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Canadian scientists crack stem cell reprogramming code

By Sheryl Ubelacker The Canadian Press

WATCH: Dr. Andras Nagy describes the scientific breakthrough he led in solving the mystery of the stem cell reprogramming code.

TORONTO A Canadian-led international team of researchers has begun solving the mystery of just how a specialized cell taken from a persons skin is reprogrammed into an embryonic-like stem cell, from which virtually any other cell type in the body can be generated.

The research is being touted as a breakthrough in regenerative medicine that will allow scientists to one day harness stem cells to treat or even cure a host of conditions, from blindness and Parkinsons disease to diabetes and spinal cord injuries.

Besides creating the reprogramming roadmap, the scientists also identified a new type of stem cell, called an F-class stem cell due to its fuzzy appearance. Their work is detailed in five papers published Wednesday in the prestigious journals Nature and Nature Communications.

Dr. Andras Nagy, a senior scientist at Mount Sinai Hospital in Toronto, led the team of 50 researchers from Canada, the Netherlands, South Korea and Australia, which spent four years analyzing and cataloguing the day-by-day process that occurs in stem cell reprogramming.

The work builds on the 2006-2007 papers by Shinya Yamanaka, who showed that adult skin cells could be turned into embryonic-like, or pluripotent, stem cells through genetic manipulation, a discovery that garnered the Japanese scientist the Nobel Prize in 2012.

Nagy likened the roughly 21-day process to complete that transformation to a black box, so called because scientists did not know what went on within the cells as they morphed from one cell type into the other.

It was just like a black box, Nagy said Wednesday, following a briefing at the hospital. You start with a skin cell, you arrive at a stem cell but we had no idea what was happening inside the cell.

Nagys team set about cataloguing the changes as they occurred by removing cells from culture dishes at set points during the three-week period, then analyzing such cellular material as DNA and proteins present at that moment.

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Canadian scientists crack stem cell reprogramming code

Stem cells: The black box of reprogramming

Nik Spencer/Nature

Eggs and sperm do it when they combine to make an embryo. John Gurdon did it in the 1960s, when he used intestinal cells from tadpoles to generate genetically identical frogs. Ian Wilmut did it too, when he used an adult mammalian cell to make Dolly the sheep in 1996. Reprogramming reverting differentiated cells back to an embryonic state, with the extraordinary ability to create all the cells in the body has been going on for a very long time.

Scientific interest in reprogramming rocketed after 2006, when scientists showed that adult mouse cells could be reprogrammed by the introduction of just four genes, creating what they called induced pluripotent stem (iPS) cells1. The method was simple enough for almost any lab to attempt, and now it accounts for more than a thousand papers per year. The hope is that pluripotent cells could be used to repair damaged or diseased tissue something that moved closer to reality this year, when retinal cells derived from iPS cells were transplanted into a woman with eye disease, marking the first time that reprogrammed cells were transplanted into humans (see Nature http://doi.org/xhz; 2004).

There is just one hitch. No one, not even the dozen or so groups of scientists who intensively study reprogramming, knows how it happens. They understand that differentiated cells go in, and pluripotent cells come out the other end, but what happens in between is one of biology's impenetrable black boxes. We're throwing everything we've got at it, says molecular biologist Knut Woltjen of the Center for iPS Cell Research and Application at Kyoto University in Japan. It's still a really confusing process. It's very complicated, what we're doing.

Kerri Smith talks to researcher Andras Nagy and reporter David Cyranoski about reprogramming cells.

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One of the problems, stem-cell biologists say, is that their starting population contains a mix of cells, each in a slightly different molecular state. And the process for making iPS cells is currently inefficient and variable: only a tiny fraction end up fully reprogrammed and even these may differ from one another in subtle but important ways. What is more, the path to reprogramming may vary depending on the conditions under which cells are being grown, and from one lab to the next. This makes it difficult to compare experimental results, and it raises safety concerns should a mix of poorly characterized cells be used in the clinic.

