Category Archives: Massachusetts Stem Cells

Organisers: Olivier Pourqui, Benoit Bruneau, Gordon Keller and Austin Smith

Date: 25th 28th September 2016

Location: Southbridge Hotel & Conference Center, Massachusetts, USA

Our understanding of human embryonic development is limited by the experimental inaccessibility of the system. Thus, we have been forced to make assumptions about how humans develop based on our knowledge of other mammals, especially the mouse. However, the recent explosion in stem cell research, particularly the generation of human pluripotent stem cells and the development of organoid culture systems, has provided new opportunities for investigating lineage choice, cell differentiation, tissue organisation and even organ morphogenesis using human cells. Such work promises not only to provide a more complete knowledge of our own developmental origins, but also to inform our efforts to understand and treat developmental disorders and, perhaps most importantly, to help bring regenerative therapies to the clinic.

Following on from our highly successful inaugural meeting in 2014, the second in this series of meetings From Stem Cells to Human Development brings together scientists with a common interest in understanding human development using stem cell systems. Topics to be discussed will include the regulation of pluripotency and differentiation, development of the major lineages and tissue morphogenesis, as well as translational aspects of human stem cell research.

The fees include;

It is expected that all attendees will stay for the duration of the Meeting.

A limited number of day delegate places are available, please email meetings@biologists.com for more information.

Southbridge Hotel & Conference Center is located in the USA, minutes from Sturbridge and less than an hours drive from Boston, Springfield, Hartford, CT, and Providence, RI. The building was originally constructed as an optical factory and has been refurnished and remodelled into a superb conference centre.

Southbridge Hotel & Conference Center 14 Mechanic Street Southbridge MA 01550 USA Tel: +1 508 765 8000

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From Stem Cells to Human Development - September 2016 ...

The stem cell controversy is the consideration of the ethics of research involving the development, use, and destruction of human embryos. Most commonly, this controversy focuses on embryonic stem cells. Not all stem cell research involves the human embryos. For example, adult stem cells, amniotic stem cells, and induced pluripotent stem cells do not involve creating, using, or destroying human embryos, thus are minimally, if at all, controversial. Many less controversial sources of acquiring stem cells include using cells from the umbilical cord, breast milk, and bone marrow, which are not pluripotent.

For many decades, stem cells have played an important role in medical research, beginning in 1868 when Ernst Haeckel first used the phrase to describe the fertilized egg which eventually gestates into an organism. The term was later used in 1886 by William Sedgwick to describe the parts of a plant that grow and regenerate. Further work by Alexander Maximow and Leroy Stevens introduced the concept that stem cells are pluripotent, i.e. able to become many types of different cell. This significant discovery led to the first human bone marrow transplant by E. Donnal Thomas in 1968, which although successful in saving lives, has generated much controversy since. This has included the many complications inherent in stem cell transplantation (almost 200 allogeneic marrow transplants were performed in humans, with no long-term successes before the first successful treatment was made), through to more modern problems, such as how many cells are sufficient for engraftment of various types of hematopoietic stem cell transplants, whether older patients should undergo transplant therapy, and the role of irradiation-based therapies in preparation for transplantation.

The discovery of adult stem cells led scientists to develop an interest in the role of embroynic stem cells, and in separate studies in 1981 Gail Martin and Martin Evans derived pluripotent stem cells from the embryos of mice for the first time. This paved the way for Mario Capecchi, Martin Evans, and Oliver Smithies to create the first knockout mouse, ushering in a whole new era of research on human disease.

In 1998, James Thomson and Jeffrey Jones derived the first human embryonic stem cells, with even greater potential for drug discovery and therapeutic transplantation. However, the use of the technique on human embryos led to more widespread controversy as criticism of the technique now began from the wider non-scientific public who debated the moral ethics of questions concerning research involving human embryonic cells.

Since pluripotent stem cells have the ability to differentiate into any type of cell, they are used in the development of medical treatments for a wide range of conditions. Treatments that have been proposed include treatment for physical trauma, degenerative conditions, and genetic diseases (in combination with gene therapy). Yet further treatments using stem cells could potentially be developed due to their ability to repair extensive tissue damage.[1]

Great levels of success and potential have been realized from research using adult stem cells. In early 2009, the FDA approved the first human clinical trials using embryonic stem cells. These can become any cell type of the body, excluding placental cells. This ability is called pluripotency. Only cells from an embryo at the morula stage or earlier are truly totipotent, meaning that they are able to form all cell types including placental cells. Adult stem cells are generally limited to differentiating into different cell types of their tissue of origin. However, some evidence suggests that adult stem cell plasticity may exist, increasing the number of cell types a given adult stem cell can become.

Many of the debates surrounding human embryonic stem cells concern issues such as what restrictions should be made on studies using these types of cells. At what point does one consider life to begin? Is it just to destroy an embryo cell if it has the potential to cure countless numbers of patients? Political leaders are debating how to regulate and fund research studies that involve the techniques used to remove the embryo cells. No clear consensus has emerged. Other recent discoveries may extinguish the need for embryonic stem cells.[2]

Much of the criticism has been a result of religious beliefs, and in the most high-profile case, Christian US President George W Bush signed an executive order banning the use of federal funding for any cell lines other than those already in existence, stating at the time, "My position on these issues is shaped by deeply held beliefs," and "I also believe human life is a sacred gift from our creator."[3] This ban was in part revoked by his successor Barack Obama, who stated "As a person of faith, I believe we are called to care for each other and work to ease human suffering. I believe we have been given the capacity and will to pursue this research and the humanity and conscience to do so responsibly." [4]

Some stem cell researchers are working to develop techniques of isolating stem cells that are as potent as embryonic stem cells, but do not require a human embryo.

