People Want to be Asked before Sharing Genetic Data

Group Health study is first to ask patients about sharing their data
Thursday, 02 September 2010

People want to be informed and asked for consent before deciding whether to let researchers share their genetic information in a federal database. This is according to a team of investigators at Group Health Research Institute and the University of Washington (UW). The team's report, called "Glad You Asked," is in the September 2010 Journal of Empirical Research on Human Research Ethics.

To the team's knowledge, it is the first to ask research participants' opinions about the need for informed consent for sharing their own information. The team explored participants' preferences while collaborating on the Electronic Medical Records and Genomics (eMERGE) Network. The Network involves volunteers enrolled in the joint Group Health-UW Adult Changes in Thought (ACT) study. ACT is a longitudinal cohort study that tracks aging-related changes in thousands of older Group Health patients over time.

When the team asked Group Health patients who participate in ACT whether their "de-identified" (anonymous) genetic and medical record information could be shared in the database, 86 percent said yes. Then the team surveyed 365 ACT study participants who had agreed to let their genetic information be shared, mostly because of a "desire to help others." In the survey, 90 percent of participants said they thought it was important to have been asked for this reconsent.

Reconsent means getting additional informed consent from research participants before using their information for a purpose beyond what they agreed to originally. Alternatives to reconsent — including opting out, being notified, or neither individual permission nor notification — were unacceptable to 40 percent, 67 percent, and 70 percent of the surveyed participants, respectively.

Evette J. Ludman, Ph.D..

Credit: Group Health

Research Institute.

"We were surprised that so many people felt it was important for us to ask them, even though they decided to give their consent," said lead author Evette Ludman, PhD, a senior research associate at Group Health Research Institute.

"This indicates that even if most of a study's participants would agree to data sharing, it's still crucial to ask them."

Since 2008, the National Institutes of Health (NIH) has strongly encouraged many studies to submit genetic information to the federal database of Genotypes and Phenotypes (dbGaP). The reason is that genomic research on large numbers of people can yield insights that are not possible with smaller numbers.

For new studies that will enrol participants prospectively, informed consent can — and should — address such sharing. But sharing genetic data raises ethical questions for longitudinal cohort studies, including ACT, which started long before dbGaP was established in 2006. Few existing informed consents address data sharing through this new mechanism. Ideally, Dr. Ludman suggested, research grants would include funding and time to pursue reconsent. In this study, it cost around $50 for each participant who was asked.

"Trust is a two-way street, and human research requires lots of trust," Dr. Ludman said.

"People have an understandable feeling of ownership over their bodies and medical records, including their genetic information," she added.

"Researchers show we're worthy of trust when we ask research participants for permission to use their information in a way that they haven't already agreed to."

Recent high-profile legal cases have highlighted the issue of consent and trust in research, including the Havasupai tribe vs. Arizona State University and parents vs. the Texas health department over storing newborn blood samples without parental consent. So too has the bestselling book, “The Immortal Life of Henrietta Lacks”, about the history surrounding the HeLa cell line, the world's most widely grown human cells.

About:
The eMERGE Network:
The Electronic Medical Records and Genomics (eMERGE) Network is a national consortium formed to develop, disseminate, and apply approaches to research that combine DNA biorepositories with electronic medical record (EMR) systems for large-scale, high-throughput genetic research. The Network brings together researchers with a wide range of expertise in genomics, statistics, ethics, informatics, and clinical medicine from leading medical research institutions across the country: Group Health Cooperative with the UW; Marshfield Clinic; Mayo Clinic; Northwestern University; and Vanderbilt University.


Group Health Research Institute:
Founded in 1947, Group Health Cooperative is a Seattle-based, consumer-governed, non-profit health care system. Group Health Research Institute changed its name from Group Health Center for Health Studies on September 8, 2009. Since 1983, the Institute has conducted non-proprietary public-interest research on preventing, diagnosing, and treating major health problems. Government and private research grants provide its main funding.


UW Medicine:
The UW Medicine health system includes UW Medical Center, Harborview Medical Center, Northwest Hospital, the UW School of Medicine, UW Medicine Neighborhood Clinics, UW Physicians, Airlift Northwest, and the UW's partnership in the Seattle Cancer Care Alliance with Seattle Children's and Fred Hutchinson Cancer Research Center. UW Medicine has major academic and service affiliations with Seattle Children's Hospital, Fred Hutchinson Cancer Research Center, and the Veterans Affairs Puget Sound Health Care System in Seattle and the VA Hospital in Boise. The UW School of Medicine is the top public institution for biomedical research in funding received from the National Institutes of Health.

