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After years of failed attempts, researchers have finally generated stem cells from adults using the same cloning technique that produced Dolly the sheep in 1996.

A previous claim that Korean investigators had succeeded in the feat turned out to be fraudulent. Then last year, a group at Oregon Health & Science University generated stem cells using the Dolly technique, but with cells from fetuses and infants.

MORE: Stem-Cell Research: The Quest Resumes

In this case, cells from a 35-year-old man and a 75-year-old man were used to generate two separate lines of stem cells. The process, known as nuclear transfer, involves taking the DNA from a donor and inserting it into an egg that has been stripped of its DNA. The resulting hybrid is stimulated to fuse and start dividing; after a few days the embryo creates a lining of stem cells that are destined to develop into all of the cells and tissues in the human body. Researchers extract these cells and grow them in the lab, where they are treated with the appropriate growth factors and other agents to develop into specific types of cells, like neurons, muscle, or insulin-producing cells.

Reporting in the journal Cell Stem Cell, Dr. Robert Lanza, chief scientific officer at biotechnology company Advanced Cell Technology, and his colleagues found that tweaking the Oregon teams process was the key to success with reprogramming the older cells. Like the earlier team, Lanzas group used caffeine to prevent the fused egg from dividing prematurely. Rather than leaving the egg with its newly introduced DNA for 30 minutes before activating the dividing stage, they let the eggs rest for about two hours. This gave the DNA enough time to acclimate to its new environment and interact with the eggs development factors, which erased each of the donor cells existing history and reprogrammed it to act like a brand new cell in an embryo.

VIDEO: Breakthrough in Cloning Human Stem Cells: Explainer

The team, which included an international group of stem cell scientists, used 77 eggs from four different donors. They tested their new method by waiting for 30 minutes before activating 38 of the resulting embryos, and waiting two hours before triggering 39 of them. None of the 38 developed into the next stage, while two of the embryos getting extended time did. There is a massive molecular change occurring. You are taking a fully differentiated cell, and you need to have the egg do its magic, says Lanza. You need to extend the reprogramming time before you can force the cell to divide.

While a 5% efficiency may not seem laudable, Lanza says that its not so bad given that the stem cells appear to have had their genetic history completely erased and returned to that of a blank slate. This procedure works well, and works with adult cells, says Lanza.

The results also teach stem cell scientists some important lessons. First, that the nuclear transfer method that the Oregon team used is valid, and that with some changes it can be replicated using older adult cells. It looks like the protocols we described are real, they are universal, they work in different hands, in different labs and with different cells, says Shoukhrat Mitalopov, director of the center for embryonic cell and gene therapy at Oregon Health & Science University, and lead investigator of that study.

Originally posted here:
Researchers Clone Cells From Two Adult Men

The first volunteers are expected to be treated by late 2016. If successful, the trial could pave the way to the wide-scale use of artificial blood derived from stem cells.

Blood cells freshly made in the laboratory are likely to have a longer life span than those taken from donors, which typically last no more than 120 days.

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They would also be free from infectious agents such as viruses or the rogue prion proteins that cause Creuzfeldt-Jakob Disease (CJD). Professor Marc Turner, medical director at the Scottish National Blood Transfusion Service (SNBTS), who is leading the 5 million project at the University of Edinburgh, said: "Producing a cellular therapy which is of the scale, quality and safety required for human clinical trials is a very significant challenge. But if we can achieve success with this first-in-man clinical study it will be an important step forward to enable populations all over the world to benefit from blood transfusions.

"These developments will also provide information of value to other researchers working on the development of cellular therapies."

The pilot study will involve no more than about three patients, who may be healthy volunteers or individuals suffering from a red blood cell disorder such as thalassaemia. They will receive a small, five millilitre dose of laboratory-made blood to see how it behaves and survives in their bodies.

The blood cells will be created from ordinary donated skin cells called fibroblasts which are genetically reprogrammed into a stem cell-like state.

The resulting induced pluripotent stem (iPS) cells have the same ability as embryonic stem cells to develop into virtually any kind of body tissue.

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Scientists pioneer lab-grown red cells

The first volunteers are expected to be treated by late 2016. If successful, the trial could pave the way to the wide-scale use of artificial blood derived from stem cells.

Blood cells freshly made in the laboratory are likely to have a longer life span than those taken from donors, which typically last no more than 120 days.

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They would also be free from infectious agents such as viruses or the rogue prion proteins that cause Creuzfeldt-Jakob Disease (CJD).

Professor Marc Turner, medical director at the Scottish National Blood Transfusion Service (SNBTS), who is leading the 5 million project at the University of Edinburgh, said: "Producing a cellular therapy which is of the scale, quality and safety required for human clinical trials is a very significant challenge.

"But if we can achieve success with this first-in-man clinical study it will be an important step forward to enable populations all over the world to benefit from blood transfusions.

"These developments will also provide information of value to other researchers working on the development of cellular therapies."

The pilot study will involve no more than about three patients, who may be healthy volunteers or individuals suffering from a red blood cell disorder such as thalassaemia.

They will receive a small, five millilitre dose of laboratory-made blood to see how it behaves and survives in their bodies.

The blood cells will be created from ordinary donated skin cells called fibroblasts which are genetically reprogrammed into a stem cell-like state.

Read the original here:
In the blood: Scottish scientists pioneer lab-grown cells

14/04/2014 - 13:40:33Back to World Home

Red blood cells grown in a laboratory are to be tested in patients for the first time by pioneering scientists.

The first volunteers are expected to be treated by late 2016. If successful, the trial could pave the way to the wide-scale use of artificial blood derived from stem cells.