Foremost among these was the discovery in August 2006 that adult cells can be reprogrammed into a pluripotent state by the introduction of four specific transcription factors, resulting in induced pluripotent stem cells.[5] This major breakthrough won a Nobel Prize for the discoverers, Shinya Yamanaka and John Gurdon.[6]

In an alternative technique, researchers at Harvard University, led by Kevin Eggan and Savitri Marajh, have transferred the nucleus of a somatic cell into an existing embryonic stem cell, thus creating a new stem cell line.[7]

Researchers at Advanced Cell Technology, led by Robert Lanza and Travis Wahl, reported the successful derivation of a stem cell line using a process similar to preimplantation genetic diagnosis, in which a single blastomere is extracted from a blastocyst.[8] At the 2007 meeting of the International Society for Stem Cell Research (ISSCR),[9] Lanza announced that his team had succeeded in producing three new stem cell lines without destroying the parent embryos. "These are the first human embryonic cell lines in existence that didn't result from the destruction of an embryo." Lanza is currently in discussions with the National Institutes of Health to determine whether the new technique sidesteps U.S. restrictions on federal funding for ES cell research.[10]

Anthony Atala of Wake Forest University says that the fluid surrounding the fetus has been found to contain stem cells that, when used correctly, "can be differentiated towards cell types such as fat, bone, muscle, blood vessel, nerve and liver cells". The extraction of this fluid is not thought to harm the fetus in any way. He hopes "that these cells will provide a valuable resource for tissue repair and for engineered organs, as well".[11]

The status of the human embryo and human embryonic stem cell research is a controversial issue, as with the present state of technology, the creation of a human embryonic stem cell line requires the destruction of a human embryo. Most of these embryos are discarded. Stem cell debates have motivated and reinvigorated the pro-life movement, whose members are concerned with the rights and status of the embryo as an early-aged human life. They believe that embryonic stem cell research instrumentalizes and violates the sanctity of life and is tantamount to murder.[12] The fundamental assertion of those who oppose embryonic stem cell research is the belief that human life is inviolable, combined with the belief that human life begins when a sperm cell fertilizes an egg cell to form a single cell. The view of those in favor is that these embryos would otherwise be discarded, and if used as stem cells, they can survive as a part of a living human being.

A portion of stem cell researchers use embryos that were created but not used in in vitro fertility treatments to derive new stem cell lines. Most of these embryos are to be destroyed, or stored for long periods of time, long past their viable storage life. In the United States alone, an estimated at least 400,000 such embryos exist.[13] This has led some opponents of abortion, such as Senator Orrin Hatch, to support human embryonic stem cell research.[14] See also embryo donation.

Medical researchers widely report that stem cell research has the potential to dramatically alter approaches to understanding and treating diseases, and to alleviate suffering. In the future, most medical researchers anticipate being able to use technologies derived from stem cell research to treat a variety of diseases and impairments. Spinal cord injuries and Parkinson's disease are two examples that have been championed by high-profile media personalities (for instance, Christopher Reeve and Michael J. Fox, who have lived with these conditions, respectively). The anticipated medical benefits of stem cell research add urgency to the debates, which has been appealed to by proponents of embryonic stem cell research.

In August 2000, The U.S. National Institutes of Health's Guidelines stated:

...research involving human pluripotent stem cells...promises new treatments and possible cures for many debilitating diseases and injuries, including Parkinson's disease, diabetes, heart disease, multiple sclerosis, burns and spinal cord injuries. The NIH believes the potential medical benefits of human pluripotent stem cell technology are compelling and worthy of pursuit in accordance with appropriate ethical standards.[15]

In 2006, researchers at Advanced Cell Technology of Worcester, Massachusetts, succeeded in obtaining stem cells from mouse embryos without destroying the embryos.[16] If this technique and its reliability are improved, it would alleviate some of the ethical concerns related to embryonic stem cell research.

Another technique announced in 2007 may also defuse the longstanding debate and controversy. Research teams in the United States and Japan have developed a simple and cost-effective method of reprogramming human skin cells to function much like embryonic stem cells by introducing artificial viruses. While extracting and cloning stem cells is complex and extremely expensive, the newly discovered method of reprogramming cells is much cheaper. However, the technique may disrupt the DNA in the new stem cells, resulting in damaged and cancerous tissue. More research will be required before noncancerous stem cells can be created.[17][18][19][20]

Update article to include 2009/2010 current stem cell usages in clinical trials.[21][22] The planned treatment trials will focus on the effects of oral lithium on neurological function in people with chronic spinal cord injury and those who have received umbilical cord blood mononuclear cell transplants to the spinal cord. The interest in these two treatments derives from recent reports indicating that umbilical cord blood stem cells may be beneficial for spinal cord injury and that lithium may promote regeneration and recovery of function after spinal cord injury. Both lithium and umbilical cord blood are widely available therapies that have long been used to treat diseases in humans.

This argument often goes hand-in-hand with the utilitarian argument, and can be presented in several forms:

This is usually presented as a counter-argument to using adult stem cells as an alternative that does not involve embryonic destruction.

This argument is used by opponents of embryonic destruction, as well as researchers specializing in adult stem cell research.

