WAISMAN SCIENTISTS MODEL HUMAN DISEASE IN STEM CELLS
The technology depends on work pioneered over the past decade or so by Su-Chun Zhang, a neuroscientist who
leads the iPS Core at Waisman, which also produces cells for other investigators on campus.

The multidisciplinary Waisman Center, now in its 40th year, combines treatment with clinical and basic research to
address many of the most complex and disabling disorders of development.

"Animals are small and incredibly helpful," says Zhang, a professor of neuroscience and neurology, "but if we take the
neurological disorders that the Waisman Center focuses on, including Parkinson's, Huntington's, retinal
degeneration, ALS, spinal muscular dystrophy, Down syndrome and autism, animal models often do not precisely
mimic what we see in patients."

Zhang was the first in the world to overcome the primary challenge for using embryonic stem cells, and now iPS cells,
to model neurological disease: mastering the subtle chemical cues that force a stem cell to develop into neurons,
which carry nerve signals. "Now, we can not only direct iPS cells to become neurons, but also into very defined types
of neurons that are involved in the diseases that most interest us," he says.

In his own research, Zhang focuses on ALS (Lou Gehrig's disease) and other fatal diseases that destroy the neurons
that control movement. "IPS cells can create motor neurons that grow in a Petri dish and tell you, 'I am sick.' We see
the same characteristic blobs and tangles in the long fiber of the nerve cells. Something is blocking traffic so the
sub-units inside the cell cannot pass through these long fibers. This is exactly what we see in patients."

Using iPS-derived cells, Zhang is attempting to find drugs that ease the traffic. "We can take the traffic jam and use it
as a readout - a signal - in a dish, and screen as many as 1,000 compounds and approved drugs at a time, to see if
we can find something that can open this traffic jam."

Drug screening, in fact, is only one goal of the focus on iPS cells as neurological disease models at Waisman:  

- Matthew Jensen, an assistant professor of neurology at the School of Medicine and Public Health, is generating
several types of iPS-derived neural cells for testing in animals, with the aim of exploring brain regeneration after the
most common type of stroke. The iPS cells are developed into neurons and support cells called glia, and grafted into
a rat that models a stroke that follows the interruption of blood flow. "Currently, we think it's most promising to
transplant cells that have not quite fully matured," Jensen says. "We want to see if the cells can integrate into the rat's
brain, contribute to repairing damage caused by the blood stoppage, and restore some of the function lost due to the
stroke."

- Samuel Gubbels, another physician-scientist at Waisman, is using iPS-derived cells to explore mysterious
conditions in the inner ear, where specialized "hair cells" convert sound waves into nerve signals. The hair cells are
housed in a delicate, fluid-filled organ inside the body's densest bone, Gubbels notes. "Too often, we have no way to
determine the cause of hearing decline in a patient; the tests and labs are mostly normal, so we have to do some
guesswork. That's very frustrating for both sides." By developing a system to generate hair cells and supporting cells
from a skin biopsy, "we're aiming to determine the cause of hearing loss that has a genetic basis," Gubbels says.
"Then we would be in a better position to decide what is not functioning correctly in our patients, and that could
become the basis for prevention or treatment."

- Ophthalmologist David Gamm, director of the McPherson Eye Institute on campus, is using iPS models to explore
diseases of the retina. "Hundreds of mutations are associated with degenerative disease of the retina, but often we
don't understand why the cells become dysfunctional," he says. "IPS-derived cells are an economical, straightforward
way to bridge the gap between genetics and biology." Gamm is also making iPS cells from tissue donated by patients
with inherited blindness due to Best disease. "This effort may not lead directly to improvement in the research
participant's vision, but it empowers them to help future generations.  These people have lived their whole life with this
degenerative disease that robs them of their sight, and now with iPS cell technology they are able to donate cells and
be part of research that helps them understand what they are dealing with and where to go from here," Gamm says.
"They know this will help others, including members of their own families."
Su-Chun Zhang (left) talks with postdoctoral
student Lin Yao as she prepares stem-cell
cultures in the Zhang's research lab at the
Waisman Center.
Photo credit: Jeff Miller
From UW-Madison

June 25, 2013, MADISON - Many scientists use animals to model
human diseases. Mice can be obese or display symptoms of
Parkinson's disease. Rats get Alzheimer's and diabetes.

But animal models are seldom perfect, and so scientists are
looking at a relatively new type of stem cell, called the induced
pluripotent stem cell (iPS cell), that can be grown into specialized
cells that become useful models for human disease.

PS cells are usually produced by reprogramming a skin sample
into a primitive form that is able to develop into all of the
specialized cells in the body. In the laboratories at the Waisman
Center at the University of Wisconsin-Madison, scientists are
growing iPS cells into models of disorders caused by defective
nerve cells.
- Krishanu Saha, an assistant professor of biomedical engineering at Wisconsin Institute
for Discovery, collaborates closely with Waisman investigators in the use of biomaterials
to manipulate stem-cell development, especially in relation to Rett and Fragile X
syndromes, both common causes of neurodevelopmental difficulties. "The question we
are interested in is how to engineer biomaterials in Petri dishes to see these diseases
better, and to guide the reprogrammed cells to become neurons or other parts of body that
are diseased," says Saha. Another area of interest is altering the human genome to study
mutations. "We want to put in markers to see better when and where a critical gene may
be turned on and off. Eventually, we would like to mix-and-match cell types with different
variants of important genes, to gain a better understanding of how specific mutations affect
disease."

- Anita Bhattacharyya, a senior scientist at Waisman, focuses on Down syndrome, which is
the most common genetic cause of developmental disorders, and Fragile X syndrome, a
single-gene mutation that can cause autism. Using iPS cells from people with these
conditions, she has embarked on in-the-lab studies "to answer some very basic
questions, try to define these conditions further, and then maybe move toward drug
discovery." In Down syndrome, she reports, the main difficulty is that "neurons talk less to
each other due to a 50 percent  reduction in the number of synapses (connections) in long
projection neurons in the brain. The iPS model mirrors in a dish what we see in
post-mortem brain samples." To further explore the impact of this one mutation,
Bhattacharyya may provide human cells with Fragile X to Waisman neuroscientist Xinyu
Zhao, for transplantation into mice.

That example is one of many that show the value of collaboration at the Waisman Center,
says Bhattacharyya. "Our studies go from genetics and cell culture to treatment and the
family history of disease, and we actually know what is going on with disparate
researchers working on different aspects of these difficult problems. That's the quickest,
surest route to progress that will benefit the people we serve."
Qiang Chang
-Qiang Chang, an assistant professor of medical genetics and neurology, works on Rett
syndrome, a developmental disorder caused by mutations that deform an essential
protein called MECP2. Rett syndrome shares many characteristics with autism. "Because
MECP2 is such an important protein, its level needs to be tightly controlled," says Chang.
Because the gene is on the X chromosome, women can have one good gene and one
defective one. By growing iPS cells from Rett patients, Chang can develop batches of
neurons that differ only in the presence or absence of the MECP2 mutation, which gives
him the ideal system for modeling Rett syndrome. The iPS-derived neurons, he says,
"have the hallmark disease pathology of Rett: defects in nerve fibers called dendrites. In
patients and animal models, the Rett mutation causes shrinkage of these fibers. In these
cells, we have found something very similar."
Krishanu Saha
Anita Bhattacharyya