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Fri 24 Oct 2008 04:00 AM

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The Harvard report

News from the Harvard Medical School research community.

News from the Harvard Medical School research community.

Stem cell research

Harvard scientists create 10 disease-specific stem cell lines

Harvard Stem Cell Institute researcher George Daley, MD, PhD, also associate director of the Stem Cell Program at Children's Hospital Boston, and HSCI colleagues Konrad Hochedlinger and Chad Cowan have produced a robust new collection of disease-specific stem cell lines, all of which were developed using the new induced pluripotent stem cell (iPS) technique. The paper is published in the August 6 online edition of the journal Cell.

The findings hint at potential new treatment approaches for medullablastoma by targeting the origins of the tumours and further suggest that not all patients’ tumours may be born from the same cells.

The new iPS lines, developed from the cells of patients ranging in age from 1 month to 57 years and suffering from a range of conditions from Down Syndrome to Parkinson's disease, will be deposited in a new HSCI "core" facility being established at Massachusetts General Hospital (MGH), HSCI co-director Doug Melton announced yesterday. The operations of the iPS Core will be overseen by a faculty committee, which Daley will chair.

The cell lines the researchers produced carry the genes or genetic components for 10 different diseases, including Parkinson's Disease, Type I diabetes, Huntington's Disease, Down Syndrome, a form of combined immunodeficiency ("Bubble Boy's Disease"), Lesch-Nyhan syndrome, Gaucher's Disease, and 2 forms of muscular dystrophy, among others.

"We wanted to produce a large number of disease models for ourselves, our collaborators, and the stem cell research community to accelerate research," Daley said. "The original embryonic stem cell lines are generic, and allow you to ask only basic questions. But these new lines are valuable tools for attacking the root causes of disease. Our work is just the beginning for studying thousands of diseases in a petri dish," he said.

Melton said that the HSCI iPS Core will serve as a repository for iPS cells produced by HSCI scientists.

"The Core will also function as a technical laboratory to produce these disease- specific lines for use by scientists around the world," Melton said. He went on to say that "the suite of iPS cell lines reported by the Daley group marks an important achievement and a very significant advance for patients suffering from degenerative diseases.

These disease-specific iPS cells are invaluable tools that will allow researchers to watch the development of diseases in petri dishes, outside of the patients. And we have good reason to believe that this will make it possible to find new treatments, and eventually drugs, to slow or even stop the course of a number of diseases. In years ahead," Melton said, "this report will be seen as opening the door to a new approach to develop therapies."

"One of our goals in creating the NIH Director's Pioneer Award programs was to enable exceptionally creative scientists to move quickly in promising new directions, thereby speeding the intellectual and technical breakthroughs needed to address major challenges in biomedical or behavioural research," said National Institutes of Health Director Dr Elias Zerhouni.

"This is certainly the case for Drs Daley and Hochedlinger, who deployed their Director's award resources to advance our ability to use induced pluripotent stem cells for disease-specific studies and drug development."Daley and his colleagues, led by first-author and Children's researcher In Hyun Park, PhD, intentionally produced some stem cell lines for highly heritable, single-gene diseases, such as Gaucher's; complex genetic syndromes, such as Down Syndrome; and then complex diseases, such as Parkinson's, that involve genetic, cellular, and perhaps environmental components.

"The cell lines available from the iPS Core will allow stem cell researchers around the world to explore possible gene therapies for some conditions, and will aid in the development of drugs for others," Daley said.

Improving patient safety

Though the majority of errors occur at the time of admission, the potential to cause harm generally occurs at discharge.

New research highlights how and when errors in inpatient medication reconciliation occur

The Joint Commission made inpatient medication reconciliation a National Patient Safety Goal in 2005, focusing nationwide attention on the issue of errors in inpatient medication records as they move in and out of the hospital.

According to a new study from researchers at Brigham and Women's Hospital (BWH) and Massachusetts General Hospital, inpatients experience an average of nearly 11/2 potentially harmful errors in their medication record during a hospital stay.

Unique from previous research, the study goes on to uncover the frequency of different kinds of errors, at what point during the process they most often occur, and factors that place a patient at risk for having these errors occur. These findings appear in the September 2008 issue of the Journal of General Internal Medicine.

Inpatient medication reconciliation is the process of identifying the most accurate list of all medications a patient is taking and using the list to provide correct medications for the patient.

Until now, the attention has been on meeting this requirement without understanding where efforts should be focused. This study exposes the specific times during an inpatient visit when medication reconciliation errors most often occur.

72% of potentially harmful discrepancies are due to errors in taking patients' medication history, while only 26% occur while reconciling medication history with discharge orders.

Also, the majority of discrepancies are due to the omission of medications, which account for more errors than incorrect reports of dosage, frequency, substitutions, and the addition of medications combined.