Pro-life supporters often claim that the use of adult stem cells from sources such as umbilical cord blood has consistently produced more promising results than the use of embryonic stem cells.[30] Furthermore, adult stem cell research may be able to make greater advances if less money and resources were channeled into embryonic stem cell research.[31]

In the past, it has been a necessity to research embryonic stem cells and in doing so destroy them for research to progress.[32] As a result of the research done with both embryonic and adult stem cells, new techniques may make the necessity for embryonic cell research obsolete. Because many of the restrictions placed on stem cell research have been based on moral dilemmas surrounding the use of embryonic cells, there will likely be rapid advancement in the field as the techniques that created those issues are becoming less of a necessity.[33] Many funding and research restrictions on embryonic cell research will not impact research on IPSCs (induced pluripotent stem cells) allowing for a promising portion of the field of research to continue relatively unhindered by the ethical issues of embryonic research.[34]

Adult stem cells have provided many different therapies for illnesses such as Parkinson's disease, leukemia, multiple sclerosis, lupus, sickle-cell anemia, and heart damage[35] (to date, embryonic stem cells have also been used in treatment),[36] Moreover, there have been many advances in adult stem cell research, including a recent study where pluripotent adult stem cells were manufactured from differentiated fibroblast by the addition of specific transcription factors.[37] Newly created stem cells were developed into an embryo and were integrated into newborn mouse tissues, analogous to the properties of embryonic stem cells.

Austria, Denmark, France, Germany, and Ireland do not allow the production of embryonic stem cell lines,[38] but the creation of embryonic stem cell lines is permitted in Finland, Greece, the Netherlands, Sweden, and the United Kingdom.[38]

In 1973, Roe v. Wade legalized abortion in the United States. Five years later, the first successful human in vitro fertilization resulted in the birth of Louise Brown in England. These developments prompted the federal government to create regulations barring the use of federal funds for research that experimented on human embryos. In 1995, the NIH Human Embryo Research Panel advised the administration of President Bill Clinton to permit federal funding for research on embryos left over from in vitro fertility treatments and also recommended federal funding of research on embryos specifically created for experimentation. In response to the panel's recommendations, the Clinton administration, citing moral and ethical concerns, declined to fund research on embryos created solely for research purposes,[39] but did agree to fund research on leftover embryos created by in vitro fertility treatments. At this point, the Congress intervened and passed the Dickey Amendment in 1995 (the final bill, which included the Dickey Amendment, was signed into law by Bill Clinton) which prohibited any federal funding for the Department of Health and Human Services be used for research that resulted in the destruction of an embryo regardless of the source of that embryo.

In 1998, privately funded research led to the breakthrough discovery of human embryonic stem cells (hESC). This prompted the Clinton administration to re-examine guidelines for federal funding of embryonic research. In 1999, the president's National Bioethics Advisory Commission recommended that hESC harvested from embryos discarded after in vitro fertility treatments, but not from embryos created expressly for experimentation, be eligible for federal funding. Though embryo destruction had been inevitable in the process of harvesting hESC in the past (this is no longer the case[40][41][42][43]), the Clinton administration had decided that it would be permissible under the Dickey Amendment to fund hESC research as long as such research did not itself directly cause the destruction of an embryo. Therefore, HHS issued its proposed regulation concerning hESC funding in 2001. Enactment of the new guidelines was delayed by the incoming George W. Bush administration which decided to reconsider the issue.

President Bush announced, on August 9, 2001, that federal funds, for the first time, would be made available for hESC research on currently existing embryonic stem cell lines. President Bush authorized research on existing human embryonic stem cell lines, not on human embryos under a specific, unrealistic timeline in which the stem cell lines must have been developed. However, the Bush Administration chose not to permit taxpayer funding for research on hESC cell lines not currently in existence, thus limiting federal funding to research in which "the life-and-death decision has already been made".[44] The Bush Administration's guidelines differ from the Clinton Administration guidelines which did not distinguish between currently existing and not-yet-existing hESC. Both the Bush and Clinton guidelines agree that the federal government should not fund hESC research that directly destroys embryos.

Neither Congress nor any administration has ever prohibited private funding of embryonic research. Public and private funding of research on adult and cord blood stem cells is unrestricted.

In April 2004, 206 members of Congress signed a letter urging President Bush to expand federal funding of embryonic stem cell research beyond what Bush had already supported.

In May 2005, the House of Representatives voted 238194 to loosen the limitations on federally funded embryonic stem-cell researchby allowing government-funded research on surplus frozen embryos from in vitro fertilization clinics to be used for stem cell research with the permission of donorsdespite Bush's promise to veto the bill if passed.[45] On July 29, 2005, Senate Majority Leader William H. Frist (R-TN), announced that he too favored loosening restrictions on federal funding of embryonic stem cell research.[46] On July 18, 2006, the Senate passed three different bills concerning stem cell research. The Senate passed the first bill (the Stem Cell Research Enhancement Act) 6337, which would have made it legal for the federal government to spend federal money on embryonic stem cell research that uses embryos left over from in vitro fertilization procedures.[47] On July 19, 2006 President Bush vetoed this bill. The second bill makes it illegal to create, grow, and abort fetuses for research purposes. The third bill would encourage research that would isolate pluripotent, i.e., embryonic-like, stem cells without the destruction of human embryos.

