Stem Cells Reveal How Illness-Linked Genetic Variation Affects Neurons

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Newswise A genetic variation linked to schizophrenia, bipolar disorder and severe depression wreaks havoc on connections among neurons in the developing brain, a team of researchers reports. The study, led by Guo-li Ming, M.D., Ph.D., and Hongjun Song, Ph.D., of the Johns Hopkins University School of Medicine and described online Aug. 17 in the journal Nature, used stem cells generated from people with and without mental illness to observe the effects of a rare and pernicious genetic variation on young brain cells. The results add to evidence that several major mental illnesses have common roots in faulty wiring during early brain development.

This was the next best thing to going back in time to see what happened while a person was in the womb to later cause mental illness, says Ming. We found the most convincing evidence yet that the answer lies in the synapses that connect brain cells to one another.

Previous evidence for the relationship came from autopsies and from studies suggesting that some genetic variants that affect synapses also increase the chance of mental illness. But those studies could not show a direct cause-and-effect relationship, Ming says.

One difficulty in studying the genetics of common mental illnesses is that they are generally caused by environmental factors in combination with multiple gene variants, any one of which usually could not by itself cause disease. A rare exception is the gene known as disrupted in schizophrenia 1 (DISC1), in which some mutations have a strong effect. Two families have been found in which many members with the DISC1 mutations have mental illness.

To find out how a DISC1 variation with a few deleted DNA letters affects the developing brain, the research team collected skin cells from a mother and daughter in one of these families who have neither the variation nor mental illness, as well as the father, who has the variation and severe depression, and another daughter, who carries the variation and has schizophrenia. For comparison, they also collected samples from an unrelated healthy person. Postdoctoral fellow Zhexing Wen, Ph.D., coaxed the skin cells to form five lines of stem cells and to mature into very pure populations of synapse-forming neurons.

After growing the neurons in a dish for six weeks, collaborators at Pennsylvania State University measured their electrical activity and found that neurons with the DISC1 variation had about half the number of synapses as those without the variation. To make sure that the differences were really due to the DISC1 variation and not to other genetic differences, graduate student Ha Nam Nguyen spent two years making targeted genetic changes to three of the stem cell lines.

In one of the cell lines with the variation, he swapped out the DISC1 gene for a healthy version. He also inserted the disease-causing variation into one healthy cell line from a family member, as well as the cell line from the unrelated control. Sure enough, the researchers report, the cells without the variation now grew the normal amount of synapses, while those with the inserted mutation had half as many.

We had our definitive answer to whether this DISC1 variation is responsible for the reduced synapse growth, Ming says.

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New Blood: Tracing the Beginnings of Hematopoietic Stem Cells

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Newswise Hematopoietic stem cells (HSCs) give rise to all other blood cell types, but their development and how their fate is determined has long remained a mystery. In a paper published online this week in Nature, researchers at the University of California, San Diego School of Medicine elaborate upon a crucial signaling pathway and the role of key proteins, which may help clear the way to generate HSCs from human pluripotent precursors, similar to advances with other kinds of tissue stem cells.

Principal investigator David Traver, PhD, professor in the Department of Cellular and Molecular Medicine, and colleagues focused on the Notch signaling pathway, a system found in all animals and known to be critical to the generation of HSCs in vertebrates. Notch signaling between emitting and receiving cells is key to establishing HSC fate during development, said Traver. What has not been known is where, when and how Notch signal transduction is mediated.

Traver and colleagues discovered that the Notch signal is transduced into HSC precursor cells from signal emitting cells in the somite embryologic tissues that eventually contribute to development of major body structures, such as skeleton, muscle and connective tissues much earlier in the process than previously anticipated.

More specifically, they found that JAM proteins, best known for helping maintain tight junctions between endothelial cells to prevent vascular leakage, were key mediators of Notch signaling. When the researchers caused loss of function in JAM proteins in a zebrafish model, Notch signaling and HSCs were also lost. When they enforced Notch signaling through other means, HSC development was rescued.

To date, it has not been possible to generate HSCs de novo from human pluripotent precursors, like induced pluripotent stem cells, said Traver. This has been due in part to a lack of understanding of the complete set of factors that the embryo uses to make HSCs in vivo. It has also likely been due to not knowing in what order each required factor is needed.

Our studies demonstrate that Notch signaling is required much earlier than previously thought. In fact, it may be one of the earliest determinants of HSC fate. This finding strongly suggests that in vitro approaches to instruct HSC fate from induced pluripotent stem cells must focus on the Notch pathway at early time-points in the process. Our findings have also shown that JAM proteins serve as a sort of co-receptor for Notch signaling in that they are required to maintain close contact between signal-emitting and signal-receiving cells to permit strong activation of Notch in the precursors of HSCs.

The findings may have far-reaching implications for eventual development of hematopoietic stem cell-based therapies for diseases like leukemia and congenital blood disorders. Currently, it is not possible to create HSCs from differentiation of embryonic stem cells or induced pluripotent stem cells pluripotent cells artificially derived from non-pluripotent cells, such as skin cells that are being used in other therapeutic research efforts.