Blood cells freshly made in the laboratory are likely to have a longer life span than those taken from donors, which typically last no more than 120 days.

They would also be free from infectious agents such as viruses or the rogue prion proteins that cause Creuzfeldt-Jakob Disease (CJD).

Professor Marc Turner, medical director at the Scottish National Blood Transfusion Service (SNBTS), who is leading the 5m project at the University of Edinburgh, said: Producing a cellular therapy which is of the scale, quality and safety required for human clinical trials is a very significant challenge. But if we can achieve success with this first-in-man clinical study it will be an important step forward to enable populations all over the world to benefit from blood transfusions.

These developments will also provide information of value to other researchers working on the development of cellular therapies.

The pilot study will involve no more than about three patients, who may be healthy volunteers or individuals suffering from a red blood cell disorder such as thalassaemia.

They will receive a small, five millilitre dose of laboratory-made blood to see how it behaves and survives in their bodies.

The blood cells will be created from ordinary donated skin cells called fibroblasts which are genetically reprogrammed into a stem cell-like state.

View original post here:
Scientists to test artificial blood in humans

Bradley J. Fikes

Stem-cell biologist Mahendra Rao expected five projects to receive support to set up clinical trials.

Stem-cell researchers at the US National Institutes of Health (NIH) have been left frustrated and confused following the demise of the agencys Center for Regenerative Medicine (CRM). The intramural programmes director, stem-cell biologist Mahendra Rao, left the NIH, in Bethesda, Maryland, on 28March, and the centres website was taken down on 4 April. Although no official announcement had been made at the time Nature went to press, NIH officials say that they are rethinking how they will conduct in-house stem-cell research.

Researchers affiliated with the centre say that they have been left in the dark. When contacted by Nature on 7April, George Daley, a stem-cell biologist at Harvard Medical School in Boston, Massachusetts, and a member of the centres external advisory board, said that he had not yet been told of Raos departure or the centres closure.

The CRM was established in 2010 to centralize the NIHs stem-cell programme. Its goal was to develop useful therapies from induced pluripotent stem (iPS) cells adult cells that have been converted into embryonic-like stem cells and shepherd them towards clinical trials and regulatory approval. Its budget was intended to be $52million over seven years.

Rao took the helm in 2011. Relations seem to have soured last month owing to an NIH decision to award funding to only one project aiming to move iPS cells into a clinical trial. Rao says he resigned after this became clear. He says that he had hoped that five trials would be funded, especially because the centre had already sorted out complex issues relating to tissue sources, patents and informed consent.

James Anderson, director of the NIHs Division of Program Coordination, Planning, and Strategic Initiatives, which administered the CRM, counters that only one application that made by Kapil Bharti of the National Eye Institute in Bethesda and his colleagues received a high enough score from an external review board to justify continued funding. The team aims to use iPS cells to treat age-related macular degeneration of the retina, and hopes to commence human trials within a few years. Several other proposals, which involved the treatment of cardiac disease, cancer and Parkinsons disease, will not receive funding to ready them for clinical trials. Anderson stresses that Bhartis trial will not be affected by the CRMs closure.

NIH

Therapies based on induced pluripotent stem cells, here differentiating into retinal cells on a scaffold, were the focus of the Center for Regenerative Medicine.

Other human iPS-cell trials are further along. For example, one on macular degeneration designed by Masayo Takahashi at the RIKEN Center for Developmental Biology in Kobe, Japan, began recruiting patients last August.

Link:
NIH stem-cell programme closes

Mouse cells exposed to an acidic environment turned into embryonic-like "STAP" cells. These were used to generate an entire fetus.

A coauthor of a disputed study on a new way generating stem cells through exposure to acid and other stresses has asked for its retraction, it was reported Monday.

Teruhiko Wakayama asked for retraction of two papers describing so-called STAP cells, according to the Yomiuri Shimbun. The papers had been published in the Jan. 30 edition of the journal Nature. Other news outlets, including the Wall Street Journal and the Boston Globe, quickly followed up with the call for retraction.

The original announcement gained worldwide attention because it promised an easy way to generate pluripotent stem cells, which act like embryonic stem cells. Simply immersing cells in an acid bath or squeezing them was enough to reprogram them to the embryonic-like state, the scientists reported. The acronym STAP stands for stimulus-triggered acquisition of pluripotency.

However, researchers attempting to replicate the experiment, including those at the Salk Institute and The Scripps Research Institute in La Jolla, have so far reported failure. And errors in the papers, including duplication of images, have caused scientists to question the findings.

The first author of both papers is Haruko Obokata, 30, of the Riken Center for Developmental Biology in Japan. She was hailed as a scientific prodigy after the research was published. Another coauthor, Charles Vacanti, chairman of the Anesthesiology department at Brigham and Womens Hospital in Boston, had previously said the errors were caused by overwork and didn't affect the results.

As recently as Feb. 27, Wakayama said scientists should give replication efforts a year before passing judgment.

But on Monday, Wakayama said the irregularities render the findings questionable.

"Wakayama said images that show pluripotency of STAP cells look almost identical to those used in Obokatas doctoral thesis about pluripotent stem cells that exist in human body," the Yomiuri Shimbun reported.

Wakayama is probably acting out of a sense of duty, said Jeanne Loring, a stem cell scientist at The Scripps Research Institute.

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STAP cells paper coauthor asks for retraction

PUBLIC RELEASE DATE:

9-Mar-2014

Contact: Henry Rummins h.rummins@ucl.ac.uk 44-207-679-9063 University College London

Japanese pharmaceutical company Takeda will work with University College London (UCL) to drive research into tackling muscle disorders, in particular muscular dystrophy.

