Category Archives: Massachusetts Stem Cells

Harvard scientists claim to have made a breakthrough in the obesity crisis Discovery could be 'the first step towards a pill that replaces the treadmill' Team found two compounds that turn white 'bad' fat cells into brown or 'good' fat cells in the human body When a person eats too many calories and doesn't burn them off, they're stored as white fat cells, causing a person to pile on the pounds New study found two molecules that convert fat stem cells, which would normally produce white fat, into brown fat cells The brown fat cells burn excess energy, reducing number of white fat cells

By Lizzie Parry for MailOnline

Published: 11:11 EST, 8 December 2014 | Updated: 17:07 EST, 8 December 2014

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An obesity pill that transforms 'bad' fat to 'good' could replace exercise, helping people shed pounds and with them their risk of type 2 diabetes, heart disease and cancer.

That is the claim by scientists who believe they have made a breakthrough in the battle against the bulge.

They said the discovery could be 'the first step towards a pill that can replace the treadmill'.

Harvard Stem Cell Institute at Havard and Massachusetts General Hospital have identified two compounds that can turn white or 'bad' fat cells into brown 'good' fat cells in the body.

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The obesity pill that could replace exercise by turning 'bad' fat to 'good'

"People often think about disease in black and white - that there's 'healthy' and there's 'disease' - but in reality most disease develops gradually over months or years, said assistant professor and senior author Steven McCarroll at Harvard Medical School.

The mutations are thought to originate in blood stem cells, which then produce mutated cells which reproduce at an accelerated rate until they account for a large fraction of the cells in a person's blood.

"Cancer is the end-stage of the process," said Siddhartha Jaiswal, a Broad associated scientist and clinical fellow from Massachusetts General Hospital who was first author of Ebert's paper.

"By the time a cancer has become clinically detectable it has accumulated several mutations that have evolved over many years. What we are primarily detecting here is an early, pre-malignant stage in which the cells have acquired just one initiating mutation."

Individuals with these mutations had a higher risk of Type 2 diabetes, coronary heart disease, and ischemic stroke as well.

The researchers involved emphasised that there is no clinical benefit today for testing for the mutations as there are currently no treatments that can prevent blood cancer.

However, they say the results open the door to entirely new directions for blood cancer research, toward early detection and even prevention.

"The results demonstrate a way to identify high-risk cohorts - people who are at much higher than average risk of progressing to cancer - which could be a population for clinical trials of future prevention strategies," added Prof McCarroll.

"The abundance of these mutated cells could also serve as a biomarker - like LDL cholesterol is for cardiovascular disease - to test the effects of potential prevention therapies in clinical trials."

The research was published in New England Journal of Medicine.

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Blood test could pick up risk of cancer five years in advance, say Harvard scientists

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Sensations such as itching and pain are detected by specific proteins on a nerve cell's surface.

Nerve cells that transmit pain, itch and other sensations to the brain have been made in the lab for the first time. Researchers say that the cells will be useful for developing new painkillers and anti-itch remedies, as well as understanding why some people experience unexplained extreme pain and itching.

The short take-home message would be pain and itch in a dish, and we think thats very important, says Kristin Baldwin, a stem-cell scientist at the Scripps Research Institute in La Jolla, California, whose team converted mouse and human cells called fibroblasts into neurons that detect sensations such as pain, itch or temperature1. In a second paper2, a separate team took a similar approach to making pain-sensing cells. Both efforts were published on 24 November in Nature Neuroscience.

Peripheral sensory neurons, as these cells are called, produce specialized receptor proteins that detect chemical and physical stimuli and convey them to the brain. The receptor that a cell makes determines its properties some pain-sensing cells respond to chilli oil, for example, and others respond to different pain-causing chemicals. Mutations in the genes encoding these receptors can cause some people to experience chronic pain or, in rare cases, to become impervious to pain.