Source: Group Health Research Institute
Contact: Rebecca Hughes
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Live Imaging Puts New Light on Stem Cell Division

University of Oregon team finds, in fruit flies, that the mitotic spindle does not act alone to divide a cell
Thursday, 02 September 2010

The asymmetrical division of a stem cell — in this case a neuroblast of a fruit fly — is shown, the result of research in the lab of Chris Doe at the University of Oregon. Credit: Courtesy of Clemens Cabernard.

A long-held assumption about asymmetrical division of stem cells has cracked. Researchers at the University of Oregon report that the mitotic spindle does not act alone — that cortical proteins help to position a cleavage furrow in the right location.

Their discovery, described in the Sept. 2 issue of the journal Nature, provides a new window on how stem cells divide to produce two unequal daughter cells: one that lives on as a new stem cell and other, smaller cell, which adopts a new function, in this case as a neuron.

A three-member team focused on drosophila (fruit flies) neural stem cells known as neuroblasts, long known for dividing asymmetrically. What is learned in these flies often applies to many other mitotic (dividing) cells in other organisms such as mammals, including humans.

Clemens Cabernard, a postdoctoral researcher
at the University of Oregon, provided new
insight on the asymmetrical division of
neuroblasts (stem cells) in fruit flies. Credit:
Photo by Jim Barlow.

"This addresses a fundamental question in cell biology, namely how a cell knows where to place a cleavage furrow and thus divide in a symmetrical or asymmetrical fashion," said Clemens Cabernard, a postdoctoral fellow in the lab of Chris Doe, a Howard Hughes Medical Institute investigator in the UO Institute of Molecular Biology and director of the UO Institute of Neuroscience. Also on the team was Kenneth E. Prehoda, a UO biochemist and member of the Institute of Molecular Biology.

What the UO team found is that neuroblasts have two distinct dividing pathways that appear to work redundantly: one that is polarity induced and one that is spindle induced, Cabernard said.

Theories on cleavage furrow positioning during cell division have centred on the mitotic spindle, a network of fibres called microtubules.

One idea is that microtubules from spindle poles reach to the cortex, which delivers a positive or negative signal to determine the position of the cleavage ring. Another idea is that microtubule fibres from the centre of the spindle reach out to the cortex resulting in the assembly of a cleavage ring (a complex consisting of several proteins, one of which is called myosin). A third model involves both. It was thought that asymmetrically dividing cells, such as drosophila neuroblasts, generate an asymmetric spindle and can position the cleavage ring in an asymmetric position, as opposed to symmetrically dividing cells that construct a symmetric spindle.

"We found a new mechanism in which a cleavage furrow can be placed at an asymmetric position," Cabernard said.

"First, by way of a couple of experiments, we ruled out that the cleavage furrow is solely dependent on the position and symmetry/asymmetry of the mitotic spindle."

First researchers used mutants that lack astral microtubules, the microtubule fibres reaching out from the spindle poles towards the cortex and watched with live imaging what happens to the cleavage furrow. A cleavage furrow still occurred in an asymmetric position. This has been seen before but not using the same markers, Cabernard said.

Next, researchers removed the entire spindle from the picture with targeted drugs. Usually cells stop dividing in this condition, but a genetic trick allows these cells to initiate cell division despite the lack of a mitotic spindle. Surprisingly, researchers found, the proteins involved in constructing a cleavage furrow became localized in an asymmetric fashion and positioned a cleavage furrow in an asymmetric position — pretty much like in wild-type neuroblasts.

"Although cell division could not be completed, the dividing point was correctly marked," Cabernard said.

"This told us that there must be a mechanism independent of the spindle."

In a third set of experiments, the research team rotated the mitotic spindle of neuroblasts using genetic mutants and thus changed the position of any spindle-derived signal. Interestingly, the team found that two cleavage furrows now formed, but only one coincided with the new position of the mitotic spindle, strongly supporting the hypothesis that a spindle independent signal also is used. Further experiments revealed that a cortical protein, required for proper neural stem cell divisions in mice and humans, is necessary for the asymmetric positioning of the cleavage furrow.

One of the marker proteins watched closely in the experiments was myosin. When a cell starts the division process, Cabernard said, the spindle is symmetrical but the myosin markers segregated toward the basal side — and is localized in an asymmetric fashion — which becomes smaller and transforms into a neuron upon cell division.

Although this research addresses a basic question in cell biology, the findings have important implications. Asymmetric cell division in fly or human stem cells is important to generate a number of differentiating cells while retaining a stem cell as a back up copy.