The research which is being conducted by the research group of Dr Francesco Saverio Tedesco is being supported through funding of $250,000 from the company's New Frontier Sciences group. Takeda's NFS aims to support innovative, cutting-edge research which could eventually lead to drug discovery and development.

Dr Tedesco's team will focus on the study of muscular regeneration and the potential for stem cell therapies to treat muscular dystrophy, in particular induced pluripotent (iPS) stem cells.

The team is also investigating the potential for treating muscular dystrophy through developing novel gene and cell therapy strategies using artificial human chromosomes and novel biomaterials.

Using this approach, Dr Tedesco hopes to overcome a number of current limitations to developing effective treatments for muscular dystrophies. It is hoped that through the use of these modified stem cells, large quantities of progenitor cells could be produced to be transplanted into a patient's muscle following genetic correction or to be used for drug development platforms.

Importantly, the team will attempt to produce these cells which can be applied more easily in a clinical context, in order to reduce the hurdles that might limit their possible future use in clinical studies.

Through previous work using a mouse model of Duchenne muscular dystrophy, the team has already demonstrated the potential of pre-clinical gene replacement therapy using an artificial human chromosome.

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Takeda and UCL to work together to tackle muscle disorders

Doubts keep growing about the stunning discovery that super stem cells could be created merely by placing white blood cells from young mice in acid or otherwise stressing them, says Paul Knoepfler, a stem cell researcher at UC Davis.

Among other inconsistencies, Knoepfler referred to several unexplained anomalies in images of these STAP cells in two papers, published by the prestigious journal Nature on Jan. 29. One image appears to suggest signs that virtually all cells treated with an acid bath were being reprogrammed, a result that would be extraordinary. Stem cell reprogramming to date has been inefficient, with a low percentage of treated cells being reprogrammed.

"The more I look at these two STAP papers, the more concerned I get ... The bottom line for me now is that some level a part of me still clings to a tiny and receding hope this has all been overblown due to simple misunderstandings, but that seems increasingly unlikely," Knoepfler wrote Sunday on his blog, IPS Cell.

This undated image made available by the journal Nature shows a mouse embryo formed with specially-treated cells from a newborn mouse that had been transformed into stem cells. Researchers in Boston and Japan say they created stem cells from various tissues of newborn mice. If the same technique works for humans, it may provide a new way to grow tissue for treating illnesses like diabetes and Parkinson's disease. The report was published online on Wednesday, Jan. 29, 2014 in the journal Nature. (AP Photo/RIKEN Center for Developmental Biology, Haruko Obokata)

Nature is conducting its own investigation, Knoepfler noted. But in addition, the journal should release "unmodified, original versions" of the images and data in the papers, Knoepfler wrote.

The images contained "minor errors" that didn't change the basic findings, said Charles Vacanti, a Harvard University professor who is part of the scientific team reporting the discovery, according to a Feb. 22 article in a Japanese newspaper, the Asahi Shimbun.

Controversy is normal for any major scientific advance. Skeptics must be converted, and the only way to do that is to show the data. The 1997 announcement of the first mammalian clone, Dolly the sheep, was greeted with considerable doubt because it was believed that genetic imprinting made such cloning impossible. But others were eventually able to confirm the finding.

In this case, doubters say such an apparently easy method of reprogramming cells would generate pluripotent stem cells far too easily, because stress is common in animals. Such stem cells are known to cause tumors, so evolution should have selected against such a response.

Nature's own role has been criticized. The journal was taken to task for its handling of online journalism Feb. 20 by another stem cell blogger, Alexey Bersenev. He chided Nature for not linking to sources.

"In scientific journalism, every claim must be linked to appropriate original source," Berseney wrote. "Nature consistently refuses to acknowledge bloggers, online discussions and other web resources with valid credible information. This is not acceptable for sci journalism."

The rest is here:
STAP stem cell doubts keep proliferating

La Jolla, CAA study led by researchers at the Salk Institute for Biological Studies, has catapulted the field of regenerative medicine significantly forward, proving in principle that a human genetic disease can be cured using a combination of gene therapy and induced pluripotent stem (iPS) cell technology. The study, published in the May 31, 2009 early online edition of Nature, is a major milestone on the path from the laboratory to the clinic.

"It's been ten years since human stem cells were first cultured in a Petri dish," says the study's leader Juan-Carlos Izpisa Belmonte, Ph.D., a professor in the Gene Expression Laboratory and director of the Center of Regenerative Medicine in Barcelona (CMRB), Spain. "The hope in the field has always been that we'll be able to correct a disease genetically and then make iPS cells that differentiate into the type of tissue where the disease is manifested and bring it to clinic."

Genetically-corrected fibroblasts from Fanconi anemia patients (shown in green at the top) are reprogrammed to generate induced pluripotent stem cells, which, in turn, can be differentiated into disease-free hematopoietic progenitors, capable of producing blood cells in vitro (bottom: Erythroid colonies.)

Image: Courtesy of Dr. Juan-Carlos Belmonte, Salk Institute for Biological Studies.

Although several studies have demonstrated the efficacy of the approach in mice, its feasibility in humans had not been established. The Salk study offers the first proof that this technology can work in human cells.

Belmonte's team, working with Salk colleague Inder Verma, Ph.D., a professor in the Laboratory of Genetics, and colleagues at the CMRB, and the CIEMAT in Madrid, Spain, decided to focus on Fanconi anemia (FA), a genetic disorder responsible for a series of hematological abnormalities that impair the body's ability to fight infection, deliver oxygen, and clot blood. Caused by mutations in one of 13 Fanconi anemia (FA) genes, the disease often leads to bone marrow failure, leukemia, and other cancers. Even after receiving bone marrow transplants to correct the hematological problems, patients remain at high risk of developing cancer and other serious health conditions.