Co-authors include Isao Kobayashi, Jingjing Kobayashi-Sun, Albert D. Kim and Claire Pouget, UC San Diego Department of Cellular and Molecular Medicine; Naonobu Fujita, UC San Diego Section of Cell and Developmental Biology; and Toshio Suda, Keio University, Japan.

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Science Scandal Triggers Suicide, Soul-Searching in Japan

Yoshiki Sasais death has generated mixed emotions among Japan's scientific community

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Researchers death shocks Japan

Yoshiki Sasai was a top stem-cell researcher

Hans Sautter

Yoshiki Sasai, one of Japans top stem-cell researchers, died this morning (5 August) in an apparent suicide. He was 52.

Sasai, who worked at the RIKEN Center for Developmental Biology (CDB) in Kobe, Japan, was famous for his ability to coax embryonic stem cells to differentiate into other cell types. In 2011, he stunned the world by mimicking an early stage in the development of the eye a three-dimensional structure called an optical cup in vitro,using embryonic stem cells.

But lately he had been immersed in controversy over two papers, published inNaturein January, that claimed a simple method of creating embryonic-like cells, called stimulus-triggered acquisition of pluripotency (STAP). Various problems in the papers led to a judgement of scientific misconduct for their lead author, Haruko Obokata, also of the CDB. The papers were retracted on 2 July.

Sasai, who was a co-author of both papers,was cleared of any direct involvement in the misconduct. But he has been harshly criticized for failure of oversight in helping to draft the paper. Some critics, often on the basis of unsupported conjecture, alleged deeper involvement of the CDB. An independent committee recommended on 12 June that the CDB, where Sasai was a vice-director, be dismantled.Sasai had been instrumental in launching the CDB and helped it to develop into one of the worlds premier research centres.

Just after9 a.m., Sasai was found hanging in a stairwell of the Institute of Biomedical Research and Innovation, next to the CDB, where he also had a laboratory. He was pronounced dead just after11 a.m., according to reports byJapanese media.A bag found at the scene contained three letters: one addressed to CDB management, one to his laboratory members and one to Obokata.

In a brief statement released this morning, RIKEN president Ryoji Noyori mourned the death of the pioneering researcher. The world scientific community has lost an irreplaceable scientist, he said.

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Yoshiki Sasai Suicide: Japanese Stem Cell Scientist Found Dead In Kobe Facility

A Japanese scientist who was among a team of researchers accused of falsifying the results of two stem cell studies committed suicide Tuesday at a government science institute in western Japan. Yoshiki Sasai, deputy director of the Riken Center for Developmental Biology, was found by a security guard at the Kobe facility with a rope around his neck, the Associated Press reports. Authorities said he had suffered from cardiac arrest and was pronounced dead two hours later.

Sasai, 52, was considered an expert in embryonic stem cell research and co-authored two research papers published in January in the journal Nature that detailed a seemingly groundbreaking method of harvesting stem cells to grow new human tissue. Sasai and lead author Haruko Obokata reported having successfully altered ordinary mouse cells into versatile stem cells by immersing them in a mildly acidic solution. The resulting cells were named stimulus-triggered acquisition of pluripotency (STAP) cells.

The studies were initially praised as being on the cutting edge of stem cell treatment, but were quickly disputed when other scientists could not replicate the experimental procedure. The papers were retracted six months later after the journal found they contained erroneous data, among other flaws.

Scientists at RIKEN Center for Developmental Biology in Kobe are deeply concerned about the allegations regarding the recently reported STAP cells, the center said in a statement released in March. We wish to express our strong commitment to maintaining the highest level of scientific integrity to the public and the scientific community. We are fully aware that trust from the society is crucial for research activities carried out in RIKEN.

The scandal apparently affected Sasais health. Following the initial revelation that the research he was involved in may have been flubbed, he was hospitalized in March for stress, according to Riken spokesman Satoru Kagaya, who told reporters during a televised news conference on Tuesday that Sasai “seemed completely exhausted” when they talked over the phone in May.

Several suicide notes were found on Sasais secretarys desk, according to the Wall Street Journal. The content of the notes has not been made public, but officials said two of the notes were addressed to Riken officials, one of whom was Obokata.

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STAP stem cell controversy ends in suicide for Japanese scientist

A Japanese scientist who played an instrumental role in two discredited studies about a new type of stem cells hanged himself at his research institute in Kobe, according to media reports there.

Yoshiki Sasai, a deputy director of the RIKEN Center for Developmental Biology, left behind five apparent suicide notes, Japan Times reported Tuesday.

I am overcome with grief at this terrible news, RIKEN President Ryoji Noyori said in a statement released Tuesday. The scientific world has lost a talented and dedicated researcher, who earned our deep respect for the advanced research he carried out over many years. I would like to express my deepest condolences to Dr. Sasais family and colleagues.