Previous work by Cabernard and Doe showed that if drosophila neuroblasts divide in a symmetric manner, which does not normally happen, two neuroblasts are generated. Thus, the researchers said, it is crucial for a stem cell to know where to place a cleavage furrow to produce all the required neurons. Similar results have been observed in neural stem cells in mice.

Source: University of Oregon
Contact: Jim Barlow

Reference:
A spindle-independent cleavage furrow positioning pathway
Clemens Cabernard, Kenneth E. Prehoda & Chris Q. Doe
Nature Vol.: 467, 91–94, (02 September 2010), doi:10.1038/nature09334
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ZenMaster

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For more on stem cells and cloning, go to CellNEWS at
http://cellnews-blog.blogspot.com/

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Liver Cells Created from Patients' Skin Cells

Research paves way for new liver disease research and possibly cell-based therapy
Thursday, 26 August 2010

By creating diseased liver cells from a small sample of human skin, scientists have for the first time shown that stem cells can be used to model a diverse range of inherited disorders. The University of Cambridge researchers' findings, which will hopefully lead to new treatments for those suffering from liver diseases, were published today in The Journal of Clinical Investigation.

Because liver cells (hepatocytes) cannot be grown in the laboratory, researching liver disorders is extremely difficult. However, today's new research, which was funded by the Wellcome Trust and the Medical Research Council (MRC), demonstrates how to create diseased liver-like cells from patients suffering from a variety of liver disorders.

By replicating the organ's cells, researchers can not only investigate exactly what is happening in a diseased cell, they can also test the effectiveness of new therapies to treat these conditions. It is hoped that their discovery will lead to tailored treatments for specific individuals and eventually cell-based therapy - when cells from patients with genetic diseases are 'cured' and transplanted back. Additionally, as the process could be used to model cells from other parts of the body, their findings could have implications for conditions affecting other organs.

Dr Ludovic Vallier of the MRC Centre for Stem Cell Biology and Regenerative Medicine, University of Cambridge, principal investigator of the research, said:

"Our work represents an important step towards delivering the clinical promises of stem cells. However, more work remains to be done and our group is dedicated to achieving this ultimate goal by increasing the knowledge necessary for the development of new therapies."

In the UK, liver disease is the fifth largest cause of death after cardiovascular, cancer, stroke, and respiratory diseases. Over the past 30 years mortality from liver disease in young and middle-aged people has increased over six times, with the number of individuals dying from the disease increasing at a rate of 8-10 per cent every year.

By 2012, the UK is expected to have the highest liver disease death rates in Europe and, without action to tackle the disease, it could overtake stroke and coronary heart disease as the leading cause of death within the next 10-20 years. In the United States, it accounts for approximately 25,000 deaths a year.

For their research, the scientists took skin biopsies from seven patients who suffered from a variety of inherited liver diseases and three healthy individuals (the control group). They then reprogrammed cells from the skin samples back into stem cells. These stem cells were then used to generate liver cells, which mimicked a broad range of liver diseases - the first time patient-specific liver diseases have been modelled using stem cells - and to create 'healthy' liver cells from the control group. Importantly, the three diseases the scientists modelled covered a diverse range of pathological mechanisms, thereby demonstrating the potential application of their research on a wide variety of disorders.

Dr Tamir Rashid of the Laboratory for Regenerative Medicine, University of Cambridge, lead author of the paper, said:

"We know that given the shortage of donor liver organs alternative strategies must urgently be sought. Our study improves the possibility that such alternatives will be found - either using new drugs or a cell-based therapeutic approach."

Professor Mark Thursz, a specialist in liver disease and Professor of Hepatology at Imperial College (who was not affiliated with the study), commented on the importance of the research:

"Liver disease is the fifth most common cause of mortality in many developed countries and unlike the other leading causes of death, the rate of liver related mortality is increasing.”

"The development of patient specific liver cell lines from stem cells is a significant advance in the battle against liver diseases. This technology holds promise in the short term by providing new tools to explore the biology of liver diseases and in the long term as a potential source of liver cells for patients with liver failure."

Source: University of Cambridge
Contact: Genevieve Maul

Reference:
Modeling inherited metabolic disorders of the liver using human induced pluripotent stem cells
S. Tamir Rashid, Sebastien Corbineau, Nick Hannan, Stefan J. Marciniak, Elena Miranda, Graeme Alexander, Isabel Huang-Doran, Julian Griffin, Lars Ahrlund-Richter, Jeremy Skepper, Robert Semple, Anne Weber, David A. Lomas, Ludovic Vallier
J Clin Invest. doi:10.1172/JCI43122
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ZenMaster

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For more on stem cells and cloning, go to CellNEWS at
http://cellnews-blog.blogspot.com/

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