After taking hair or skin cells from patients with Fanconi anemia, the investigators corrected the defective gene in the patients' cells using gene therapy techniques pioneered in Verma's laboratory. They then successfully reprogrammed the repaired cells into induced pluripotent stem (iPS) cells using a combination of transcription factors, OCT4, SOX2, KLF4 and cMYC. The resulting FA-iPS cells were indistinguishable from human embryonic stem cells and iPS cells generated from healthy donors.

Since bone marrow failure as a result of the progressive decline in the numbers of functional hematopoietic stem cells is the most prominent feature of Fanconi anemia, the researchers then tested whether patient-specific iPS cells could be used as a source for transplantable hematopoietic stem cells. They found that FA-iPS cells readily differentiated into hematopoietic progenitor cells primed to differentiate into healthy blood cells.

"We haven't cured a human being, but we have cured a cell," Belmonte explains. "In theory we could transplant it into a human and cure the disease."

Although hurdles still loom before that theory can become practice-in particular, preventing the reprogrammed cells from inducing tumors-in coming months Belmonte and Verma will be exploring ways to overcome that and other obstacles. In April 2009, they received a $6.6 million from the California Institute Regenerative Medicine (CIRM) to pursue research aimed at translating basic science into clinical cures.

Link:
Genetic Re-disposition: Combined stem cell-gene therapy ...

5 hours ago This image shows iPS cells (green) generated using histone variants TH2A and TH2B and two Yamanaka factors (Oct3/4 and Klf4). Credit: RIKEN

One major challenge in stem cell research has been to reprogram differentiated cells to a totipotent state. Researchers from RIKEN in Japan have identified a duo of histone proteins that dramatically enhance the generation of induced pluripotent stem cells (iPS cells) and may be the key to generating induced totipotent stem cells.

Differentiated cells can be coaxed into returning to a stem-like pluripotent state either by artificially inducing the expression of four factors called the Yamanaka factors, or as recently shown by shocking them with sublethal stress, such as low pH or pressure. However, attempts to create totipotent stem cells capable of giving rise to a fully formed organism, from differentiated cells, have failed.

The study, published today in the journal Cell Stem Cell and led by Dr. Shunsuke Ishii from RIKEN, sought to identify the molecule in the mammalian oocyte that induces the complete reprograming of the genome leading to the generation of totipotent embryonic stem cells. This is the mechanism underlying normal fertilization, as well as the cloning technique called Somatic-Cell Nuclear Transfer (SCNT).

SCNT has been used successfully to clone various species of mammals, but the technique has serious limitations and its use on human cells has been controversial for ethical reasons.

Ishii and his team chose to focus on two histone variants named TH2A and TH2B, known to be specific to the testes where they bind tightly to DNA and affect gene expression.

The study demonstrates that, when added to the Yamanaka cocktail to reprogram mouse fibroblasts, the duo TH2A/TH2B increases the efficiency of iPSC cell generation about twentyfold and the speed of the process two- to threefold. And TH2A and TH2B function as substitutes for two of the Yamanaka factors (Sox2 and c-Myc).

By creating knockout mice lacking both proteins, the researchers show that TH2A and TH2B function as a pair, are highly expressed in oocytes and fertilized eggs and are needed for the development of the embryo after fertilization, although their levels decrease as the embryo grows.

In the early embryo, TH2A and TH2B bind to DNA and induce an open chromatin structure in the paternal genome, thereby contributing to its activation after fertilization.

These results indicate that TH2A/TH2B might induce reprogramming by regulating a different set of genes than the Yamanaka factors, and that these genes are involved in the generation of totipotent cells in oocyte-based reprogramming as seen in SCNT.

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Histones may hold the key to the generation of totipotent stem cells

Mouse cells exposed to an acidic environment turned into embryonic-like "STAP" cells. These were used to generate an entire fetus.

A simple lab treatment can turn ordinary cells from mice into a new kind of stem cell, according to a surprising study that hints at a new way to grow tissue for treating illnesses like diabetes and Parkinsons disease.

Researchers in Boston and Japan exposed spleen cells from newborn mice to an acidic environment. In lab tests, that made the cells act like embryonic stem cells, showing enough versatility to produce the tissues of a mouse embryo, for example.

Cells from skin, muscle, fat and other tissue of newborn mice went through the same change, which could be triggered by exposing cells to any of a variety of stressful situations, researchers said.

Its very simple to do. I think you could do this actually in a college lab, said Dr. Charles Vacanti of Brigham and Womens Hospital in Boston, an author of two papers published online Wednesday by the journal Nature. They can be found here and here.

If it works in humans, the method could improve upon an existing method of generating artificial embryonic stem cells, called induced pluripotent stem cells. These IPS cells can be made from patients, then turned into the needed cells, reducing the possibility of transplant rejection. Pluripotent is a term for cells that act like embryonic stem cells, which can turn into nearly any tissue of the body, except for placental tissues.

In San Diego, scientists led by The Scripps Research Institutes Jeanne Loring propose to treat Parkinsons disease patients with brain cells generated from their own IPS cells. Because these cells arent taken from human embryos, they dont raise the ethical concerns some have with using embryonic stem cells.

However induced pluripotent stem cells are made by reprogramming ordinary cells with added genes or chemicals, which raises concerns about safety. The new method, in contrast, causes the cell to change its own behavior after researchers have applied an external stress. The actual DNA sequence is unaltered, creating a change that is epigenetic, or taking place outside the genome. Researchers dubbed the new cells STAP cells, for stimulus-triggered acquisition of pluripotency.