In 2005 and 2007, Congressman Ron Paul introduced the Cures Can Be Found Act,[48] with 10 cosponsors. With an income tax credit, the bill favors research upon nonembryonic stem cells obtained from placentas, umbilical cord blood, amniotic fluid, humans after birth, or unborn human offspring who died of natural causes; the bill was referred to committee. Paul argued that hESC research is outside of federal jurisdiction either to ban or to subsidize.[49]

Bush vetoed another bill, the Stem Cell Research Enhancement Act of 2007,[50] which would have amended the Public Health Service Act to provide for human embryonic stem cell research. The bill passed the Senate on April 11 by a vote of 63-34, then passed the House on June 7 by a vote of 247176. President Bush vetoed the bill on July 19, 2007.[51]

On March 9, 2009, President Obama removed the restriction on federal funding for newer stem cell lines. [52] Two days after Obama removed the restriction, the president then signed the Omnibus Appropriations Act of 2009, which still contained the long-standing Dickey-Wicker provision which bans federal funding of "research in which a human embryo or embryos are destroyed, discarded, or knowingly subjected to risk of injury or death;"[53] the Congressional provision effectively prevents federal funding being used to create new stem cell lines by many of the known methods. So, while scientists might not be free to create new lines with federal funding, President Obama's policy allows the potential of applying for such funding into research involving the hundreds of existing stem cell lines as well as any further lines created using private funds or state-level funding. The ability to apply for federal funding for stem cell lines created in the private sector is a significant expansion of options over the limits imposed by President Bush, who restricted funding to the 21 viable stem cell lines that were created before he announced his decision in 2001.[54] The ethical concerns raised during Clinton's time in office continue to restrict hESC research and dozens of stem cell lines have been excluded from funding, now by judgment of an administrative office rather than presidential or legislative discretion.[55]

In 2005, the NIH funded $607 million worth of stem cell research, of which $39 million was specifically used for hESC.[56]Sigrid Fry-Revere has argued that private organizations, not the federal government, should provide funding for stem-cell research, so that shifts in public opinion and government policy would not bring valuable scientific research to a grinding halt.[57]

In 2005, the State of California took out $3 billion in bond loans to fund embryonic stem cell research in that state.[58]

China has one of the most permissive human embryonic stem cell policies in the world. In the absence of a public controversy, human embryo stem cell research is supported by policies that allow the use of human embryos and therapeutic cloning.[59]

According to Rabbi Levi Yitzchak Halperin of the Institute for Science and Jewish Law in Jerusalem, embryonic stem cell research is permitted so long as it has not been implanted in the womb. Not only is it permitted, but research is encouraged, rather than wasting it.

However in order to remove all doubt [as to the permissibility of destroying it], it is preferable not to destroy the pre-embryo unless it will otherwise not be implanted in the woman who gave the eggs (either because there are many fertilized eggs, or because one of the parties refuses to go on with the procedurethe husband or wifeor for any other reason). Certainly it should not be implanted into another woman.... The best and worthiest solution is to use it for life-saving purposes, such as for the treatment of people that suffered trauma to their nervous system, etc.

Similarly, the sole Jewish majority state, Israel, permits research on embryonic stem cells.

The Catholic Church opposes human embryonic stem cell research calling it "an absolutely unacceptable act." The Church supports research that involves stem cells from adult tissues and the umbilical cord, as it "involves no harm to human beings at any state of development."[60]

The Southern Baptist Convention opposes human embryonic stem cell research on the grounds that "Bible teaches that human beings are made in the image and likeness of God (Gen. 1:27; 9:6) and protectable human life begins at fertilization."[61] However, it supports adult stem cell research as it does "not require the destruction of embryos."[61]

The United Methodist Church opposes human embryonic stem cell research, saying, "a human embryo, even at its earliest stages, commands our reverence."[62] However, it supports adult stem cell research, stating that there are "few moral questions" raised by this issue.[62]

The Assemblies of God opposes human embryonic stem cell research, saying, it "perpetuates the evil of abortion and should be prohibited."[63]

The religion of Islam favors the stance that scientific research and development in terms of stem cell research is allowed as long as it benefits society while using the least amount of harm to the subjects. "Stem cell research is one of the most controversial topics of our time period and has raised many religious and ethical questions regarding the research being done. With there being no true guidelines set forth in the Qur'an against the study of biomedical testing, Muslims have adopted any new studies as long as the studies do not contradict another teaching in the Qur'an. One of the teachings of the Qur'an states that Whosoever saves the life of one, it shall be if he saves the life of humankind (5:32), it is this teaching that makes stem cell research acceptable in the Muslim faith because of its promise of potential medical breakthrough."[64]

The First Presidency of The Church of Jesus Christ of Latter-day Saints "has not taken a position regarding the use of embryonic stem cells for research purposes. The absence of a position should not be interpreted as support for or opposition to any other statement made by Church members, whether they are for or against embryonic stem cell research.[65]

See more here:
Stem cell controversy - Wikipedia

Stem cells are unique in their ability to self-renew: to divide and create two cells, each identical to the original. Understanding stem cell self-renewal is central to understanding how organisms are made and maintained, and may lead to insights that permit physicians to modulate tissue regeneration and repair in their patients with chronic diseases.

Stem cells can also produce offspring that are more specialized (differentiated) than the parental cell. Directing the differentiation of stem cells into specialized cell types will enable cell replacement therapies. Replacing pancreatic beta cells in type I diabetics, or dopaminergic neurons in Parkinson's patients, are two possible examples. It is no accident that the spectacular advances in hematology depended in large part on the discovery and manipulation of blood stem cells, including the discovery of drugs that stimulate stem cell mobilization into the blood or enhance the differentiation of cells into mature blood cells. Moreover, intensive chemotherapy or irradiation for cancer is made possible by rescuing' the patient with an injection of blood stem cells. Because stem cell research is fundamentally about the ability to form, maintain and repair tissues, the insights gained from this research directly informs an understanding of abnormal processes such as cancer and degenerative disease.

There are two types of stem cells, adult stem cells and embryonic stem cells. Adult stem cells are found in mature tissues (bone marrow, skin, brain etc) that can self-renew and give rise to other cell types from their tissue of origin, thereby producing a steady supply of new cells to maintain that tissue throughout life. In general, adult stem cells from one organ do not give rise to cell types from other organs.

