For the first time, the University of Michigan added this year 10 lines to the National Institutes of Health National Human Embryonic Stem Cell Registry, a list of 184 lines, mostly from U.S. institutions, but also from a few around the world.

These lines are approved for federal research funds by the NIH. Some carry no known disease, important lines for researchers wanting to learn more about how healthy cells develop or to use them as a comparison against the development of diseased cells.

U-M is focused on diseased lines, which can help researchers watch as genetics take hold in developing tissue.

MICHIGAN: Michigan has huge hopes for tiny stem cells

The lines from U-M:

UM14-1, UM14-2 and UM4-6: They carry no known disease.

UM11-1PGD: Line carries the mutation for one of the most common inherited neurological disorders, Charcot-Marie-Tooth disease Type IA. The condition disables the peripheral nerves, and affects about 1 in 2,500 people in the U.S.

UM15-4 PGD: Line carries the genetic mutation for a rare hormone disorder that interferes with development of the reproductive organs. The disorder is called hydroxysteroid dehydrogenase deficiency.

UM17-1 PGD: Line carries a genetic mutation for the hereditary, degenerative brain disorder Huntington's disease. Early symptoms might include depression, mood swings, forgetfulness, clumsiness, twitching and a lack of coordination, but the disease eventually robs patients of their ability to walk, speak and even swallow.

FUNDING: Stem cells' promise hits funding wall in Michigan

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What U-M is working to cure with stem cells

ScienceDaily (Nov. 18, 2012) Stanford University School of Medicine scientists have demonstrated, in a study conducted jointly with researchers at Yale University, that induced-pluripotent stem cells -- the embryonic-stem-cell look-alikes whose discovery a few years ago won this year's Nobel Prize in medicine -- are not as genetically unstable as was thought.

The new study, published online Nov. 18 in Nature, showed that what seemed to be changes in iPS cells' genetic makeup -- presumed to be inflicted either in the course of their generation from adult cells or during their propagation and maintenance in laboratory culture dishes -- instead are often accurate reflections of existing but previously undetected genetic variations among the cells comprising our bodies.

That's good news for researchers hoping to use the cells to study disease or, someday, for regenerative medicine. But it raises the question of whether and to what extent we humans are really walking mosaics whose constituent cells differ genetically from one to the next in possibly significant respects, said Alexander Urban, PhD, assistant professor of psychiatry and behavioral sciences. Urban shared senior authorship of the study with bioinformatics professor Mark Gerstein, PhD, and neurobiology professor Flora Vaccarino, MD, both of Yale.

It's only a few years ago that human iPS cells started becoming available to researchers. These cells hold great promise because they act almost exactly like embryonic stem cells, which can be nudged to differentiate into virtually any of the body's roughly 200 different cell types. But iPS cells can be derived easily from a person's skin, alleviating numerous ethical concerns arising from the necessity of obtaining embryonic stem cells from fertilized eggs.

At least in principle, iPS cells' genetic makeup closely reflects that of the individual from whom they were derived. Today, "heart cells" derived from a heart patient's skin can be produced in a laboratory dish so scientists can learn more about that particular patient's condition and to screen drugs that might treat it. Tomorrow, perhaps, such cells could be administered to that patient to restore heart health without being perceived as foreign tissue by the patient's immune system, which would otherwise reject the implanted cells.

However, Urban said, several previous studies have raised worries regarding iPS cells' genomic stability. Whether it was the reprogramming procedure researchers use to convert ordinary adult cells into iPS cells or the culturing techniques employed to keep them alive and thriving afterward, something appeared to be inducing an upswing in these cells' manifestation of copy number variations, or CNVs -- the disappearance or duplication of chunks of genetic material at specific locations along the vast stretches of DNA that coil to form the chromosomes residing in all human cells.