This is part of a shift in our view of pluripotency, Loring said by email. Eight years ago we thought that cells were stable -- whatever they are, they stay that way. Now, were thinking in terms of how powerful epigenetics is -- that we can change cell fate without changing their DNA.

Loring said it will take years to apply the new method for human therapy.

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New stem cell may aid medicine

PARIS: Scientists on Wednesday reported a simple way to turn animal cells back to a youthful, neutral state, a feat hailed as a "game-changer" in the quest to grow transplant tissue in the lab.

The research, reported in the journal Nature, could be the third great advance in stem cells -- a futuristic field that aims to reverse Alzheimer's, cancer and other crippling or lethal diseases.

The latest breakthrough comes from Japan, as did its predecessor which earned its inventor a Nobel Prize.

The new approach, provided it overcomes safety hurdles, could smash cost and technical barriers in stem-cell research, said independent commentators.

"If it works in man, this could be the game-changer that ultimately makes a wide range of cell therapies available using the patient's own cells as starting material," said Chris Mason, a professor of regenerative medicine at University College London.

"The age of personalised medicine will have arrived."

Stem cells are primitive cells that, as they grow, differentiate into the various specialised cells that make up the different organs -- the brain, the heart, the kidney and so on.

The goal is to create stem cells in the lab and nudge them to grow into these differentiated cells, thus replenishing organs damaged by disease or accident.

One of the obstacles, though, is ensuring that these transplanted cells are not attacked as alien by the body's immune system.

To achieve that, the stem cells would have to carry the patient's own genetic code, to identify them as friendly.

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Stem cells in "revolutionary" boost

Jan. 13, 2014 Geneticists from Ohio, California and Japan joined forces in a quest to correct a faulty chromosome through cellular reprogramming. Their study, published online today in Nature, used stem cells to correct a defective "ring chromosome" with a normal chromosome. Such therapy has the promise to correct chromosome abnormalities that give rise to birth defects, mental disabilities and growth limitations.

"In the future, it may be possible to use this approach to take cells from a patient that has a defective chromosome with multiple missing or duplicated genes and rescue those cells by removing the defective chromosome and replacing it with a normal chromosome," said senior author Anthony Wynshaw-Boris, MD, PhD, James H. Jewell MD '34 Professor of Genetics and chair of Case Western Reserve School of Medicine Department of Genetics and Genome Sciences and University Hospitals Case Medical Center.

Wynshaw-Boris led this research while a professor in pediatrics, the Institute for Human Genetics and the Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research at UC, San Francisco (UCSF) before joining the faculty at Case Western Reserve in June 2013.

Individuals with ring chromosomes may display a variety of birth defects, but nearly all persons with ring chromosomes at least display short stature due to problems with cell division. A normal chromosome is linear, with its ends protected, but with ring chromosomes, the two ends of the chromosome fuse together, forming a circle. This fusion can be associated with large terminal deletions, a process where portions of the chromosome or DNA sequences are missing. These deletions can result in disabling genetic disorders if the genes in the deletion are necessary for normal cellular functions.

The prospect for effective counter measures has evaded scientists -- until now. The international research team discovered the potential for substituting the malfunctioning ring chromosome with an appropriately functioning one during reprogramming of patient cells into induced pluripotent stem cells (iPSCs). iPSC reprogramming is a technique that was developed by Shinya Yamanaka, MD, PhD, a co-corresponding author on the Nature paper. Yamanaka is a senior investigator at the UCSF-affiliated Gladstone Institutes, a professor of anatomy at UCSF, and the director of the Center for iPS Cell Research and Application (CiRA) at the Institute for Integrated Cell-Material Sciences (iCeMS) in Kyoto University. He won the Nobel Prize in Medicine in 2012 for developing the reprogramming technique.

Marina Bershteyn, PhD, a postdoctoral fellow in the Wynshaw-Boris lab at UCSF, along with Yohei Hayashi, PhD, a postdoctoral fellow in the Yamanaka lab at the Gladstone Institutes, reprogrammed skin cells from three patients with abnormal brain development due to a rare disorder called Miller Dieker Syndrome, which results from large terminal deletions in one arm of chromosome 17. One patient had a ring chromosome 17 with the deletion and the other two patients had large terminal deletions in one of their chromosome 17, but not a ring. Additionally, each of these patients had one normal chromosome 17.

The researchers observed that, after reprogramming, the ring chromosome 17 that had the deletion vanished entirely and was replaced by a duplicated copy of the normal chromosome 17. However, the terminal deletions in the other two patients remained after reprogramming. To make sure this phenomenon was not unique to ring chromosome 17, they reprogrammed cells from two different patients that each had ring chromosomes 13. These reprogrammed cells also lost the ring chromosome, and contained a duplicated copy of the normal chromosome 13.

"It appears that ring chromosomes are lost during rapid and continuous cell divisions during reprogramming," said Yamanaka. "The duplication of the normal chromosome then corrects for that lost chromosome."

"Ring loss and duplication of whole chromosomes occur with a certain frequency in stem cells," explained Bershteyn. "When chromosome duplication compensates for the loss of the corresponding ring chromosome with a deletion, this provides a possible avenue to correct large-scale problems in a chromosome that have no chance of being corrected by any other means."

"It is likely that our findings apply to other ring chromosomes, since the loss of the ring chromosome occurred in cells reprogrammed from three different patients," said Hayashi.

Originally posted here:
Study discovers chromosome therapy to correct severe chromosome defect

WASHINGTON Every year, the editors of Science huddle together and pick an outstanding scientific achievement as the Breakthrough of the Year. This year's winner is:

CANCER IMMUNOTHERAPY: harnessing the immune system to battle tumors.