However, the embryonic stem (ES) cell warrants special attention as it is uniquely malleable and can make any part of the body. In some sense, ES cells represent the parent of all stem cells and provide a window into the first stages of the life. It is also important to note that mouse ES cells have precipitated a virtual revolution in our understanding of the relationship between genes and their function in intact animals. A close association of researchers working on ES cells and adult stem cells is critical to accelerate the understanding that will lead to stem cell therapies.

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Friday, April 24, 2015

New animal model of breast-to-brain cancer spread allows testing of therapeutic stem cell approach

Investigators from Massachusetts General Hospital (MGH) and the Harvard Stem Cell Institute have developed an imageable mouse model of brain-metastatic breast cancer and shown the potential of a stem-cell-based therapy to eliminate metastatic cells from the brain and prolong survival. The study published online in the journal Brain also describes a strategy of preventing the potential negative consequences of stem cell therapy.

Metastatic brain tumors often from lung, breast or skin cancers are the most commonly observed tumors within the brain and account for about 30 percent of advanced breast cancer metastases, says Khalid Shah, MS, PhD, director of the Molecular Neurotherapy and Imaging Laboratory in the MGH Departments of Radiology and Neurology, who led the study. Our results are the first to provide insight into ways of targeting brain metastases with stem-cell-directed molecules that specifically induce the death of tumor cells and then eliminating the therapeutic stem cells.

Tagged therapeutic stem cells (green) targeting breast cancer metastases (red) in the brain of a mouse model. (Khalid Shah, MS, PhD, Massachusetts General Hospital)

In their search for novel, tumor-specific therapies that could target multiple brain metastases without damaging adjacent tissues, the research team first developed a mouse model that more closely mimics what is seen in patients. They found that injecting into the carotid artery breast cancer cells that express markers allowing them to enter the brain cells labelled with bioluminescent and fluorescent markers to enable tracking by imaging technologies resulted in the formation of many metastatic tumors throughout the brain, mimicking what is seen in advanced breast cancer patients. Current therapeutic options for such patients are limited, particularly when there are many metastases.

To devise a potential new therapy, the investigators engineered a population of neural stem cells to express a potent version of a gene called TRAIL, which codes for a molecule that activates cell-death-inducing receptors found only on the surface of cancer cells. Previous research by Shah and his colleagues had shown that two types of stem cells are naturally attracted toward tumors in the brain. After first verifying in their model that stem cells injected to the brain would travel to multiple metastatic sites and not to tumor-free areas, the team implanted TRAIL-expressing stem cells into the brains of metastasis-bearing mice, which reduced the growth of tumors. Injecting the TRAIL-expressing stem cells into the carotid artery, a likely strategy for clinical application, led to significantly slower tumor growth and increased survival, compared with animals receiving unaltered stem cells or control injections.

The safe use of a stem-cell-based therapy against brain metastasis would require preventing the engineered cells from persisting within the brain, where they could affect normal tissue and possibly give rise to new tumors. To facilitate removal of the therapeutic stem cells from the brain at the conclusion of therapy, the researchers created cells that, in addition to TRAIL, express a viral gene called HSV-TK, which renders them susceptible to the effects of the antiviral drug ganciclovir. Several tests in cultured cells indicated that ganciclovir would cause the death of HSV-TK-expressing stem cells, and testing in the mouse model confirmed that administration of the drug after successful treatment of brain metastases successfully eliminated therapeutic stem cells that also expressed HSV-TK.

Shah and his team are currently developing similar animal models of brain metastasis from lung cancers and from melanoma. They also are working to improve understanding of the therapeutic efficacy of simultaneously targeting multiple tumor-specific molecules on the surface of metastatic cells within the brain and anticipate that their findings will make a major contribution towards developing novel targeted therapies for metastatic tumors in the brain. In addition to Shah, who is an associate professor at Harvard Medical School and a principal faculty member at Harvard Stem Cell Institute, the authors of the Brain report are co-lead authors Wanlu Du, PhD, and Tugba Bagci-Onder, PhD, along with Jose-Luiz Figueiredo, MD, and Jordi Martinez-Quintanilla, PhD all of the MGH Molecular Neurotherapy and Imaging Laboratory. The study was supported by National Institutes of Health grants CA138922 and NS071197 and a grant from the James McDonald Foundation.

Massachusetts General Hospital, founded in 1811, is the original and largest teaching hospital of Harvard Medical School. The MGH conducts the largest hospital-based research program in the United States, with an annual research budget of more than $760 million and major research centers in AIDS, cardiovascular research, cancer, computational and integrative biology, cutaneous biology, human genetics, medical imaging, neurodegenerative disorders, regenerative medicine, reproductive biology, systems biology, transplantation biology and photomedicine.

Katie Marquedant, kmarquedant@partners.org, 617 726-0337

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Why are doctors and scientists so excited about stem cells?

Stem cells have potential in many different areas of health and medical research.

Adult and embryonic stem cells differ in the type of cells that they can develop into.Embryonic stem cells can become all cell types of the body (they arepluripotent). Adult stem cells are found in mature tissues (bone marrow, skin, brain, etc.) and give rise to other cell types from their tissue or origin (they are are multipotent). For example, adult blood stem cells give rise to red blood cells, white blood cells and platelets.

Adult stem cells are thought to exist in every type of tissue in the body. But, to date, the isolation of many types of adult stem cells has been limited. Hematopoietic (blood) stem cells are readily available via bone marrow aspiration. But stem cells for solid organs such as liver or brain have proven more difficult to identify and derive. The hope is that hESCs can be used to derive every type of adult stem cell in the body and allow research that is currently not possible.