To create these cells in the lab, independent teams led by Baldwin and by Clifford Woolf, a neuroscientist at Boston Childrens Hospital in Massachusetts, identified combinations of proteins that when expressed in fibroblasts transformed them into sensory neurons after several days. Baldwin's team identified neurons that make receptors that detect sensations including pain, itch, and temperature, whereas Woolfs team looked only at pain-detecting cells. Both teams generated cells that resembled neurons in shape and fired in response to capsaicin, which gives chilli peppers their kick, and mustard oil.

Both teams say that pain cells in a dish could speed the search for new painkillers, as they could be used in screening drugs for their ability to block or alter the activity of these cells. The number of people who take analgesics is very large, and theres a pretty big medical need among people who have untreatable pain during chemotherapy, says Baldwin. The anti-malarial drug chloroquine causes some people to itch especially people of African ancestry and studying itch cells made from their fibroblasts could help to explain why, she adds.

It will be important to make sure that the cells respond to stimuli similarly to bona fide sensory cells, says John Wood, a neuroscientist at University College London, and to determine how they communicate with immune cells and the rest of the nervous system, which both have roles in pain. This is important work, he says. Nociceptive [pain-sensing] neurons play a key role in almost all acute and chronic pain conditions, and a better understanding of their biologyshould produce new analgesic drug targets.

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Pain and itch neurons grown in a dish

Harvard Stem Cell Institute (HSCI) researchers, representing five Harvard departments and affiliated institutions as well as the Massachusetts Institute of Technology (MIT), have demonstrated that adult cells, reprogrammed into another cell type in a living animal, can remain functional over a long period.

The work by Joe Zhou, an associate professor in Harvard's Department of Stem Cell and Regenerative Biology, and his collaborators is an important advance in the effort to develop cell-based therapies for tissue repair, and specifically in the effort to develop improved treatment for diabetes.

The researchers used a combination of genes to change pancreatic exocrine cells -- one of the main forms of cells in the pancreas -- in adult mice that have diabetes into insulin-producing beta cells that appeared to cure about a third of the mice of the metabolic disease, and improved insulin production in most of the other mice.

A report on the work was published today in the journal Nature Biotechnology.

The new findings are a major advance in work by HSCI co-director Doug Melton and Zhou, who in 2008 reported having converted exocrine cells into functional beta cells in mice. At that time, however, it was not known how long, and how well, the repurposed cells would function.

"The efficiency of reprogramming has always been an issue," Zhou said. "Until now, the new cells have either dropped dramatically in number or disappeared completely," he said, noting that since his work with Melton in 2008 there have been reports published in other programing systems that question whether the reprogrammed cells could be stable enough ultimately to be useful.

"What we have demonstrated is that yes, the reprogrammed cells can be useful, and for that to happen you have to create a niche environment in which the cells can survive," Zhou continued. "We have improved the reprogramming efficiency to a point where one can create a large enough number of the new cells that the new cells create their own niche environment."

Zhou said that the researchers studied the mice for up to about 13 months, approximately half their normal life span, and found that "the cells are still there, and fairly robust. These are diabetic animals, and we were able to, I wouldn't use the word 'cure' because that's a very freighted word for me to use, but they became highly glycemic animals -- though not every animal became normal. That may be because to completely control the glucose level of the animal, you not only need beta cells, you need about a quarter of a million functional beta cells. If you are short of this number, even if the beta cells are perfectly normal," they can't completely control blood sugar levels, Zhou said.

When discussing the implications of the study for the field of cellular reprogramming, Zhou cautioned that the pancreas has a particularly simple cellular organization and structure, and thus findings in the pancreas might not necessarily apply to other organs.

Diabetes is a metabolic disease that is seen in two basic forms.

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Reprogramming cells, long term

When stem cells are propagated in the laboratory, they typically differentiate into one or another specialized cell type, usually forming cell masses that show little organization or spatial coherence. Exceptions include the emergence, in culture, of retinal and anterior cortex-like tissues. For the most part, however, stem cell aggregates in the laboratory prefer to remain lumps.

