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Stem cells show promise for treating Huntington’s disease

The song of the canary aids the quest to create medium spiny neurons

Paying close attention to how a canary learns a new song has helped scientists open a new avenue of research against Huntington’s disease – a fatal disorder for which there is currently no cure or even a treatment to slow the disease.

In a paper published Sept. 20 in the Journal of Clinical Investigation, scientists at the University of Rochester Medical Center have shown how stem-cell therapy might someday be used to treat the disease. The team used gene therapy to guide the development of endogenous stem cells in the brains of mice affected by a form of Huntington’s. The mice that were treated lived significantly longer, were healthier, and had many more new, viable brain cells than their counterparts that did not receive the treatment.

While it’s too early to predict whether such a treatment might work in people, it does offer a new approach in the fight against Huntington’s, says neurologist Steven Goldman, M.D., Ph.D., the lead author of the study. The defective gene that causes the disease has been known for more than a decade, but that knowledge hasn’t yet translated to better care for patients.

“There isn’t much out there right now for patients who suffer from this utterly devastating disease,” said Goldman, who is at the forefront developing new techniques to try to bring stem-cell therapy to the bedside of patients. “While the promise of stem cells is broadly discussed for many diseases, it’s actually conditions like Huntington’s – where a very specific type of brain cell in a particular region of the brain is vulnerable – that are most likely to benefit from stem-cell-based therapy.”

The lead authors of the latest paper are Abdellatif Benraiss, Ph.D., research assistant professor at the University, and former post-doctoral associate Sung-Rae Cho, Ph.D., now at Yonsei University in South Korea.

The latest results have their roots in research Goldman did more than 20 years ago as a graduate student at Rockefeller University. In basic neuroscience studies, Goldman was investigating how canaries learn new songs, and he found that every time a canary learns a new song, it creates new brain cells called neurons. His doctoral thesis in 1983 was the first report of neurogenesis – the production of new brain cells – in the adult brain, and opened the door to the possibility that the brain has a font of stem cells that could serve as the source for new cells.

The finding led to a career for Goldman, who has created ways to isolate stem cells. These techniques have allowed Goldman’s group to discover the molecular signals that help determine what specific types of cells they become, and re-create those signals to direct the cells’ development. Benraiss has worked closely with Goldman for more than 10 years on the Huntington’s project.

“The type of brain cell that allows a canary to learn a new song is the same cell type that dies in patients with Huntington’s disease,” said Goldman, professor of Neurology, Neurosurgery, and Pediatrics, and chief of the Division of Cell and Gene Therapy. “Once we worked out the molecular signals that control the development of these brain cells, the next logical step was to try to trigger their regeneration in Huntington’s disease.”

Huntington’s is an inherited disorder that affects about 30,000 people in the U.S. A defective gene results in the death of vital brain cells known as medium spiny neurons, resulting in involuntary movements, problems with coordination, cognitive difficulties, and depression and irritability. The disease usually strikes in young to mid adulthood, in a patient’s 30s or 40s; there is currently no way to slow the progression of the disease, which is fatal.

Stem cells offer a potential pool to replace neurons lost in almost any disease, but first scientists must learn the extensive molecular signaling that shapes their development. The fate of a stem cell depends on scores of biochemical signals – in the brain, a stem cell might become a dopamine-producing neuron, perhaps, or maybe a medium spiny neuron, cells that are destroyed by Parkinson’s and Huntington’s diseases, respectively.

To do this work, Goldman’s team set up a one-two molecular punch as a recipe for generating new medium spiny neurons, to replace those that had become defective in mice with the disease. The team used a cold virus known as adenovirus to carry extra copies of two genes into a region of the mouse brain, called the ventricular wall, that is home to stem cells. This area happens to be very close to the area of the brain, known as the neostriatum, which is affected by Huntington’s disease.

The team put in extra copies of a gene called Noggin, which helps stop stem cells from becoming another type of cell in the brain, an astrocyte. They also put in extra copies of the gene for BDNF (brain-derived neurotrophic factor), which helps stem cells become neurons. Basically, stem cells were bathed in a brew that had extra Noggin and BDNF to direct their development into medium spiny neurons.

The results in mice, which had a severe form of Huntington’s disease, were dramatic. The mice had several thousand newly formed medium spiny neurons in the neostriatum, compared to no new neurons in mice that weren’t treated, and the new neurons formed connections like medium spiny neurons normally do. The mice lived about 17 percent longer and were healthier, more active and more coordinated significantly longer than the untreated mice.

The experiment was designed to test the idea that scientists could generate new medium spiny neurons in an organism where those neurons had already become sick. Now that the capability has been demonstrated, Goldman is working on ways to extend the duration of the improvement. Ultimately he hopes to assess this potential approach to treatment in patients.

