is possible to acquire neural stem cells from the
embryonic central nervous system of living people through rather penetrative biopsies,
these cells, depending on their region of origin, differ in their potential for genetic
stability. In addition, neural stem cells generally fail to capture the genetic variability of
human beings. For all of these reasons, there has been a huge push to find different, less
controversial ways to procure human stem cells (Vaccarino 505). Until this occurs, the
best option available involves using animal models, such as mice, to make pluripotent
stem cells that will reproduce human disease structures. The problem with this is that the
cortices of rodents are significantly less-developed in the prefrontal and temporal regions.
These regions are crucial for the study of neuropsychiatric illnesses in humans
(Dolmetsch and Geschwind). Not surprisingly, the differing genetic and environmental
influences between animals and humans lead to imperfect correlations and imperfect
results. Thus, the lack of human-geared treatment due to developmental differences and
untranslatable, animal-specific results has often proven to be problematic (Dechant,
Eigentler and Nat 477). Lastly, the brains of deceased persons who had been affected by
mental illness have been studied time and time again. Unfortunately, postmortem tissue
can shed only so much light on the brain at a final level, and it has not been significant in
figuring out the patterns and progression of mental diseases (Dolmetsch and Geschwind).
Now that all of these specific resources and trials have been exhausted,
researchers have, in essence, had to go back to the basics – somatic cells. The most
common type of somatic cells utilized in the production of induced pluripotent stem cells
are skin cells, or skin fibroblasts, which have been documented as being used in over
80% of experiments that deal with the reprogramming of cells into iPS cells. The
reprogramming of these cells can be performed using a variety of methods, ranging from
the delivery of retroviruses, plasmids, and nucleic acids, to introducing specific
microRNAs and proteins into the cells. These cell-reprogramming approaches can vary in
efficiency depending on the conditions and external environment of the cells being
reprogrammed (Dechant, Eigentler and Nat 478-480). The question of why induced
pluripotent stem cells are so necessary to this breakthrough is answered by its definition:
“cells isolated from fully differentiated tissues such as skin fibroblasts, that upon forced
expression of key transcription factors, alone or in combination with small chemical
compounds, revert to a pluripotency state similar to that of embryonic stem cells,
characterized by indefinite self-renewal and ability to differentiate into all cell types of
that organism” (Vaccarino 505).
As illustrated above, the ability to turn human somatic cells into induced
pluripotent stem cells is a breakthrough in itself, so the ability to cultivate these cells into
neurons has been no easy feat. With the introduction of particular morphogens under
specifc culture conditions, iPS cells are able to form into differing “regional identities” of
the brain – such as the midbrain, hindbrain, forebrain, and spinal cord (Brennand and
Gage 2). Though this is extraordinary, Brennand and Gage also point out that “it is
important to note that researchers cannot generate artificial brain structures in vitro, such
as specific brain regions implicated in neurological disease” and that “although the
relative frequency of a specific neuronal cell type might be favored, differentiated
populations generally contain several types of neurons, as well as astrocytes,
oligodendrocytes, neural precursors and even non-neural cells (3). Though there is still a
long way to go until it is possible to completely replicate aspects of the brain in vitro, the
advances made thus far have had a major impact on the study of psychiatric illnesses.
Schizophrenia, occurring in roughly 1 percent of the population, is due to genetic
and environmental factors, and often leads to high rates of abnormal genetic mutations
that affect brain development. Most scientists believe that the imbalance of
neurotransmitters acts as a high contributing factor to this brain disorder
(“Schizophrenia”). Schizophrenia was successfully modeled using iPS cells cultivated
into neurons in a study done by Brannand and her cohorts at the Salk Institute for
Biological Studies. In contrast to examining a brain plagued with schizophrenia
postmortem, which is how most information about the illness has been obtained, the
reprogrammed somatic cells allowed the researchers to study the live neurons grown in
culture and taken from actual people with schizophrenia. After comparing these cells to
those from people without the disease, the researchers actually introduced a rabies virus
to both sets of cells. As the rabies spread, it was noted that the neurotransmitters of the
schizophrenic cells failed to form as many connections as did the healthy cells.