Despite coaxing, they refuse to organize themselves into structures that resemble embryos. In particular, they avoid taking the earliest steps of embryonic developmentaxis formation and gastrulation, the organized movement of cells that, using the initial axis as a reference, positions the head and the tail, the front and the back.

Now, however, researchers at the University of Cambridge have managed to reconstruct the early stages of mammalian development using mouse embryonic stem cells, showing that a critical mass of cellsnot too few, but not too manyis needed for the cells to begin self-organizing into the correct structure for an embryo to form. The researchers, led by Professor Alfonso Martinez-Arias, presented their finding in a pair of papers that appeared in the November issue of the journal Development.

In one article, Symmetry breaking, germ layer specification and axial organization in aggregates of mouse embryonic stem cells, the authors report that small aggregates of [mouse embryonic stem cells], of about 300 cells, self-organize into polarized structures that exhibit collective behaviors reminiscent of those that cells exhibit in early mouse embryos.

The researchers showed that if the number of cells aggregated initially is similar to that of a mouse embryo, the cells generate a single axis and this serves as a template for a sequence of events that mimics those of the early embryo. By manipulating the signals that the cells see at a particular time, the researchers were able to influence what type of cell they become and how they are organized. In one of the experiments, for example, activation of a particular signal at the correct time elicits the appearance of the mesoderm, endoderm, and ectodermthe precursors of all cell typeswith a spatial organization similar to that of an embryo.

In another article, Wnt/-catenin and FGF signalling direct the specification and maintenance of a neuromesodermal axial progenitor in ensembles of mouse embryonic stem cells, the authors detailed how a specialized population of cells emerges at the end of gastrulation that, under the influence of Wnt and FGF signaling, expands and generates the spinal cord and the paraxial mesoderm.

In other words, the researchers were able to generate the early stages of a spinal cord, which they showed forms as part of the process of gastrulation. This finding complements previous research from the University of Edinburgh and the National Institute for Medical Research showing that embryonic stem cells can be coaxed into becoming spinal cord cells; the Cambridge researchers went further, however, showing that in the embryo-like aggregates, the structural organization is more robust and allows for the polarized growth of the tissue.

It is early days, but this system promises insights into the early stages of development and what determines the specification of the different cell types, said Professor Martinez-Arias. This will allow more robust protocols for differentiation with cues that mimic those that the cells are subject to in embryos.

Most significantly, the system will provide a means to test, experimentally, how a homogeneous group of cells organizes itself in space, a central process in the development of any organism, and the ability to recreate in culture the niches that adult stem cells create during embryogenesis and which have remained elusive experimentally.

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Critical Mass of Stem Cells Sets Off Embryonic Development ...

Harvard Stem Cell Institute (HSCI) researchers at Massachusetts General (MGH) and Boston Children's hospitals (BCH) for the first time have used a relatively new gene-editing technique to create what could prove to be an effective technique for blocking HIV from invading and destroying patients' immune systems.

This is the first published report of a group using CRISPR Cas technology to efficiently and precisely edit clinically relevant genes out of cells collected directly from people, in this case human blood forming stem cells and T-cells.

Though the researchers that believe this new approach to HIV therapy might be ready for human safety trials in less than five years, they themselves offered three strong points of caution:

The first and most obvious is that they could run into unexpected complications; the second is that the history of the HIV/AIDS epidemic is littered with "cures" that turned out not to be; and finally, even if this new approach works perfectly, it will require additional developments to be applicable in the areas of the world that have been the hardest hit by the epidemic.

The work, led by Chad Cowan, and Derrick Rossi, associate professors in Harvard's Department of Stem Cell and Regenerative Biology, is featured on the cover of today's issue of the journal Cell Stem Cell.