“This offers a strategy to restore brain cells that have been lost due to disease. That could perhaps be coupled with other treatments currently under development,” said Goldman. Many of those treatments are being studied at the University, which is home to a Huntington’s Disease Center of Excellence and is the base for the Huntington Study Group.

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In addition to Benraiss, Cho, and Goldman, other authors include former Cornell graduate student Eva Chmielnicki, Ph.D.; Johns Hopkins neurosurgeon Amer Samdani, M.D., now at Shriners Children’s Hospital in Philadelphia; and Aris Economides of Regeneron Pharmaceuticals. The work was funded by the National Institute of Neurological Disorders and Stroke, the Hereditary Disease Foundation, and the High Q Foundation.

Contact: Tom Rickey
tom_rickey@urmc.rochester.edu
585-275-7954
University of Rochester Medical Center

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September 25, 2007 Posted by | Global Health Vision, Global News, Huntington's disease, Journal of Clinical Investigation, RSS Feed, Stem Cells, University of Rochester | 3 Comments

One species’ entire genome discovered inside another’s

Whole-genome transfer raises questions about evolution, sequencing

Scientists at the University of Rochester and the J. Craig Venter Institute have discovered a copy of the entire genome of a bacterial parasite residing inside the genome of its host species.

The finding, reported in today’s Science, suggests that lateral gene transfer—the movement of genes between unrelated species—may happen much more frequently between bacteria and multicellular organisms than scientists previously believed, posing dramatic implications for evolution.

Such large-scale heritable gene transfers may allow species to acquire new genes and functions extremely quickly, says Jack Werren, a principle investigator of the study.

Wolbachia in yellow with host cells in red.

The results also have serious repercussions for genome-sequencing projects. Bacterial DNA is routinely discarded when scientists are assembling invertebrate genomes, yet these genes may very well be part of the organism’s genome, and might even be responsible for functioning traits.

“This study establishes the widespread occurrence and high frequency of a process that we would have dismissed as science fiction until just a few years ago,” says W. Ford Doolittle, Canada Research Chair in Comparative Microbial Genomics at Dalhousie University, who is not connected to the study. “This is stunning evidence for increased frequency of gene transfer.”

Fruit fly ovaries showing wolbachia infection within.

“It didn’t seem possible at first,” says Werren, professor of biology at the University of Rochester and a world-leading authority on the parasite, called Wolbachia. “This parasite has implanted itself inside the cells of 70 percent of the world’s invertebrates, coevolving with them. And now, we’ve found at least one species where the parasite’s entire or nearly entire genome has been absorbed and integrated into the host’s. The host’s genes actually hold the coding information for a completely separate species.”

Wolbachia may be the most prolific parasite in the world—a “pandemic,” as Werren calls it. The bacterium invades a member of a species, most often an insect, and eventually makes its way into the host’s eggs or sperm. Once there, the Wolbachia is ensured passage to the next generation of its host, and any genetic exchanges between it and the host also are much more likely to be passed on.

Since Wolbachia typically live within the reproductive organs of their hosts, Werren reasoned that gene exchanges between the two would frequently pass on to subsequent generations. Based on this and an earlier discovery of a Wolbachia gene in a beetle by the Fukatsu team at the University of Tokyo, Japan, the researchers in Werren’s lab and collaborators at J. Craig Venter Institute (JCVI) decided to systematically screen invertebrates. Julie Dunning-Hotopp at JCVI found evidence that some of the Wolbachia genes seemed to be fused to the genes of the fruitfly, Drosophila ananassae, as if they were part of the same genome.

Michael Clark, a research associate at Rochester then brought a colony of ananassae into Werren’s lab to look into the mystery. To isolate the fly’s genome from the parasite’s, Clark fed the flies a simple antibiotic, killing the Wolbachia. To confirm the ananassae flies were indeed cured of the wolbachia, Clark tested a few samples of DNA for the presence of several Wolbachia genes.

To his dismay, he found them.

“For several months, I thought I was just failing,” says Clark. “I kept administering antibiotics, but every single Wolbachia gene I tested for was still there. I started thinking maybe the strain had grown antibiotic resistance. After months of this I finally went back and looked at the tissue again, and there was no Wolbachia there at all.”

Clark had cured the fly of the parasite, but a copy of the parasite’s genome was still present in the fly’s genome. Clark was able to see that Wolbachia genes were present on the second chromosome of the insect.

Clark confirmed that the Wolbachia genes are inherited like “normal” insect genes in the chromosomes, and Dunning-Hotopp showed that some of the genes are “transcribed” in uninfected flies, meaning that copies of the gene sequence are made in cells that could be used to make Wolbachia proteins.

Werren doesn’t believe that the Wolbachia “intentionally” insert their genes into the hosts. Rather, it is a consequence of cells routinely repairing their damaged DNA. As cells go about their regular business, they can accidentally absorb bits of DNA into their nuclei, often sewing those foreign genes into their own DNA. But integrating an entire genome was definitely an unexpected find.