But new techniques are starting to clarify the picture. By carrying out meticulous analyses of single cells and amassing reams of detailed molecular data, biologists are identifying a number of essential events that take place en route to a reprogrammed state. This week, the biggest such project an international collaboration audaciously called Project Grandiose unveiled its results26. The scientists involved used a battery of tests to take fine-scale snapshots of every stage of reprogramming and in the process, revealed an alternative state of pluripotency. It was the first high-resolution analysis of change in cell state over time, says Andras Nagy, a stem-cell biologist at Mount Sinai Hospital in Toronto, Canada, who led the project. I'm not shy about saying grandiose.

I'm not shy about saying grandiose.

But there is more to do if scientists want to control the process well enough to generate therapeutic cells with ease. Yes, we can make iPS cells and yes we can differentiate them, but I think we feel that we do not control them enough says Jacob Hanna, a stem-cell biologist at the Weizmann Institute of Science in Rehovot, Israel. Controlling cell behaviour at will is very cool. And the way to do it is to understand their molecular biology with great detail.

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Stem cells: The black box of reprogramming

The NFL Has a Problem with Stem Cell Treatments

Professional athletes are getting injections of stem cells to speed up recovery from injury. Critics call it a high-tech placebo.

NFL quarterback Peyton Manning reportedly had a stem cell treatment to his neck in 2011.

Elite athletes do whatever it takes to win. Lately, thats meant getting an injection of their own stem cells.

The treatments, developed over the last eight years, typically involve extracting a small amount of a players fat or bone marrow and then injecting it into an injured joint or a strained tendon to encourage tissue regeneration. Bone marrow contains stem cells capable of generating new blood cells, cartilage, and bone.

Although the treatments have become a multimillion-dollar industry, some doctors say theres only thin medical evidence they actually speed healing. In a report issued last week, public policy researchers at Rice University criticized the National Football Leagues role in promoting unproven treatments to the public. Some players, including Peyton Manning of the Denver Broncos and Sidney Rice, whos now retired but won a Super Bowl with the Seattle Seahawks last year, have reportedly gone overseas for stem cell treatments and others have acted as spokespeople for U.S. clinics offering them.

The Rice researchers, Kirstin Matthews and Maude Cuchiara, say the NFL should create an independent panel and fund research on whether stem cell treatments actually work, similar to what it did after facing questions around concussions and brain injury. I think they should be more proactive. They should get ahead of this one, says Matthews.

Sports Illustrated reports that hundreds of football players have gotten stem cell treatments, with many travelling abroad for types of therapy not offered in the United States.But its not only football players trying them. The tennis player Rafael Nadal is reportedly undergoing stem cell treatments for back pain, and the injections are also being sought out by soccer players and high school athletes.

The NFL didnt respond to questions from MIT Technology Review. Doctors offering the treatments say theyre promising and should be given a chance. Others say theres not enough data. Any of these injections have a placebo effect, says Freddie Fu, an orthopedic surgeon who is chairman of sports medicine at the University of Pittsburgh Medical Center and top doctor for the schools sports teams. We dont know what we are putting in. We dont really know what exactly what it does, biologically.

Orthopedic surgeons hope one day to use stem cells to regenerate cartilage and other lost tissue. But wishful thinking, and profits, have gotten ahead of the facts, says Fu. Theres a lot of marketing in orthopedics right now. I would say 15 to 20 percent of treatments are not effective, he says.

Unlike a drug, which gets tested for years and is then weighed by experts and the U.S. Food and Drug Administration before hitting the market, the bone marrow treatments offered in the U.S. arent regulated.

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The NFL Has a Problem with Stem Cell Treatments

This New Kind of Stem Cell May Revolutionize How We Treat Diseases

TIME Health medicine This New Kind of Stem Cell May Revolutionize How We Treat Diseases Scientists have created a new type of stem cell that could speed treatments for diseases and make them safer

Ever since Japanese researcher Shinya Yamanaka found a way to treat skin cells with four genes and reprogram them back to their embryonic state, scientists have been buzzing over the promise of stem cell therapies. Stem cells can be coaxed to become any of the bodys cell types, so they could potentially replace diseased or missing cells in conditions such as diabetes or Alzheimers. And Yamanakas method also meant that these cells could be made from patients themselves, so they wouldnt trigger dangerous immune rejections.

Now scientists led by Dr. Andras Nagy at Mount Sinai Hospital Lunenfeld-Tannenbaum Research Institute in Toronto report an exciting new advance that could push stem cells even closer to the clinic. In a series of papers in the journals Nature and Nature Communications, the group describes a new class of stem cell, which they called F class, that they generated in the lab.