Additionally, the researchers analyzed genetic activity within the cells, identifying around
600 genes with active differences from the non-schizophrenic cells. To further illustrate
the unreliability of postmortem brain examination in matters of psychiatric disease, it was
noted that only around 25 percent of the 600 genes observed within the cells had been
previously identified in postmortem studies of brain tissue. Afterwards, the researchers
treated the cells with psychiatric drugs for three weeks, and only one was ruled effective.
Loxapine repaired connectivity in the cells of all of the patient cultures (Humphries).
The possible causes of bipolar disorder, like schizophrenia, are still being
researched and narrowed down. It seems to be mainly a hereditary mental disorder, as
current studies indicate that particular genes seem to promote the development of the
disorder (“Bipolar Disorder”). A team of scientists from the University of Michigan
Medical School recently conducted the first stem cell study on bipolar disorder. The team
cultivated iPS cells into neurons affected by bipolar disorder, compared them to cells
sampled from people without the disorder, and observed the differences in neuronal
behavior. The findings revealed that the receptors and channels associated in the cell’s
interaction with calcium signals were expressed more within the bipolar neurons than the
non-bipolar ones. The team added lithium to the bipolar cells, which changed the sending
and receiving of calcium signals (Gavin). It is already widely known that lithium has an
effect on bipolar disorder, but this visual study of it in action provides sturdier ground for
more intimate research on the interaction between them.
Schizophrenia and bipolar disorder are only two examples of psychiatric illnesses
studied by reprogrammed induced pluripotent stem cells, but the possibilities are
seemingly endless and seem to have quickly spilled over into the world of
neurodegenerative diseases. Even so, there are still a lot of questions remaining about the
reliability of using iPS cells. There are a few “catches” to the reprogramming of cells into
induced pluripotent stem cells, one being their underlying past. iPS cells continue to
harbor information about their past specialties, according to a group of scientists headed
by Kitai Kim, Ryan Lister and Mattia Pelizzola. Simply put, a cell can be reprogrammed
into a stem cell, but it will always carry the informational history of what its actual DNA
is (Yong). Ed Yong illustrates this downfall with a metaphor: “They are like Post-It notes
– you can stick them to a book to point out parts to read or ignore, without editing the
underlying text.”
Another flaw in the reprogramming of iPS cells for psychiatric research is that in
vitro laboratory research tends to take place in environmental conditions that are strictly
controlled. This lack of environmental variability means that the effects of external forces
that are known to have a causative effect on psychiatric illnesses are not taken into
consideration. Furthermore, mental illnesses develop on a whole-brain basis, with the
mentality of the individual and the influence from external factors. Though the possible
solid groundwork of uprooting particular psychiatric illnesses may have began with these
iPS cell models, they are simple in comparison to the complexities of the human brain.
Thus, they should not be viewed as the ultimate way to answer the questions associated
with these illnesses (Bray, Kapur and Price).
Despite the few downfalls of observing reprogrammed iPS cells affected by
psychiatric disorder, the future holds the promise of a better understanding of these
illnesses. According to Fred Gage, a professor of genetics at the Salk Institute for
Biological Studies, iPS cells reprogrammed to observe schizophrenia led to new
discoveries about “the development of normal human neurons” and “a deep knowledge
base in terms of understanding how cells mature and differentiate, how synapses behave,
and perhaps circuits involving neurons behave” (“Diseases in a Dish”). Ultimately this
can only direct scientists to a deeper understanding of mental illnesses. When the
reactions and interactions of synapses and neurotransmitters are better understood, doors
are opened for the world of psychiatric medicine to aid in the regulation of such illnesses.
It is all best summed up by Melvin McInnis, M.D., from the Prechter Bipolar Research
Fund, who states, “We can now envision being able to test new drug candidates in these
cells, to screen possible medications proactively instead of having to discover them
fortuitously” (“Bipolar Disorder”). Though it is true that the varied complexities of the
human brain and mental disorders cannot be encapsulated and extracted from mere cell
models, the study of neural cells has the future potential to provide advanced and
individualized treatments as well as invaluable knowledge about the workings of
psychiatric illnesses.
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