Werren and Clark are now looking further into the huge insert found in the fruitfly, and whether it is providing a benefit. “The chance that a chunk of DNA of this magnitude is totally neutral, I think, is pretty small, so the implication is that it has imparted of some selective advantage to the host,” says Werren. “The question is, are these foreign genes providing new functions for the host” This is something we need to figure out.”

Evolutionary biologists will certainly take note of this discovery, but scientists conducting genome-sequencing projects around the world also may have to readjust their thinking.

Before this study, geneticists knew of examples where genes from a parasite had crossed into the host, but such an event was considered a rare anomaly except in very simple organisms. Bacterial DNA is very conspicuous in its structure, so if scientists sequencing a nematode genome, for example, come across bacterial DNA, they would likely discard it, reasonably assuming that it was merely contamination—perhaps a bit of bacteria in the gut of the animal, or on its skin.

But those genes may not be contamination. They may very well be in the host’s own genome. This is exactly what happened with the original sequencing of the genome of the anannassae fruitfly—the huge Wolbachia insert was discarded from the final assembly, despite the fact that it is part of the fly’s genome.

In the early days of the Human Genome Project, some studies appeared to show bacterial DNA residing in our own genome, but those were shown indeed to be caused by contamination. Wolbachia is not known to infect any vertebrates such as humans.

“Such transfers have happened before in the distant past” notes Werren. “In our very own cells and those of nearly all plants and animals are mitochondria, special structures responsible for generating most of our cells’ supply of chemical energy. These were once bacteria that lived inside cells, much like Wolbachia does today. Mitochondria still retain their own, albeit tiny, DNA, and most of the genes moved into the nucleus in the very distant past. Like wolbachia, they have passively exchanged DNA with their host cells. It’s possible wolbachia may follow in the path of mitochondria, eventually becoming a necessary and useful part of a cell.

“In a way, wolbachia could be the next mitochondria,” says Werren. “A hundred million years from now, everyone may have a wolbachia organelle.”

“Well, not us,” he laughs. “We’ll be long gone, but wolbachia will still be around.”

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This research was funded by the National Science Foundation.

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August 30, 2007 Posted by | Genome, Global Health Vision, Global News, Research, RSS, Science, University of Rochester | 1 Comment

Study shows an electronic medical records system can pay for itself within 16 months

CHICAGO (July 12, 2007) — A new study to be published in the July issue of the Journal of the American College of Surgeons shows that one academic medical center recouped its investment in electronic health records within 16 months. The new analysis counters concerns of health care providers reluctant to invest in electronic medical records systems.

The widespread loss of paper medical records in New Orleans after Hurricane Katrina is one of several factors behind the recent push to get surgeons and other health care providers to go electronic, according to David A. Krusch, MD, FACS, of the University of Rochester Department of Surgery and co-author of the study.

“Health care providers most frequently cite cost as primary obstacle to adopting an electronic medical records system. And, until this point, evidence supporting a positive return on investment for electronic health records technologies has been largely anecdotal,” said Dr. Krusch.

The study measured the return on investment of installing electronic health records at five ambulatory offices representing 28 providers within the University of Rochester (NY) Medical Center. Starting in November 2003, the offices implemented a Touchworks EHR system from Chicago-based Allscripts over the next five months. The study compared the cost of activities such as pulling charts, creating new charts, filing time, support staff salary, and transcription when done electronically in the third quarter of 2005, versus the cost of those same activities performed manually in the third quarter of 2003.

The University of Rochester Medical Center estimated that the new electronic medical records system reduced costs by $393,662 per year, nearly two-thirds of that coming from a sharp reduction in the time required to manually pull charts. Given that its electronic system cost $484,577 to install and operate, it took the University of Rochester Medical Center 16 months to recoup its investment. After the first year, it cost about $114,016 annually to operate the new system, which translates to a savings of $279,546 a year for the medical center, or $9,983 per provider.

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The complete study, “A Pilot Study to Document the Return on Investment for Implementing an Ambulatory Electronic Health Record at an Academic Medical Center”, will appear in the July issue of the Journal of the American College of Surgeons. In addition to Krusch, Dara L. Grieger, MD, of the University of Rochester Department of Surgery and Stephen H. Cohen, MN, CPE, also co-authored the article.

The American College of Surgeons is a scientific and educational organization of surgeons that was founded in 1913 to raise the standards of surgical practice and to improve the care of the surgical patient. The College is dedicated to the ethical and competent practice of surgery. Its achievements have significantly influenced the course of scientific surgery in America and have established it as an important advocate for all surgical patients. The College has more than 71,000 members and it is the largest organization of surgeons in the world. For more information, visit http://www.facs.org.

Contact: Sally Garneski
pressinquiry@facs.org
Weber Shandwick Worldwide

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