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Medicineworld.org: Creation Of Patient-specific Embryonic Stem Cells

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Creation Of Patient-specific Embryonic Stem Cells

Creation Of Patient-specific Embryonic Stem Cells A high-magnification view of a small colony of human embryonic stem cells. The cells have been stained to make their components more visible. photo: M. W. Lensch
Scientists at Children's Hospital Boston have begun attempts to create human embryonic stem cells using nuclear transfer with human eggs and embryos, after receiving approval from the Institutional Review Boards and ESCRO (Embryonic Stem Cell Research Oversight) committees of Children's Hospital Boston and Partners HealthCare. The work is underway in the Children's Hospital laboratory of George Daley, MD, PhD, Associate Director of the Children's Hospital Stem Cell Program and a member of the Executive Committee of the Harvard Stem Cell Institute. Daley is an internationally recognized expert in diseases of the blood.

Because of Federal funding restrictions on human embryonic stem cell research, these studies are being funded through private philanthropy donated to Children's Hospital Boston and the Harvard Stem Cell Institute (HSCI), a collaborative effort that brings together researchers across Harvard University and all its affiliated hospitals to address the promise of stem cell biology as the basis for cures and therapy for a wide range of chronic medical conditions. HSCI funds research, operates core facilities, conducts undergraduate and graduate education, and coordinates the efforts of hundreds of stem cell researchers and clinicians throughout the Harvard community. Two other HSCI researchers at Harvard University, Doug Melton, PhD, and Kevin Eggan, PhD, have likewise received approval to begin similar experiments aimed at producing disease-specific embryonic stem cells.

The first goal of Daley and his Children's colleagues is to gain proficiency in creating stem cell lines; ultimately, they intend to create patient-specific stem cell lines to treat patients using their own cells. The work in the Daley laboratory is utilizing donor eggs and embryos from women undergoing in vitro fertilization (IVF) therapy at Brigham and Women's Hospital's (BWH) Center for Reproductive Medicine. BWH is a member hospital of the Partners HealthCare system. During IVF therapy, a subset of retrieved eggs do not fertilize, and some embryos are not of sufficient quality to successfully produce a pregnancy. These eggs and embryos are typically disposed of as medical waste. However, these materials are capable of providing human embryonic stem cells (hESCs). They offer invaluable study opportunities for medical researchers.

"The availability of top quality eggs and embryos is extremely limited and this can slow the research," explains Daley, an HSCI senior investigator. "The eggs and embryos described in our initial protocol--since they are regularly available as a byproduct of IVF--will give us a ready supply of material for research. This will allow us to immediately investigate some basic questions of biology, such as how stem cells form and how they behave".

The study protocol was carefully designed by teams at both Children's and BWH and approved by research oversight and human-subjects review panels at both institutions. Donations of eggs and embryos are anonymous and unpaid, and all donors, including men contributing sperm to create the embryos, are asked to voluntarily sign a consent form. Neither caregivers nor the embryologists who examine the eggs and embryos are told whether the women have opted to be donors.

In the future, Daley's team will also seek approval to derive hESCs from healthy eggs and embryos, and from patient tissues such as skin cells, and eventually to begin treating patients at Children's Hospital Boston with stem-cell-based therapies.

The plan of work.

In this initial protocol, Daley and his colleagues hope to obtain failed-to-fertilize eggs and poor-quality embryos. They will then use two methods to create hESCs:.

1) Nuclear transfer. This technique involves using a microscopic needle to remove the nucleus from an egg, and replacing this nucleus with a donor nucleus, containing the donor's genetic material, or DNA. The process of transferring the donor nucleus into the egg "reprograms" it, reactivating the full set of genes for making all the tissues of the body. The resulting "reprogrammed" cell is encouraged to develop and divide, and by about day 5, forms a blastocyst--a ball of 50-200 cells. The blastocyst's outer cells are destined to become the placenta, while the inner cells have the potential to form all of the tissues of the body. At this point, development is halted and the inner cells are isolated to derive hESCs. Because the nucleus implanted into the egg contained the patient's DNA, the hESCs derived by this method are genetically matched to the patient.

In the future, under separately approved protocols, Daley and his colleagues hope to obtain donor cells from actual patients, and to transfer the donor nucleus into a fresh egg from a donor or from the patient herself, if female. The donor cell would be of a type easy to obtain, such as a skin cell.

For now, under the approved study protocol, Daley and his colleagues will obtain the donor nucleus from a blastomere, a single cell from a poor-quality embryo of less than 8 days' gestation. They will then transfer this nucleus into a failed-to-fertilize egg, wait for a blastocyst to develop, and isolate hESCs from its inner cell mass.

"Our long-term goal is to create embryonic stem cells from a patient's tissues, correct the genetic defects, and get the repaired cells back into the patients," Daley says. "In the meantime, however, using an embryonic cell rather than a skin cell will increase the chances that nuclear transfer will be successful, because the nucleus of an embryonic cell is much easier to reprogram than the nucleus of a skin cell. This will allow us to answer some basic questions of stem cell biology while becoming technically proficient in creating stem cell lines."

2) In a second technique, hESCs will be created directly from poor-quality embryos, and eventually from frozen, good-quality embryos, without nuclear transfer. The scientists will add feeder cells, chemicals and growth factors to encourage the embryo to grow to the blastocyst stage. They will then stop development and derive hESCs from the blastocyst's inner cell mass. This procedure will generate "generic" hESC lines -- not customized to an individual -- that can be used to study how stem cells behave and differentiate.

Leonard Zon, MD, director of Children's Stem Cell Program, Chair of HSCI's Executive Committee, and Chair of the State Biomedical Research Advisory Committee that oversees Human Stem Cell Research in Massachusetts, was responsible for orchestrating the institutional and administrative oversight and review structures that have allowed the work to be done at Children's. "The work, if successful, will have a major impact on our understanding of human development and tissue formation, and will provide a scaffold for the therapy of a number of diseases of children and adults," Zon says. Zon also emphasizes that the program explicitly prohibits using these techniques for reproductive purposes - that is, to clone a human being, or to grow one from a donated embryo. "There will be no transfer of cloned embryos to a womb, and no embryo will be allowed to grow beyond the blastocyst stage." .

Future goals.

In the future, the Daley laboratory hopes to combine hESC creation with gene treatment to treat patients with specific genetic defects. Already, the lab has restored immune function in mice with a severe immune deficiency (similar to "boy in the bubble" disease) by making ESCs through nuclear transfer, correcting the gene defects, differentiating the repaired cells into blood stem cells, and returning the normal blood cells back to the mice. Using similar methods, Daley's team is also treating mice with thalassemia, a disorder of red blood cells that leads to chronic anemia and the need for children to undergo a lifetime of blood transfusions Other research goals of Daley's lab include: .



Posted by: Scott    Source




Did you know?
Scientists at Children's Hospital Boston have begun attempts to create human embryonic stem cells using nuclear transfer with human eggs and embryos, after receiving approval from the Institutional Review Boards and ESCRO (Embryonic Stem Cell Research Oversight) committees of Children's Hospital Boston and Partners HealthCare. The work is underway in the Children's Hospital laboratory of George Daley, MD, PhD, Associate Director of the Children's Hospital Stem Cell Program and a member of the Executive Committee of the Harvard Stem Cell Institute. Daley is an internationally recognized expert in diseases of the blood.

Medicineworld.org: Creation Of Patient-specific Embryonic Stem Cells

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