Scientists have thought for decades that such an approach to cancer therapy should be possible, but it has been incredibly difficult to make it work. Now many oncologists say we have turned a corner, because two different techniques are helping a subset of patients. One involves antibodies that release a brake on T cells, giving them the power to tackle tumors. Another involves genetically modifying an individual's T cells outside the body so that they are better able to target cancer, and then re-infusing them so they can do just that.

We are still at the beginning of this story and have a long way to go. Only a very small proportion of cancer patients have received these therapies, and many are not helped by them. Doctors and scientists still have a lot to learn about why the treatments do and do not work. But the results have been repeated at different centers and in different tumor types, giving doctors hope that immunotherapy for cancer may benefit more and more people in the future

The editors also singled out nine runners-up for special praise:

GENETIC MICROSURGERY

A year-old gene-editing technique called CRISPR touched off an explosion of research in 2013. It's short for "clustered regularly interspaced short palindromic repeats": repetitive stretches of DNA that bacteria have evolved to combat predatory viruses by slicing up the viral genomes. The "knife" is a protein called Cas9; in 2012, researchers showed they could use it as a scalpel to perform microsurgery on genes. This year the new technology became red hot, as more than a dozen teams wielded it to manipulate specific genes in mice, rats, bacteria, yeast, zebrafish, nematodes, fruit flies, plants and human cells, paving the way for understanding how these genes function and possibly harnessing them to improve health.

CLARITY BRAIN IMAGING

This year, researchers invented a new way of imaging the brain which many say will fundamentally change the way labs study the intricate organ. CLARITY, a method of rendering brain tissue transparent, removes the biggest obstacle to traditional brain imaging: the fatty, light-scattering molecules, called lipids, which form cellular membranes. By replacing lipids with single molecules of a clear gel, the technique renders brain tissue transparent while leaving all neurons, other brain cells and their organelles intact. This allows researchers to infiltrate the brain with labels for specific cell types, neurotransmitters, or proteins, wash them out, and image the brain again with different labels - a process they say could speed up by a hundredfold tasks such as counting all the neurons in a given brain region.

CLONING HUMAN STEM CELLS

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Science's top 10 breakthroughs of 2013

The most successful stem cell therapybone marrow transplanthas been around for more than 40 years. Johns Hopkins researchers played an integral role in establishing the methods for how bone marrow transplants are done, which you can read about in Human Stem Cells at Johns Hopkins: A Forty Year History. The latest developments in bone marrow transplants are Half-Matched Transplants, which may be helpful in treating more diseases than ever before. In The Promise of the Future, three Hopkins researchers who study blood diseases share their ideas about which technologies hold most promise for developing therapies.

Induced pluripotent stem cells, or iPS cells, are adult cells that are engineered to behave like stem cells and to regain the ability to differentiate into various cell types. Engineered Blood describes current research in generating blood cells that contain disease traits with Those Magic Scissors so we can learn more in the lab about diseases like sickle cell anemia.

Adult stem cells are being used in other applications as well. Stem Cells Enhance Healing tells of an undergraduate biomedical engineering team at Hopkins that has devised medical sutures containing stem cells which speed up healing when stitched in. And A New Path for Cardiac Stem Cells tells of how a patients own heart stem cells were used to repair his heart after a heart attack.

In the podcast What Anti-Depression Treatments Actually Target In The Brain, Hongjun Song reveals that current antidepressant therapies may have unknowingly been targeting stem cells all along.

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Stem Cell Research at Johns Hopkins Medicine: Stem Cell Therapy

Gypenosides pre-treatment protects the brain against cerebral ischemia and increases neural stem cells/progenitors in the subventricular zone.

Gypenosides pre-treatment protects the brain against cerebral ischemia and increases neural stem cells/progenitors in the subventricular zone.

Int J Dev Neurosci. 2013 Dec 12;

Authors: Wang XJ, Sun T, Kong L, Shang ZH, Yang KQ, Zhang QY, Jing FM, Dong L, Xu XF, Liu JX, Xin H, Chen ZY

Abstract Gypenosides (GPs) have been reported to have neuroprotective effects in addition to other bioactivities. The protective activity of GPs during stroke and their effects on neural stem cells (NSCs) in the ischemic brain have not been fully elucidated. Here, we test the effects of GPs during stroke and on the NSCs within the subventricular zone (SVZ) of middle cerebral artery occlusion (MCAO) rats. Our results show that pre-treatment with GPs can reduce infarct volume and improve motor function following MCAO. Pre-treatment with GPs significantly increased the number of BrdU-positive cells in the ipsilateral and contralateral SVZ of MCAO rats. The proliferating cells in both sides of the SVZ were glial fibrillary acidic protein (GFAP)/nestin-positive type B cells and Doublecortin (DCX)/nestin-positive type A cells. Our data indicate that GPs have neuroprotective effects during stroke which might be mediated through the enhancement of neurogenesis within the SVZ. These findings provide new evidence for a potential therapy involving GPs for the treatment of stroke.

PMID: 24334222 [PubMed - as supplied by publisher]

Cell based therapies for ischemic stroke: from basic science to bedside.