CNVs dot everybody's genomes. They occur naturally because of DNA-copying errors made during cell replication, and accumulate in our genomes over evolutionary time. The human genome, taken as a whole, is a DNA sequence consisting of four varieties of chemical units, strung together like beads on a roughly 3-billion-bead-long necklace. CNVs range in length from under 1,000 DNA units to several million. They account for up to several percent of the entire human genome, making them a major source of genetic differences between people.

But if either iPS cells' mode of generation or their subsequent maintenance in culture were promoting an increase in CNVs, it would seriously compromise these cells' utility in research and pose a fatal flaw to their use in regenerative medicine, said Urban. "You would never want to introduce iPS cells into a patient thinking that these cells had the same genome as the rest of the patient's cells, when in fact they had undergone substantial genetic modifications you knew nothing about, much less their effects," said Urban. (Similar concerns apply to embryonic stem cells.)

To see how serious a problem CNVs might pose for iPS cells' use, the collaborators performed tiny skin biopsies on seven volunteers and extracted cells called fibroblasts, which abound in skin and are amenable to cell culture in general and iPS cell generation in particular. From these, the team produced 20 separate iPS cell lines in culture. Using now-standard lab methods, the investigators determined, chemical unit by chemical unit, the full genomic sequence of the cells composing each new iPS cell line.

Urban and his colleagues, who had likewise assessed the fibroblasts from which the lines were derived, compared their genomic sequences with those of the newly generated iPS cells. The scientists were able to pinpoint numerous CNVs in the new cells that hadn't shown up in the fibroblasts. This raised the possibility that the rigors of reprogramming or life in a dish, or both, had led to new CNVs in the cells.

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Minority report: Insight into subtle genomic differences among our own cells

November 19, 2012

redOrbit Staff & Wire Reports Your Universe Online

A new study of stem cells derived from skin tissue has challenged the commonly held notion that a persons cells all share the same DNA sequence, arguing instead that genetic variation may occur to a greater extent than experts had previously believed.

Researchers at the Yale School of Medicine set out to challenge the theory that human cells are comprised of identical genetic material, and that a bodys functions are governed by that blueprint. They set out to test a competing hypothesis that as DNA is copied from mother to daughter cells, deletions, duplications, and alternations to the sequence of the DNA could occur, and could affect entire groups of genes.

According to the university, that notion has been incredibly difficult to test, but Dr. Flora Vaccarino, a professor of child psychology at Yale, and colleagues did so by using whole genome sequencing to analyze induced pluripotent stem cells (iPS) taken from the upper, inner arms of a pair of different families.

They spent 24 months characterizing those iPS cell lines and comparing them to the skin cells from which they originated, and while the genomes of each cell group were similar, Dr. Vaccarinos team was able to pinpoint multiple deletions or duplications that involved thousands of base pairs of DNA, the university explained.

Additional research showed that at least half of the variations they observed pre-existed in a small percentage of skin cells. Those differences were noticeable in the iPS cells because each line of those stem cells originated from either a single or an extremely limited number of skin cells.

We found that humans are made up of a mosaic of cells with different genomes, Dr Vaccarino said in a statement. We saw that 30 percent of skin cells harbor copy number variations (CNV), which are segments of DNA that are deleted or duplicated. Previously it was assumed that these variations only occurred in cases of disease, such as cancer. The mosaic that weve seen in the skin could also be found in the blood, in the brain, and in other parts of the human body.

In the skin, this mosaicism is extensive and at least 30 percent of skin cells harbor different deletion or duplication of DNA, each found in a small percentage of cells, she added. The observation of somatic mosaicism has far-reaching consequences for genetic analyses, which currently use only blood samples. When we look at the blood DNA, its not exactly reflecting the DNA of other tissues such as the brain. There could be mutations that were missing.