Embryonic stem cells are isolated from 3 to 5 day old human embryos at the blastocyst stage. The blastocyst is a hollow microscopic cluster of several hundred undifferentiated cells.

This is a culture of hESCs derived from a single embryo. Because stem cells can self-replicate, just a few hESCs can give rise to a whole population of identical hESCs, or a cell line.

Once established, a cell line can be grown in the laboratory indefinitely and cells may be frozen for later use or distributed to other researchers. Because each cell line has its own distinct genetic footprint, researchers are often interested in using the same cell line for a number of related experiments.

No. At this point, the promise is huge, but hESC research is still in its early stages. Human embryonic stem cell (hESC) research only began in 1998, when a group led by Dr. James Thomson at the University of Wisconsin developed a technique to isolate and grow the cells.

In late January 2009, the California-based company Geron received FDA clearance to begin the first human clinical trial of cells derived from human embryonic stem cells. View Geron press release

In contrast, research with adult stem cells such as blood-forming stem cells in bone marrow (called hematopoietic stem cells, or HSCs) has been active for over decades. And this research has resulted in treatment of patients; for example, bone marrow (stem cell) transplants have been conducted for over 40 years.

In addition, studies with a limited number of patients have demonstrated the clinical potential of adult stem cells in the treatment of other human diseases that include diabetes and advanced kidney cancer.

Induced pluripotent stem cells (iPS cells) are cells that began as normal adult cells (for example, a skin cell) and were engineered (induced) by scientists to become pluripotent, that is, able to form all cell types of the body. This process is often called 'reprogramming.' While iPS cells and embryonic stem cells share many characteristics they are not identical. Scientists are currently exploring whether they differ in clinically significant ways.

The technology used to generate iPS cells holds great promise for creating patient- and disease-specific cell lines for research purposes. These cells are already useful tools for drug development and scientists hope to use them in transplantation medicine. However, additional research is needed before the reprogramming techniques can be used to generate stem cells suitable for safe and effective therapies.

Somatic cell nuclear transfer (SCNT), is a technique in which the nucleus of a somatic cell (any cell of the body except sperm and egg cells) is injected, or transplanted, into an egg, that has had its nucleus removed. The product of SCNT has the same genetic material as the somatic cell donor.

Yes. SCNT is a technique of cloning. The product of SCNT is nearly genetically identical to the somatic cell used in the process. (Of note, the product of SCNT is not technically 100% identical in that the cytoplasm of the oocyte includes mitochondrial DNA.) While SCNT is considered cloning, it is important to differentiate between therapeutic and reproductive cloning. The following FAQ addresses these differences.

Reproductive cloning includes the placement of the product of SCNT into a uterus for the purpose of a live birth. The resulting organism would, in theory, be the genetic copy of the somatic cell donor. Reproductive cloning has been performed in animals for many years and is burdened by many technical and biological problems. Only about 1 percent of all the eggs that receive donor DNA can develop into normal surviving clones. Therapeutic cloning uses SCNT for the sole purpose of deriving cells for research, and potentially in the future for therapy. In therapeutic cloning, the product of SCNT is not placed into a uterus and hence a live birth is never a possibility. Therapeutic cloning provides two potential benefits.

Yes. Massachusetts state law that was enacted in May 2005 allows hESC research and it allows the derivation of hESCs from embryos that were created for reproductive purposes and are no longer needed for reproduction and from somatic cell nuclear transfer.

The National Academy of Sciences (NAS) issued guidelines for hESC research in April 2005, and subsequently updated those guidelines in 2007 and 2008. The current guidelines contain detailed recommendations with regard to many aspects of hESC research, including:

No. IRB approval is required for:

Until recently, the federal government limited its funding to specific hESCs derived before August 9, 2001. Specifically, federal funds were only allowed for research on hESCs listed on the National Institutes of Health (NIH) Registry, and on derivative products from hESCs on the NIH Registry. On March 9, 2009, President Obama signed an executive order clearing the way for the NIH and other federal agencies to fund research using all kinds of hESCs.

Human embryonic stem cell research at the Center for Regenerative Medicine has been supportedin partby private philanthropic donations. These donations allowed us to support a wide range of research activities that could not have been supported from other sources such as NIH funding. In the future, we expect to receive support for eligible activities from NIH and other funding agencies.

The Center for Regenerative Medicine depends upon philanthropic support. To find out how you can help accelerate research and discovery, please click here.

The Center for Regenerative Medicine is dedicated to understanding how tissues are formed and may be repaired in settings of injury. Embedded at Mass General Hospital, the Center's primary goal is to develop novel therapies to regenerate damaged tissues and thereby overcome debilitating chronic disease. The success of this effort requires a cohesive team of scientists and clinicians with diverse areas of expertise, but with a shared mission and dedication to the larger goal.

The Center for Regenerative Medicine has extensive interactions with other investigators at MGH and in the broader Harvard-MIT community. The Center helped galvanize the establishment of the Harvard Stem Cell Institute (HSCI), which is co-directed by Dr. Scadden and Dr. Douglas Melton of Harvard's Department of Stem Cell and Regenerative Biologyand the Howard Hughes Medical Institute. As an important confederated partner of HSCI, the Center brings specific features that augment other elements of HSCI, including unique stem cell clinical investigation expertise and ongoing collaborative clinical trials using stem cell transplantation. The Center emphasizes technologies that will ultimately be critical for the success of stem cell based medicine, including bioengineering, biomaterials expertise, close links to in vivo imaging capability and its GMP facility for sophisticated cell manipulation.

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Stem Cell FAQ - Massachusetts General Hospital, Boston, MA

What Are Embryonic Stem Cells?