Prog Neurobiol. 2013 Dec 12;

Authors: Liu X, Ye R, Yan T, Yu SP, Wei L, Xu G, Fan X, Jiang Y, Stetler RA, Chen J

Abstract Cell therapy is emerging as a viable therapy to restore neurological function after stroke. Many types of stem/progenitor cells from different sources have been explored for their feasibility and efficacy for the treatment of stroke. Transplanted cells not only have the potential to replace the lost circuitry, but also produce growth and trophic factors, or stimulate the release of such factors from host brain cells, thereby enhancing endogenous brain repair processes. Although stem/progenitor cells have shown a promising role in ischemic stroke in experimental studies as well as initial clinical pilot studies, cellular therapy is still at an early stage in humans. Many critical issues need to be addressed including the therapeutic time window, cell type selection, delivery route, and in vivo monitoring of their migration pattern. This review attempts to provide a comprehensive synopsis of preclinical evidence and clinical experience of various donor cell types, their restorative mechanisms, delivery routes, imaging strategies, future prospects and challenges for translating cell therapies as a neurorestorative regimen in clinical applications.

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Stroke and Stem Cell Therapy

Shutdowns, lethal viruses, typhoons and meteorites much of this years science news seemed to come straight from the set of a Hollywood disaster movie. But there were plenty of feel-good moments, too. Space exploration hit a new high, cash poured in to investigate that most cryptic of human organs, the brain, and huge leaps were made in stem-cell therapies and the treatment of HIV. Here, captured in soundbites, statistics and summaries, is everything you need to know about the science that mattered in 2013.

LUX: Carlos H. Faham

The Large Underground Xenon dark-matter experiment, deep in a mine in South Dakota.

One of the years most important cosmological results was an experimental no-show. The Large Underground Xenon (LUX, pictured) experiment at Sanford Underground Research Facility in Lead, South Dakota 370 kilograms of liquid xenon almost 1.5kilometres down in a gold mine did not see any particles of elusive dark matter flying through Earth. But it put the tightest constraints yet on the mass of dark-matter particles, and their propensity to interact with visible matter. Theoretical physicist Matthew Strassler at Rutgers University in Piscataway, New Jersey, says a consensus is forming that hints of dark matter seen by earlier experiments in the past three years were probably just statistical fluctuations.

PlancK: ESA/Planck Collaboration

Whatever dark matter is, it makes up around 84% of the Universes total matter, according to observations, released in March, of the Universes cosmic microwave background (CMB) by the European Space Agencys Planck satellite. Plancks image (pictured) also strongly supports the hypothesis of inflation, in which the Universe is thought to have expanded rapidly after the Big Bang. A better probe of inflation might be provided through its predicted influence on how the polarization of CMB photons varies across the sky (B-mode polarization). That subtle signal has not been measured yet, but astronomers hopes were raised by news of the first sighting of a related polarization signal, by the South Pole Telescope, in July. And another Antarctic telescope the underground IceCube observatory confirmed this year that the high-energy neutrinos it has detected come from far away in the cosmos, hinting at a new world of neutrino astronomy.

Jae C. Hong/AP

US workers came out in force against the shutdown.

The slow decline of US federal support for research and development spending is already down 16.3% since 2010 reached a new nadir in October, when political brinkmanship led the government to shut down for 16 days. Grant money stopped flowing; work halted at major telescopes, US Antarctic bases and most federal laboratories; and key databases maintained by the government went offline. Many government researchers were declared non-essential and barred by law from visiting their offices and laboratories, or even checking their official e-mail accounts. Since the shutdowns end, grant backlogs and missed deadlines have scrambled agency workloads.

Away from the deadlock in the United States, the European Union negotiated a path to a 201420 research budget of almost 80billion (US$110billion), a 27% rise in real terms over the previous 200713 period. And funding in South Korea, China, Germany and Japan continued to increase (the United Kingdom and France saw little change). But Japans largesse came with the clear understanding that its science investment would bring fast commercial pay-offs. Along similar lines, US Republican politicians are calling for the National Science Foundation to justify every grant it awards as being in the national interest.

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365 days: 2013 in review

Top Science Stories of 2013

From the first vat-grown hamburger to the discovery of the world's largest volcano, scientists pushed back the limits of human knowledge in 2013 and developed technologies that could radically change how we live our lives.

The Science Media Centre team, in conjunction with our colleagues at the AusSMC, have assembled the top 10 picks for the most significant international science stories of the year. Contact the SMC if you would like more information about any of these stories, including copies of the research papers associated with them.

It was also a big year for New Zealand science with researchers publishing studies in some of the world's most influential journals. See below for our Top 10 list of New Zealand science stories that captured the public's attention in 2013.

Top 10 international science stories

1. Space sounds revealed Voyager 1 had boldly gone: In September, NASA's Voyager 1 spacecraft became the first man-made object to leave our solar system and venture into interstellar space. The probe, launched in 1977 with the aim of reaching Jupiter and Saturn, is now over 19 billion kilometres from the sun. Scientists listened in to vibrations in the plasma surrounding Voyager - the sound of interstellar space - after it was hit by a massive solar wave in April. The vibrations allowed them to calculate the plasma's density, which differs between our solar system and interstellar space, confirming Voyager was no longer in our solar system.

2. Carbon dioxide hit a new peak and human influence on the climate was clearer than ever:In May, levels of carbon dioxide in the Earth's atmosphere reached a symbolic milestone, passing 400ppm (parts per million) for the first time in human history. Just a few months later in September, the leading international body for the assessment of climate change, the Intergovernmental Panel on Climate Change (IPCC), found that human influence on the climate system is clearer than ever -we are now 95 percent certain that humans are the cause of global warming. Climate scientists from New Zealand were among the more than 600 scientists and researchers who worked on the IPCC report. 3. Scientists created human stem cells using cloning techniques: In May, researchers used therapeutic cloning to create human embryonic stem cells for the first time. The process involved taking the nucleus - which contains the genetic material - from a normal cell and transferring it into an unfertilised egg with its own genetic material removed. While this approach had previously been used in monkeys and mice, it had never succeeded using human cells. This discovery, described by Australian scientists as "a major breakthrough in regenerative medicine", could help develop personalised therapies for a range of currently untreatable diseases. However, the process requires human donor eggs, which are not easy to obtain, and raises a number of ethical issues.