Vaccarinos team, which also included fellow researchers Mark Gerstein, Sherman Weissman, Alexander Eckehart Urban, Alexej Abyzov, Jessica Mariani, Dean Palejev, Ying Zhang, Michael Seamus Haney, Livia Tomasini, Anthony Ferrandino, Lior A. Rosenberg Belmaker, Anna Szekely, Michael Wilson, Arif Kocabas, Nathaniel E. Calixto, Elena L. Grigorenko, Anita Huttner, and Katarzyna Chawarska, published their findings in Sundays edition of the journal Nature.

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Study Reveals Genetic Variations Occur At The Cellular Level

Deep inside metal drums of liquid nitrogen at the University of Michigan might be the key to a replacement heart valve for 9-year-old Will Marzolf.

Or the formula for treating the Huntington's disease that killed Krissi Putansu's grandfather and uncle and now threatens her mother.

Or the clues to protecting Marlene Goodman's great-children from the genetics that have curled her fingers to useless angles.

Embryonic stem cell research is a fledgling science, but four years after Michigan voters lifted the ban on such research, U-M is staking its claim.

"They are promise," Goodman said of an embryonic stem cell line known as UM11-1PGD.

FUNDING: Stem cells' promise hits funding wall in Michigan

The line -- essentially a culture of infinitely reproducing cells -- was created earlier this year by U-M researcher Gary Smith from an embryo that carried the genetic sequencing for Charcot-Marie-Tooth disease, a condition that has dogged Goodman since she was a little girl. Over the years, it has slowly withered her muscles, gnarling her fingers.

"They're not going to help me or my children," Goodman said of the cell line, "but it will help someone's children some day."

On Wednesday, Smith submitted his 11th and 12th embryonic stem cell lines to the National Institutes of Health for inclusion on a national registry, adding to 10 lines submitted and accepted earlier this year. Inclusion on the registry places U-M and Smith, the co-director of U-M's A.A. Taubman Consortium for Stem Cell Therapies, on an impressive list of stem cell line contributors from across the country, such as Harvard University and Cedars-Sinai Medical Center in Los Angeles.

All together, 184 embryonic stem cells lines have been contributed to the registry since 2009, when President Barack Obama loosened restrictions placed by former President George W. Bush in 2001 that banned federal funding on newly developed human embryonic stem cell lines.

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Michigan has huge hopes for tiny stem cells

The promise seemed immeasurable -- a science that could not only defeat some of the most deadly human diseases but also rebuild a teetering state economy.

But four years after voters paved the way for embryonic stem cell research in Michigan, the promise of a new day in life sciences, and in particular, regenerative medicine -- the field fueled by stem cell research -- remains largely unfulfilled because of a lack of funding from private investors and the state.

Meanwhile, other states -- from California, which sets aside $300 million a year for stem cell research, to Ohio, which has focused millions of dollars in economic development funds on similar research -- are pulling ahead in the field, economic development experts and researchers say.

"Other states have made moves to make sure they're players in that space. Michigan has not," said Stephen Rapundalo, executive director of Ann Arbor-based MichBio, a biosciences industry trade association.

MICHIGAN: Michigan has huge hopes for tiny stem cells

With the economy at a tipping point in 2008, the timing of Proposal 2, which lifted the 30-year ban on embryonic stem cell lines for research by a 53%-47% margin, couldn't have been worse, he said.

Wayne State University professor Allen Goodman agrees.

In September 2008, about a month before the vote, Goodman estimated that a 1% increase in the biotech industry, sparked by new research, would create 797 direct and indirect jobs for a $51-million boost in payroll.

"Things were bad when I wrote it, and they got worse," Goodman said.

Meanwhile, tectonic shifts in another set of numbers -- demographics -- underscore a need for the most cutting-edge medicine.

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Stem cells' promise hits funding wall in Michigan

ScienceDaily (Nov. 19, 2012) Pluripotent stem cells are nature's double-edged sword. Because they can develop into a dizzying variety of cell types and tissues, they are a potentially invaluable therapeutic resource. However, that same developmental flexibility can lead to dangerous tumors called teratomas if the stem cells begin to differentiate out of control in the body.