"This information can help guide hospitals in determining where to focus their efforts for addressing this problem," said Dr Jeffrey Schnipper, MD, MPH, senior author and Hospitalist at BWH, who also notes that some hospitals are now assigning pharmacists to take inpatients' medication histories at admission.Though the majority of errors occur at the time of admission, the potential to cause harm generally occurs at discharge.

At discharge patients can be sent home without necessary medications, with additional unnecessary medications, or on the wrong doses.

"Medication discrepancies at discharge are especially dangerous because patients are no longer being monitored consistently and may not recognise signs of medication problems on their own," Schnipper said.

We now have a better idea of where these brain tumours come from and their relationship to normal stem cells in the brain.

Researchers also uncovered several predictors that can help professionals identify inpatients that are at higher risk for discrepancies in their medication records.

Indicators of a higher risk inpatient include those with 6 or more medication changes during hospitalisation; minimal understanding of pre-admission medication; a caregiver providing medication information; 13 or more outpatient visits during the previous year; an admission history taken by an intern; or 4 or more high-risk medications prescribed prior to admission.

"With patients today on more medications than in days past, the stakes are higher than ever before," Schnipper says of reconciling medication. "Knowing when and where to look for discrepancies will help hospitals prevent errors that could cause harm to patients."


Childhood brain tumour traced to normal stem cells gone bad

An aggressive childhood brain tumour known as medulloblastoma originates in normal brain "stem" cells that turn malignant when acted on by a known mutant, cancer-causing oncogene, say researchers from Dana-Farber Cancer Institute and the University of California, San Francisco (UCSF).

Reporting in the August 12 issue of Cancer Cell, the scientists say they have uncovered new origins for these tumours from early stem cells as well as more mature cells.

Previously, scientists had assumed the tumours might only come from a single source - more mature cells which become neurons and do not have "stem" cell properties.

The findings hint at potential new treatment approaches for medulloblastoma by targeting the origins of the tumours, and further suggest that not all patients' tumours may be born from the same cells.

"We now have a better idea of where these brain tumours come from and their relationship to normal stem cells in the brain," said Keith Ligon, MD, PhD, co-senior author of the report and an investigator at the Center for Molecular Oncologic Pathology at Dana-Farber and the Brigham and Womens Hospital.Co-senior author, David Rowitch, MD, PhD, currently a professor of paediatrics and neurosurgery at UCSF and a Howard Hughes Medical Institute investigator, commented that mouse experiments shed light on how normal stem cells can be transformed into tumours.

The transformation occurs when a cell-signalling pathway known as Sonic hedgehog (named for a cartoon character) is reactivated by a chance mutation. Sonic hedgehog plays an important role during the embryonic development of the brain, but normally shuts down when no longer needed. When turned on again by a mutation, the signals can trigger cell processes leading to tumours - not just in the brain, but in other organs as well.

Medulloblastomas, usually diagnosed in children between 2 and 5 years of age, affect the brains cerebellum region, which is involved in controlling body movements. They make up about 30% of childhood brain tumours, and account for 250 to 300 new cases per year.

With current treatments, approximately 60 to 70% of patients live at least 5 years, but often they are left with cognitive disabilities from surgery, chemotherapy and radiation, urgently suggesting a need for new, more-selective therapies.

"Medulloblastoma was one of the first tumours that was believed to fit the hypothesis that tumours are caused by cancer stem cells that initiate malignancies and sustain them," said Ligon, an assistant professor at Harvard Medical School. "But the prevailing hypothesis - that medulloblastomas originate from non-stem cells - just did not make perfect sense with this."

The discoveries emerged from a series of experiments begun in the Rowitch Laboratory at Dana-Farber. The initial goal was to determine whether activating the Sonic hedgehog cancer pathway in multiple types of brain cells, including neural stem cells, could help pinpoint which cells brain cancers might come from.

Surprisingly, the scientists generated just 1 tumour type, medulloblastoma, regardless of whether they activated the pathway in stem cells for other cell types called neurons and glia. This was a surprise: it had been thought that medulloblastoma arose purely from neuronal ("thinking") cells and not "glial" or supporting cells.

An intriguing question for the investigators is why these cells, known as granule neuron precursors, seem to be uniquely vulnerable to the tumour-triggering effects of the Sonic hedgehog pathway, while other brain stem and progenitor cells are not.

Explained Rowitch: "There must be susceptibility factors in the granule neuron precursor cell that predispose it to forming cancer, so we now must try to understand what it is about this cell type that makes it susceptible to forming cancer in response to Sonic hedgehog signalling. This relationship between stem cells and oncogenes suggests a new point of potential therapeutic intervention."

This article is provided courtesy of Partners Harvard Medical International.

Research Matters brings together selected research being conducted at Harvard Medical School and its affiliated teaching hospitals and research institutes. For more information, visit the Harvard Medical School website at

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