4. Do you want fries with that? The world's most expensive burger was grown in the lab: The world's first lab-grown burger was cooked and eaten at a news conference in London in August this year - generating headlines around the world. The burger patty - which one food critic described as 'close to meat' - was developed by scientists from Maastricht University in the Netherlands through research funded by Google co-founder Sergey Brin. Starting with stem cells from a biopsy of two cows (a Belgian Blue and a Blonde d'Aquitaine), the scientists grew muscle fibres in the lab. The fibres were pressed together with breadcrumbs and binding ingredients, then coloured with beetroot juice and saffron, resulting in the most expensive hamburger in history at a cost of around NZ$400,000.

5. Doctors stopped HIV in its tracks in the "Mississippi baby": A child born with HIV and treated with a series of antiviral drugs for the first 18 months of its life was found to be free of the virus more than 12 months after treatment ended. When the infant was 30 months of age, HIV-1 antibodies remained completely undetectable. However, the big question of whether this child, known as the "Mississippi baby", has truly been cured of HIV remains unanswered. "The best answer at the moment is a definitive maybe", HIV expert Scott Hammer, wrote in a New England Journal of Medicineeditorial which accompanied the research.

6. Redefining mental illness: In May, the new version of the diagnostic reference manual used by clinicians in the U.S. and around the world to diagnose mental disorders was released. The fifth revision of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) is the first update in nearly 20 years and followed a decade of review and consultation. It's publication met with widespread controversy. One of its major changes is to introduce a graded scale known as Autism Spectrum Disorder combining the former four autism-related disorders: autistic, Asperger's, childhood disintegrative, and pervasive developmental disorder. Elsewhere, several new disorders were added, new suicide risk assessment scales were introduced and the threshold for diagnosing Post Traumatic Stress Disorder (PTSD) was lowered. Critics of DSM-5, including New Zealand experts, argue that it will lead to the over-diagnosis of mental disorders, stigmatising millions of people who are essentially normal.

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Top Science Stories of 2013

A groundbreaking attempt to heal eight Parkinson's patients with their own cells could move from research to the clinic next year.

For eight Parkinson's patients seeking treatment with a new form of stem cell therapy, 2014 promises to be a milestone. If all goes well, next year the FDA will give approval to begin clinical trials. And if the patients can raise enough money, the scientists and doctors working with them will have the money to proceed.

Jeanne Loring, a stem cell scientist at The Scripps Research Institute, discusses the status of a project to treat Parkinson's patients with their own cells, turned into the kind of brain cells destroyed in Parkinson's. The project is a collaboration with Scripps Health and the Parkinson's Association of San Diego.

Scientists at The Scripps Research Institute led by Jeanne Loring have taken skin cells from all patients and grown them into artificial embryonic stem cells, called induced pluripotent stem cells. They then converted the cells into dopamine-making neurons, the kind destroyed in Parkinson's disease.

Loring discussed the project's progress on Friday morning at the 2013 World Stem Cell Summit in San Diego.

If animal studies now under way and other requirements are met, doctors at Scripps Health will perform a clinical trial. They will grow neurons until they are just short of maturity, then transplant them into the brains of the respective patients. The cells are expected to complete maturation in the brain, forming appropriate connections with their new neighbors, and begin making dopamine.

Earlier attempts to treat Parkinson's with a stem cell-like therapy mostly failed because of difficulties in quality control of the source, neural cells from aborted fetuses, Loring said. But some patients gained lasting improvement, a tantalizing hint that the trials were on the right track.

In January, a "pre-pre-IND meeting" is planned with the FDA, Loring said.

Also speaking were Ed Fitzpatrick, one of the eight patients, and Kyoto University researcher Jun Takahashi, who is independently trying the same approach in Japan.

Ed Fitzpatrick, one of eight Parkinson's patients in a program to be treated with his own cells, grown into the kind of brain cells destroyed in Parkinson's.

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Stem cells for Parkinson's getting ready for clinic

Dec. 8, 2013 at 2:49 PM ET

Jeff Swensen / for NBC News

The Mogul family at The Children's Institute in Pittsburgh, Pennsylvania where parents Stephen and Robyn have taken their daughter, Bari, 9 and Hayley, 15, to undergoing extensive therapy to help with their rare genetic disorders.

At 15, Hayley Mogul lacks the fine motor skills needed to write. Her sister Bari is 9 and still eating baby food.

There's no cure for their rare disorders, caused by unique genetic mutations. But for once, there's an advantage to having conditions so rare that drug companies cannot even think of looking for a cure. The sisters are taking part in a whole new kind of experiment in which scientists are literally turning back the clock on their cells.

Theyre using an experimental technique to transform the cells into embryonic form, and then growing these baby cells in lab dishes.

The goal is the get the cells to misfire in the lab in just the same way they are in Hayleys and Baris bodies. Its a new marriage of genetics and stem cell research, and represents one of the most promising applications of so-called pluripotent stem cells.

One day these two girls will probably change the face of medicine as we know it, said their father, Steven Mogul.

Steven and Robyn Mogul dont understand why both their daughters ended up with the rare mutations, which cause a range of neurological and metabolic problems.

We have been tested, said Mogul, a 45-year-old wealth manager living in Chicago. We dont have any mutations, and there are no developmental issues. We have no idea how it happened.

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Stem cell science: Can two girls help change the face of medicine?