To prevent this outcome, researchers must first give the cells a not-so-subtle shove toward their final developmental fate before transplanting them into laboratory animals or humans. But exactly how to do so can vary widely among laboratories. Now researchers at the Stanford University School of Medicine have used an experiment in mice to hit upon a way to possibly skip this fiddly step by instead relying mostly on signals within the body to keep the stem cells in line.

"Before we can use these cells, we have to differentiate, or 'coach,' them down a specific developmental pathway," said Michael Longaker, MD, the Deane P. and Louise Mitchell Professor in the School of Medicine. "But there's always a question as to exactly how to do that, and how many developmental doors we have to close before we can use the cells. In this study, we found that, with appropriate environmental cues, we could let the body do the work."

Allowing the body to direct differentiation could speed the U.S. Food and Drug Administration's approval of using such pluripotent stem cells, Longaker believes, by eliminating the extended periods of laboratory manipulation required during the forced differentiation of the cells.

Longaker, who co-directs Stanford's Institute for Stem Cell Biology and Regenerative Medicine, is the senior author of the research, which will be published online Nov. 19 in the Proceedings of the National Academy of Sciences. Postdoctoral scholars Benjamin Levi, MD, and Jeong Hyun, MD, and research assistant Daniel Montoro are co-first authors of the work. Longaker is also a member of the Stanford Cancer Institute.

"Once we identify the key proteins and signals coaching the tissue within the body, we can try to mimic them when we use the stem cells," said Longaker. "Just as the shape of water is determined by its container, cells respond to external cues. For example, in the future, if you want to replace a failing liver, you could put the cells in a scaffold or microenvironment that strongly promotes liver cell differentiation and place the cell-seeded scaffold into the liver to let them differentiate in the optimal macroenvironment."

In Longaker's case, the researchers were interested not in the liver, but in bone formation. Longaker himself is a pediatric plastic and reconstructive surgeon who specializes in craniofacial malformations. "Imagine being able to treat children and adults who require craniofacial skeletal reconstruction, not with surgery, but with stem cells," he said.

The researchers removed a 4 millimeter circle of bone from the skulls of anesthetized laboratory mice -- a defect just large enough to stymie the natural healing properties of the bone's endogenous stem cells. They then implanted in the damaged area a tiny, artificial scaffold coated with a protein called BMP-2 that they knew (from previous experiments) stimulated bone growth. Each scaffold was seeded with 1 million human stem cells. They then waited and watched for several months as the bone regrew.

"We found that the human cells formed bone and repaired the defect," said Longaker. "What's more, over time that human bone created by the stem cells was eventually replaced by mouse bone as part of the natural turnover process. So the repair was physiologically normal."

The researchers credit the regrowth to the tandem nature of a macroenvironment of bone damage and a microenvironment of scaffolding coated with a bone-growth-triggering molecule.

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Body may be able to 'coach' transplanted stem cells to differentiate appropriately

By Steve Boggan

PUBLISHED: 21:34 EST, 19 November 2012 | UPDATED: 21:34 EST, 19 November 2012

Professor Ian Mackenzie points to a little jumble of cells on a computer screen and smiles.

Theyre cancer stem cells, he says. Not everyone in medicine believes in them yet, but look there they are.

Even to the untrained eye, its clear there are two distinct types of cell; one that groups together a little like frogspawn, and another that looks like a slug.

Stem cells, which are found in tissue all over the body, can grow into every kind of cell, including bone, skin and blood cells

If you watched the slug-like one for long enough, youd see it move, says the professor.

We believe this type of stem cell facilitates the spread of cancer and that the other is responsible for the growth of tumours and for making them return after you think your cancer has gone away.

In Professor Mackenzies laboratory at Barts and the London Medical Schools Blizard Institute, researchers are busy extracting these cells from tumours.

Their work represents a potentially extraordinary new approach to the disease.

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Cancer: The stem cells that make cancer run riot. Kill them and you could destroy the disease...