Embryonic stem (ES) cells are a collection of cells found only in very early development which are the precursors to every celltypein the human body. The vast majority of cells in the body (somatic cells) fall into specific classes or types, such as muscle, bone and neurons, each of which have unique characteristics and functions. However, these cells are not interchangeable(a muscle cell cannot become a neuron) and most of these cells have lost the ability to multiply to create new cells. ES cells differ from all other cells in two important ways. First, they can be induced tochange, or differentiate, into virtually any cell type. Second, unlike somatic cells which have finite lifespans, ES cell can grow indefinitely in culture. These two unique characteristics give ES cells enormous potential to medicine and science.

Embryonic stem cells are important to medicine because of their ability to change into other cell types. This ability means that ES cells have the potential to repair damaged organs and replace cells that do not function properly. Since they can multiply indefinitely, the large numbers of cells necessary to repair or replace these tissues can be produced. Thus, the hope is that ES cells can be a renewable source of replacement cells that can be used to treat a number of medical problems including Parkinson's and Alzheimer's disease, strokes, burns, spinal cord damage and heart disease.

Recent publications have described the derivation of ES-like induced pluripotent stem (iPS) cells from adult mouse and human cells(Nakagawa et al., 2008;Takahashi et al., 2007;Yu et al., 2007). These researchers introduced specific sets of genes encoding transcription factors which are normally expressed in undifferentiated ES cells. The expression of these genes resulted in thereprogramming of the adult cells to a more ES-like or pluripotent state. While the initial studies indicate that these cells share characteristics of true ES cells, more detailed work is needed to determine how closely they resemble ES cells. In addition, the reintroduction of these genes can have adverse consequences. For instance, the use of retroviruses and the potential for reactivation of introduced genes such as c-myc and Oct-4 can increase the risk of cancer. These issues will need to be addressed if iPS technology will have clinical applications.

The human body has a relatively small number of cells, called adult stem cells that are capable of differentiating into a limited range of cell types. For instance, blood stem cells are capable of changing into a number or different types of blood cells. These adult ES are also of enormous importance to medicine. However, they have limitations that ES cells do not. First, they are limited in the number of types of cells into which they can change. For instance, blood stem cells cannot form bone. In addition, unlike ES cells adult stem cells do not appear to have the same capacity to multiply indefinitely. They have also been more difficult to grow in the laboratory. So, while adult stem cells are important, they cannot be viewed at this time as a replacement for ES cells. Research into all types of stem cells is needed in order to advance medicines ability to treat disease.

Types of Stem Cells

hES Cells

SCNT ES Cells

iPS Cells

Adult Stem Cells

Derivation Method

Removal of cells from ICM of blastocyst embryo from IVF.

Somatic Cell Nuclear Transfer. Transfer of somatic cell nucleus to enucleated egg, development to blastocyst, removal of ICM.

Reprogramming of somatic cells by introduction of specific regulatory factor genes.

Isolation from adult tissues.

Characteristics

Differentiate into all cell types.

Excess of IVF embryos exist.

Differentiate into all cell types.

Stem cells can be matched to patient

ES cell like characteristics.

Stem cells can be matched to patient

Doesn't require embryos.

Successful treatments demonstrated.

Stem cells can be matched to patient

Limitations

Limited number of lines available for federally funded research.

Immune rejection issues

Risk of tumors (teratomas) from transplanting undifferentiated cells.

Requires use of embryo.

Risk of tumors (teratomas) from transplanting undifferentiated cells.

Eggs difficult to obtain.

Unknown if cells can differentiate into all cell types.

Risk of tumors (teratomas) from transplanting undifferentiated cells and from expression of introduced genes.

Cells not found in all tissues.

Produce a limited number of cell types.

Difficult to identify, isolate and grow.

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Stem Cell Basics Prepared by the National Institutes of Health, this primer on stem cells answers a number of fundamental questions about the properties and potential uses of embryonic and adult stem cells with a glossary of terms and illustrations.

Tell Me About Stem Cells This site, created by Harvard and MIT, provides basic information about stem cells in plain language with illustrations.

Understanding Stem Cells Developed and published by the National Academy of Sciences, this free booklet (available as a 1.13 MB PDF, 24 pages) provides information on what stem cells are and why stem cell research is important, as well as the ethical and legal issues surrounding stem cells.

EuroStemCell This website presents information and educational resources about stem cells from a European perspective.

National Institutes of Health Stem Cell FAQs This page contains a wealth of information, from basic questions about stem cells, to research and potential clinical uses of stem cells as well as US government policies.

ISSCR Stem Cell FAQs Prepared by the International Society for Stem Cell Research, this page addresses a number of basic questions about embryonic and adult stem cells, their origins and potential uses.

MedlinePlus: Stem Cells This site offers a number of useful links for those seeking health-related information about embryonic and adult stem cells; from basic information to disease specific sites to links to clinical trials.

A Closer Look at Stem Cell Treatments This site is designed to arm patients, their families and doctors with information they need to make decisions about stem cell treatments. The content of this site is based on recommendations from the ISSCR's Task Force on Unproven Stem Cell Treatments.

21st Century Snake Oil A CBS 60 minutes story from 2010 that serves as a warning about unscrupulous stem cell therapies.

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Stem Cell Facts - University of Massachusetts Medical School

Proof-of-concept study highlights new therapeutic use of engineered human stem cells

Harvard Stem Cell Institute scientists at Massachusetts General Hospital have devised a new way to use stem cells in the fight against brain cancer. A team led by neuroscientist Khalid Shah, MS, PhD, who recently demonstrated the value of stem cells loaded with cancer-killing herpes viruses, now has a way to genetically engineer stem cells so that they can produce and secrete tumor-killing toxins.