HIV specifically targets T cells, a principal portion of the blood-based immune system, and enters via a gene receptor called CCR5 that serves as a doorway into the cells. Once inside the T cells, HIV replicates and kills off the host cells, leaving patients at the mercy of a variety of opportunistic infections.

Using the CRISPR Cas gene-editing technology, the Cowan and Rossi teams knocked the CCR5 receptor out of blood stem cells that they showed could give rise to differentiated blood cells that did not have CCR5. In theory, such gene-edited stem cells could be introduced into HIV patients via bone marrow transplantation, the procedure used to transplant blood stem cells into leukemia patients, to give rise to HIV-resistant immune systems.

"We showed that you can knock out CCR5 very efficaciously, we showed that the cells are still functional, and we did very, very deep sequencing analysis to show that there were no unwanted mutations, so it appears to be safe," Cowan said, adding that "there is obviously much more work to do.

"The next step is animal trials in collaboration with the Ragon Institute at Mass General," Cowan said. "There are excellent mouse models you can give a human immune system and then infect with HIV. We can give our cells to the mice and see if they're protected from HIV." Once those studies are completed, and if they are successful and complications do not arise, the next step would be to apply to the U.S. Food and Drug Administration to launch phase I human trials, which are designed solely to test the safety of new treatments. Cowan said it is too early to predict how soon such trials might begin.

David Scadden, a hematologist/oncologist who is both co-director of HSCI and director of the Center for Regenerative Medicine at MGH, called the new work "a tremendous first step in editing out what makes human cells vulnerable to HIV. It makes possible the idea that a person's own immune cells can attack HIV without being susceptible to it. Since this was done in stem cells, the entire immune system may be durably brought to bear on the virus. That's a powerful concept.

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Human blood stem cells genetically 'edited'

PUBLIC RELEASE DATE:

6-Nov-2014

Contact: B. D. Colen bd_colen@harvard.edu 617-413-1224 Harvard University @HarvardResearch

Harvard Stem Cell Institute (HSCI) researchers at Massachusetts General (MGH) and Boston Children's hospitals (BCH) for the first time have used a relatively new gene-editing technique to create what could prove to be an effective technique for blocking HIV from invading and destroying patients' immune systems.

This is the first published report of a group using CRISPR Cas technology to efficiently and precisely edit clinically relevant genes out of cells collected directly from people, in this case human blood forming stem cells and T-cells.

Though the researchers that believe this new approach to HIV therapy might be ready for human safety trials in less than five years, they themselves offered three strong points of caution:

The first and most obvious is that they could run into unexpected complications; the second is that the history of the HIV/AIDS epidemic is littered with "cures" that turned out not to be; and finally, even if this new approach works perfectly, it will require additional developments to be applicable in the areas of the world that have been the hardest hit by the epidemic.

The work, led by Chad Cowan, and Derrick Rossi, associate professors in Harvard's Department of Stem Cell and Regenerative Biology, is featured on the cover of today's issue of the journal "Cell Stem Cell."

HIV specifically targets T cells, a principal portion of the blood-based immune system, and enters via a gene receptor called CCR5 that serves as a doorway into the cells. Once inside the T cells, HIV replicates and kills off the host cells, leaving patients at the mercy of a variety of opportunistic infections.

Using the CRISPR Cas gene-editing technology, the Cowan and Rossi teams knocked the CCR5 receptor out of blood stem cells that they showed could give rise to differentiated blood cells that did not have CCR5. In theory, such gene-edited stem cells could be introduced into HIV patients via bone marrow transplantation, the procedure used to transplant blood stem cells into leukemia patients, to give rise to HIV-resistant immune systems.