Sasai was a coauthor on two papers published in Nature that purported to offer a quick and simple way of making highly versatile stem cells. Instead of destroying embryos or tinkering with their DNA, the scientists said they produced their flexible cells by stressing them out in an acid bath for 30 minutes and then spinning them in a centrifuge for 5 minutes.

At first, scientists hailed the creation of the so-called stimulus-triggered acquisition of pluripotency, or STAP, stem cells. But within days, serious questions arose about the researchers methods, leading to a RIKEN investigation that found several instances of scientific misconduct on that part of study leader Haruko Obokata, a rising scientist at RIKEN.

Both studies were retracted in July.

Sasai was Obokatas supervisor and was supposed to oversee her writing, Japan Times reported. RIKEN faulted Sasai for failing to check the data used in the study and for providing weak oversight that allowed Obokata to submit a manuscript with manipulated images and other serious problems.

“Research misconduct occurred due to a young researcher’s lack of experience and awareness of the importance of research ethics, the lack of leadership among researchers to help her, and a lack of mutual verification among groups,” Noyori said when RIKEN announced the results of its investigation in April.

Sasai appeared to take these criticisms to heart. He offered a very contrite statement when the studies were retracted.

As a researcher, I am deeply ashamed of the fact that two papers of which I was an author were found to contain multiple errors and, as a result, had to be retracted, he wrote. I also deeply regret the fact that as a coauthor, I was not able to identify these errors beforehand and to exercise my leadership to prevent this regrettable situation, including misconduct, from occurring. I apologize wholeheartedly for the confusion and disappointment that this situation has caused.

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Japan: Disgraced Stem Cell Scientist Yoshiki Sasai Found Dead In Apparent Suicide

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Japanese scientist ends life

Tokyo, Aug 5 (IANS) A Japanese scientist and expert on embryonic stem cells – embroiled in a recent stem-cell research controversy – committed suicide Tuesday, media reports said. The research papers by Yoshiki Sasai, deputy director of the Riken Center for Developmental Biology, appeared in the journal Nature in January and showed a revolutionary method of creating stem cells. The research was …

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Top journal retracts stem-cell study

Leading science journal Nature is withdrawing a stem-cell study published in January that had been hailed as a ‘game-changer’ in the quest to grow transplant tissue.

The announcement on Wednesday came after mistakes were discovered in some data published in two papers, photograph captions were found to be misleading, and the work itself could not be repeated by other scientists, it said.

‘All co-authors of both papers have finally concluded that they cannot stand behind the papers, and have decided to retract them,’ the journal said in an editorial.

Nature said it would tighten up procedures to vet future studies submitted for publication.

On June 4, Japan’s Riken research institute said lead scientist Haruko Obotaka, 30, had agreed to retract the papers after an investigation.

Obokata was feted after unveiling findings that appeared to show a straight-forward way to reprogram adult cells to become stem cells – precursors that are capable of developing into any other cell in the human body.

Identifying a readily-manufacturable supply of stem cells could one day help meet a need for transplant tissues, or even whole organs.

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Discovery may make it easier to develop life-saving stem cells

Jul 17, 2014 A photograph of a human egg, or oocyte. An MSU team of researchers found that certain genes taken from the oocyte can be key in the making of stem cells. Credit: Jose Cibelli

Not unlike looking for the proverbial needle in a haystack, a team of Michigan State University researchers have found a gene that could be key to the development of stem cells cells that can potentially save millions of lives by morphing into practically any cell in the body.

The gene, known as ASF1A, was not discovered by the team. However, it is at least one of the genes responsible for the mechanism of cellular reprogramming, a phenomenon that can turn one cell type into another, which is key to the making of stem cells.

In a paper published in the journal Science, the researchers describe how they analyzed more than 5,000 genes from a human egg, or oocyte, before determining that the ASF1A, along with another gene known as OCT4 and a helper soluble molecule, were the ones responsible for the reprogramming.

“This has the potential to be a major breakthrough in the way we look at how stem cells are developed,” said Elena Gonzalez-Munoz, a former MSU post-doctoral researcher and first author of the paper. “Researchers are just now figuring out how adult somatic cells such as skin cells can be turned into embryonic stem cells. Hopefully this will be the way to understand more about how that mechanism works.”

In 2006, an MSU team identified the thousands of genes that reside in the oocyte. It was from those, they concluded, that they could identify the genes responsible for cellular reprogramming.

In 2007, a team of Japanese researchers found that by introducing four other genes into cells, stem cells could be created without the use of a human egg. These cells are called induced pluripotent stem cells, or iPSCs.

“This is important because the iPSCs are derived directly from adult tissue and can be a perfect genetic match for a patient,” said Jose Cibelli, an MSU professor of animal science and a member of the team.

The researchers say that the genes ASF1A and OCT4 work in tandem with a ligand, a hormone-like substance that also is produced in the oocyte called GDF9, to facilitate the reprogramming process.

“We believe that ASF1A and GDF9 are two players among many others that remain to be discovered which are part of the cellular-reprogramming process,” Cibelli said.

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Discovery may make it easier to develop life-saving stem cells

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