In the AlphaMed Press journal STEM CELLS, Shahs team shows how the toxin-secreting stem cells can be used to eradicate cancer cells remaining in mouse brains after their main tumor has been removed. The stem cells are placed at the site encapsulated in a biodegradable gel. This method solves the delivery issue that probably led to the failure of recent clinical trials aimed at delivering purified cancer-killing toxins into patients brains. Shah and his team are currently pursuing FDA approval to bring this and other stem cell approaches developed by them to clinical trials.

Cancer-killing toxins have been used with great success in a variety of blood cancers, but they dont work as well in solid tumors because the cancers arent as accessible and the toxins have a short half-life, said Shah, who directs theMolecular Neurotherapy and Imaging Lab atMassachusetts General Hospital and Harvard Medical School.

A few years ago we recognized that stem cells could be used to continuously deliver these therapeutic toxins to tumors in the brain, but first we needed to genetically engineer stem cells that could resist being killed themselves by the toxins, he said. Now, we have toxin-resistant stem cells that can make and release cancer-killing drugs.

Cytotoxins are deadly to all cells, but since the late 1990s, researchers have been able to tag toxins in such a way that they only enter cancer cells with specific surface molecules; making it possible to get a toxin into a cancer cell without posing a risk to normal cells. Once inside of a cell, the toxin disrupts the cells ability to make proteins and, within days, the cell starts to die.

Shahs stem cells escape this fate because they are made with a mutation that doesnt allow the toxin to act inside the cell. The toxin-resistant stem cells also have an extra bit of genetic code that allows them to make and secrete the toxins. Any cancer cells that these toxins encounter do not have this natural defense and therefore die. Shah and his team induced toxin resistance in human neural stem cells and subsequently engineered them to produce targeted toxins.

We tested these stem cells in a clinically relevant mouse model of brain cancer, where you resect the tumors and then implant the stem cells encapsulated in a gel into the resection cavity, Shah said. After doing all of the molecular analysis and imaging to track the inhibition of protein synthesis within brain tumors, we do see the toxins kill the cancer cells and eventually prolonging the survival in animal models of resected brain tumors.

Shah next plans to rationally combine the toxin-secreting stem cells with a number of different therapeutic stem cells developed by his team to further enhance their positive results in mouse models of glioblastoma, the most common brain tumor in human adults. Shah predicts that he will bring these therapies into clinical trials within the next five years.

This work was supported by theNational Institutes of Health and the James S. McDonnell Foundation.

Cited: Stuckey, D. W. et al. Engineering toxin-resistant therapeutic stem cells to treat brain tumors. STEM CELLS. October 24, 2014. DOI: 10.1002/stem.1874

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Scientists engineer toxin-secreting stem cells to treat ...

13 hours ago by Ryan Garcia

A new material that triggers stem cells to begin forming bone could enable a more effective treatment for hard-to-heal bone breaks and defects, says a Texas A&M University biomedical engineer who is part of the team developing the biomaterial.

The team's research is detailed in the scientific journal ACS Nano and is supported by the National Science Foundation and the National Institutes of Health. Its findings could change the way medical professionals treat fractured bones that experience difficulty in healing and often require bone graft procedures, says Akhilesh Gaharwar, assistant professor of biomedical engineering at Texas A&M.

The biomaterial, which consists of nano-sized, two-dimensional particles embedded within a gel, stimulates bone growth through a complex signaling mechanism without the use of proteins known as growth factors, Gaharwar explains. Growth factors are used in conventional treatments, but can lead to serious side effects due to the large amounts required to stimulate cells, he says.

"We are trying to overcome these problems by avoiding the use of growth factors as we recapitulate the natural bone-healing process," Gaharwar says. "Our material is a totally different, alternative strategy in which by using minerals we can induce differentiation in stem cells and promote formation of bone-like tissue."

Those minerals, Gaharwar explains, are largely orthosilicic acid, magnesium and lithium combined in tiny nanosilicate particles that are 100,000 times thinner than a sheet of paper. The ultrathin nanoparticles are embedded in a collagen-based hydrogel, a biodegradable gel used in several biomedical applications because of its compatibility with the body.

When nanosilicates are incorporated into a gelatin matrix, several physical, chemical and biological properties of the hydrogel are enhanced, Gaharwar explains. For example, the hydrogel can be designed to remain at the injury site for specific durations by controlling the interactions between the nanosilicates and gelatin, Gaharwar adds. This customization, Gaharwar says, can allow the injected hydrogel to enter the defect cavity and help it heal while slowly degrading as it is replaced by natural tissue.

Tests on the mechanical properties of the material are also promising, Gaharwar says. In addition to its ability to be injected at the site of an injury, the material achieves three-to-four times higher stiffness once inside the body, allowing it to be locked in place. This prevents the material from flowing to other parts of the body, thereby avoiding unwanted side effects, Gaharwar says.

The results, Gaharwar says, have been positive, as evidenced by both short-term and long-term indicators of bone growth. Initial tests, he says, show a three-fold increase in alkaline phosphatase activity, a marker for early bone formation (known as osteogenesis). This is confirmation, Gaharwar explains, that the signaling process is indeed "asking" stem cells to differentiate into bone cells. Late markers are also positive, he adds, noting they demonstrate a four-fold increase in the presence of calcium phosphate, a main component of bone.

"The dynamic and bioactive nanocomposite gels we have developed show strong promise in bone tissue engineering applications," Gaharwar says.

Continued here:
Biomedical engineer developing nanomaterial for healing broken bones