The F class cells, says Nagy, have a few advantages over the Yamanaka-generated induced pluripotent stem cells, or iPS cells. While the iPS cells are created by using viruses to introduce four genes that reprogram the cells, Nagys team relied on a technique they developed several years ago using transposonssmall pieces of DNA that can insert themselves into different parts of a genome. Unlike viruses, these transposons can be popped out of the genome if theyre no longer needed, and they dont carry the potential risk of viral infection.

MORE: Stem-Cell Research: The Quest Resumes

Nagys team found that the transposons were much more reliable vehicles for delivering the reprogramming genes exactly where they were needed to efficiently turn the clock back on the skin cells. Whats more, they could use the common antibiotic doxycycline to turn the four genes on and off; adding doxycycline to the cell culture would trigger the transposons to activate, thus turning on the genes, while removing the antibiotic would turn them off.

In this way, says Nagy, he was able to pump up the efficiency of the reprogramming process. Using the Yamanaka method, it was hit-or-miss whether the viruses would find their proper place in a cells genome, and more uncertainty over how effectively it could direct the cell to activate the four reprogramming genes. F class cells are much more similar [in the culture dish], like monozygotic twins while iPS cells are more like brothers and sisters, he says.

That consistency is a potential advantage of the transposon method, since any stem cell-based treatment would require a robust population of stem cells which can then be treated with the proper compounds to develop into insulin-making pancreatic cells to treat diabetes, or new nerve cells to replace dying ones in Alzheimers, or fresh heart muscle to substitute for scarred tissue after a heart attack.

MORE: Stem Cell Miracle? New Therapies May Cure Chronic Conditions like Alzheimers

Nagys team also described, with the most detail to date, exactly how mature cells like skin cells perform the ultimate molecular feat and become forever young again when exposed to the four genes. They analyzed the changes in the cells DNA, the proteins they made, and more. Its similar to high definition TV, he says. We see things much better with much more detail. We expect that having that high resolution characterization will allow us to better understand what is happening during this process at the molecular level. And obviously that better understanding is going to affect what we can do with these cells to make them better, safer and more efficient in cell-based treatments in the future.

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This New Kind of Stem Cell May Revolutionize How We Treat Diseases

R3 Stem Cell Welcomes Beverly Hills Pain Specialists Dr. George Graf as a Featured Regenerative Medicine Doctor

Beverly Hills, CA (PRWEB) December 11, 2014

R3 Stem Cell is proud to welcome Dr. George Graf as a Featured Regenerative Medicine Doctor in the Los Angeles and Beverly Hills area. Dr. Graf is a first rate pain management doctor, who offers several types of stem cell procedures and platelet rich plasma therapy for all types of spinal conditions such as neck and back pain, arthritis, disc degeneration and more. Those interested should call (844) GET-STEM for more information and scheduling.

R3 Stem Cell is a nationwide provider of regenerative medicine products and education for both doctors and patients. The company only works with the top doctors and practices in the field of stem cell therapy. Dr. Graf is Double Board Certified and is very highly regarded by his peers and patients.

The conditions Dr. Graf treats include degenerative disc disease, spinal arthritis, scoliosis, neuropathy, failed back surgery syndrome and more. Regenerative medicine offers the potential to not only bring pain relief, but also help repair and regenerate damaged tissue.

Along with Dr. Graf being a regenerative medicine expert in the LA and Beverly Hills area, R3 also works with Dr. Raj. Dr. Raj is a Double Board Certified orthopedic specialist, who offers regenerative medicine procedures for rotator cuffs, hip and knee arthritis, sports injuries and much more. Between Dr. Graf and Dr. Raj, the whole body is covered for treatments.

All of the treatment options are outpatient and very low risk. Platelet Rich Plasma Therapy involves a person's own blood, which is immediately processed and injected into the problem area. Bone marrow derived stem cell therapy involves an aspiration from one's iliac crest, with the material being processed to concentrate stem cells and then inject into the problem area. Additionally, amniotic stem cells are offered, with the fluid being obtained from a consenting donor undergoing a scheduled C-section. The fluid is processed at an FDA regulated lab and no fetal tissue is involved whatsoever.