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Harvard researchers genetically 'edit' human blood stem cells

Stem cell technology is moving at a rapid pace at the Massachusetts General Hospital and the Harvard Stem Cell Institute. The Cardiovascular Research Center's Stem Cell Biology + Therapy Program is now developing master cardiovascular stem cells that have genetic mutations that lead to important forms of heart disease. By utilizing these stem cells as model systems, it should be possible to identify the molecular pathways that drive heart disease, and to develop specific, targeted therapy for rare and common forms of heart disease, by directly screening for both genes and drugs that can block the onset of the disease at a cellular level. At the same time, the group is studying the potential of master cardiovascular stem cells for regeneration of heart muscle and other important heart tissues, including the formation of coronary arterial blood vessels. New programs in fat and skeletal muscle stem cells have recently been added, in close collaboration with the Harvard Stem Cell Institute.

Principal Investigators: Caroline Burns, PhD Chad Cowan, PhD Ibrahim Domian, MD, PhD

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Stem Cell Therapy, Stem Cell Biology at Mass General Hospital

SternisheFan writes with news that medical researchers from Harvard Medical School and Massachusetts General Hospital have successfully cultivated stem cells that will kill brain cancer cells in mice without damaging healthy cells. "They used genetic engineering to make stem cells that spewed out cancer-killing toxins, but, crucially, were also able to resist the effects of the poison they were producing. ... In animal tests, the stem cells were surrounded in gel and placed at the site of the brain tumor after it had been removed. Their cancer cells then died as they had no defense against the toxins (abstract)." The next step in the research is to try the treatment on humans. Chris Mason, a professor of regenerative medicine, said, "This is a clever study, which signals the beginning of the next wave of therapies. It shows you can attack solid tumors by putting mini pharmacies inside the patient which deliver the toxic payload direct to the tumor. Cells can do so much. This is the way the future is going to be."

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Scientists Engineer Cancer-Killing Stem Cells

Antonio Regalado for MIT Technology Review 2014-10-15 19:15:44 UTC

When stem cells were first culled from human embryos sixteen years ago, scientists imagined they would soon be treating diabetes, heart disease, stroke, and many other diseases with cells manufactured in the lab.

It's all taken longer than they thought. But now, a Massachusetts biotech firm has reported results from the largest, and longest, human test of a treatment based on embryonic stem cells, saying it appears safe and may have partly restored vision to patients going blind from degenerative diseases.

Results of three-year study were described Tuesday in the Lancet by Advanced Cell Technology and collaborating eye specialists at the Jules Stein Eye Institute in Los Angeles who transplanted lab-grown cells into the eyes of nine people with macular degeneration and nine with Stargardt's macular dystrophy.

The idea behind Advanced Cell's treatment is to replace retinal pigment epithelium cells, known as RPE cells, a type of caretaker tissue without which a person's photoreceptors also die, with supplies grown in laboratory. It uses embryonic stem cells as a starting point, coaxing them to generate millions of specialized retina cells. In the study, each patient received a transplant of between 50,000 and 150,000 of those cells into one eye.

The main objective of the study was to prove the cells were safe. Beyond seeing no worrisome side effects, the researchers also noted some improvements in the patients. According to the researchers half of them improved enough to read two to three extra lines on an eye exam chart, results Robert Lanza, chief scientific officer of Advanced Cell, called remarkable.

"We have people saying things no one would make up, like 'Oh I can see the pattern on my furniture, or now I drive to the airport," he says. "Clearly there is something going on here."

Lanza stressed the need for a larger study, which he said the company hoped to launch later this year in Stargardt's patients. But if the vision results seen so far continue, Lanza says "this would be a therapy."

Some eye specialists said it's too soon to say whether the vision improvements were real. The patients weren't examined by independent specialists, they said, and eyesight in patients with low vision is notoriously difficult to measure. That leaves plenty of room for placebo effects or unconscious bias on the part of doctors.

"When someone gets a treatment, they try really hard to read the eye chart," says Stephen Tsang, a doctor at Columbia University who sees patients losing their vision to both diseases. It's common for patients to show quick improvements, he says, although typically not as large as what Advanced Cell is reporting.

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Stem Cell Eye Treatment May Restore Vision