To date, several small studies have shown excellent benefit with regenerative medicine procedures. This has been extremely encouraging, and allowed stem cell therapy to exponentially increase in popularity nationwide. R3 Stem Cell is at the forefront in regenerative medicine, teaming with the top doctors such as Drs. Raj and Graf to help patients achieve pain relief and avoid surgery.

Call (844) GET-STEM today for more information and scheduling with a top stem cell doctor today.

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R3 Stem Cell Welcomes Beverly Hills Pain Specialists Dr. George Graf as a Featured Regenerative Medicine Doctor

Some NFL Players Use Unproven Stem Cell Therapies: Report

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MONDAY, Dec. 8, 2014 (HealthDay News) -- Some professional football players are seeking unproven stem cell therapies to speed their recovery from injuries. But experts are concerned that they may be unaware of the potential risks, a new report shows.

Stem cell therapy has attracted the attention of elite athletes. A number of National Football League (NFL) players have highlighted their use of those therapies and their successful recoveries.

Twelve NFL players are known to have received unapproved stem cell treatments since 2009.

"The online data on NFL players and the clinics where they obtained treatment suggest that players may be unaware of the risks they are taking," report co-author Kirstin Matthews, a fellow in science and technology policy at Rice University's Baker Institute for Public Policy, said in a university news release.

"Players who are official spokespersons for these clinics could influence others to view the therapies as safe and effective despite the lack of scientific research to support these claims," she added.

Most of the players receive treatment in the United States, but several have gone to other countries for stem cell therapies that aren't available in the United States.

"With the rise of new and unproven stem cell treatments, the NFL faces a daunting task of trying to better understand and regulate the use of these therapies in order to protect the health of its players," Matthews said.

The NFL and other sports leagues may need to evaluate and possibly regulate stem cell therapies in order to ensure the safety of their players, the report authors suggested.

The paper appears in a special supplement to the journal Stem Cells and Development.

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Some NFL Players Use Unproven Stem Cell Therapies: Report

Can A Pill Help To Shed Fat?

Image Caption: Harvard researchers have created a system using human stem cells to screen for compounds that have the potential to turn white, or bad, fat cells into brown, or good, fat cells. Pictured are human pluripotent stem cell-derived fat cells. Credit: Tim Ahfeldt/Harvard University

Provided by B. D. Colen, Harvard University

Harvard stem cell researchers say they finally can turn bad fat into good

Harvard Stem Cell Institute (HSCI) researchers have taken what they describe as the first step toward a pill that can replace the treadmill for the control of obesity, though that shift, of course, would not provide all of the many benefits of exercise.

HSCI principal faculty member Chad Cowan and his team members at Harvard University and Massachusetts General Hospital (MGH), a Harvard affiliate, say they have created a system using human stem cells to screen for compounds that have the potential to turn white, or bad, fat cells into brown, or good, fat cells, and have already identified two compounds that can accomplish that in human cells.

The path from these findings to a safe and effective medication may not be easy, and the findings will have to be replicated by other research groups, as well as refined, before they could lead to a clinical treatment.

However, Cowan said that the two compounds discovered so far target the same molecule, and that molecule plays a role in the inflammatory response. So if you administered them for a long time, the person taking them could become immune-compromised, which argues against the use of these initial compounds without modifications. One, however, is already on the market, as a treatment approved by the U.S. Food and Drug Administration for rheumatoid arthritis.

White fat cells store energy as lipids and play a role in the development of obesity, type 2 diabetes, and related conditions, including heart disease, while brown fat has been shown in mice to lower triglyceride levels, reduce the insulin resistance associated with type 2 diabetes, and burn white fat.

When the body takes in excess energy, it is stored as lipids in white fat cells. When there are too many calories coming in and not enough burned, adult stem cells in the body produce more white fat cells, adding to a persons burden of fat.

Cowans group has found two small molecules that convert fat stem cells, which normally would produce white fat, into brown-like fat cells. These brown-like fat cells burn excess energy and thereby reduce the size and numbers of white fat cells.

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Can A Pill Help To Shed Fat?

Some NFL players use unproven stem cell therapies

MONDAY, Dec. 8, 2014 (HealthDay News) -- Some professional football players are seeking unproven stem cell therapies to speed their recovery from injuries. But experts are concerned that they may be unaware of the potential risks, a new report shows.

Stem cell therapy has attracted the attention of elite athletes. A number of National Football League (NFL) players have highlighted their use of those therapies and their successful recoveries.

Twelve NFL players are known to have received unapproved stem cell treatments since 2009.

"The online data on NFL players and the clinics where they obtained treatment suggest that players may be unaware of the risks they are taking," report co-author Kirstin Matthews, a fellow in science and technology policy at Rice University's Baker Institute for Public Policy, said in a university news release.

"Players who are official spokespersons for these clinics could influence others to view the therapies as safe and effective despite the lack of scientific research to support these claims," she added.

Most of the players receive treatment in the United States, but several have gone to other countries for stem cell therapies that aren't available in the United States.

"With the rise of new and unproven stem cell treatments, the NFL faces a daunting task of trying to better understand and regulate the use of these therapies in order to protect the health of its players," Matthews said.

The NFL and other sports leagues may need to evaluate and possibly regulate stem cell therapies in order to ensure the safety of their players, the report authors suggested.

The paper appears in a special supplement to the journal Stem Cells and Development.

More information

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Some NFL players use unproven stem cell therapies

Family doctor a womans ticket for coming home

Ingrid Steppan with Dr. Harry Atkins

image credit: For the Townsman

Trying to find a family doctor isn't a new challenge for people living in rural communities, but for Ingrid Steppan, it is the ticket for coming home.

Steppan is currently in Ottawa recovering from a stem-cell transplant after a four-year battle with an extremely rare disease. Though she has needed specialized treatment that required her to seek care in Ottawa, she is hopeful she can return home to continue her recovery.

However, she needs access to a family doctor to supervise her condition in order to make the move back to Cranbrook, according to her daughter Kyla Beauchamp.

Steppan has been battling stiff-person syndrome a disease with symptoms including convulsions, muscle rigidity and impaired mobility but a new treatment has dramatically improved her condition.

After symptoms began in 2008, she was told by doctors that there was no cure and that she would probably die. She bought a house in Saskatchewan to spend the remaining time she had left closer to extended family.

While in Saskatchewan, another doctor convinced her to seek out more specialized treatment in Ottawa. There, she met Dr. Harry Atkins, a bone-marrow transplant specialist with the Ottawa Hospital Research Institute, who performed a autologous stem-cell transplant, along with a group of other specialists.

The operation, which has traditionally been used to treat leukaemia, involves purifying blood-forming stem cells and reintroducing them into the body after knocking out the immune system.

Atkins has performed two similar operations on two other patients, with both those cases going into remission.

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Family doctor a womans ticket for coming home

Microsoft billionaire takes on cell biology

Allen Institute

Paul Allens latest philanthropic endeavour will be modelled on his successful brain institute.

Billionaire businessman and philanthropist Paul Allen plans to pump US$100million into investigating the most basic unit of life the cell.

The Allen Institute for Cell Science, which was launched on 8 December, will be modelled on the Microsoft co-founders Allen Institute for Brain Science in Seattle, Washington, which since 2003 has spent hundreds of millions of dollars creating a series of brain atlases that have become go-to portals for neuroscientists interested in where particular genes are active or how distant neurons communicate.

As its first project, the latest Allen institute will develop an analogous cell observatory that will display how a cells working parts, such as ribosomes, microtubules and mitochondria, interact and operate over time, says executive director Rick Horwitz. He has shuttered his cell-biology laboratory at the University of Virginia in Charlottesville to lead the institute in Seattle, Washington. The 70 or so scientific staff who will join the institute will work together on the overall goals of the observatory to build a global view of the myriad activities inside cells rather than on their own interests. Its going to be much more like the Manhattan Project, Horwitz says.

Allen Institute

Rick Horwitz shut down his lab at the University of Virginia to lead the Allen Institute for Cell Science.

Mapping every little detail of every kind of cell is a tall order, even with the backing of the worlds 27th richest person. Our problem is that this thing could blow up on us. It could be very, very big, Horwitz says. Were going to make judicious decisions to try to contain it.

Some of those choices have already been made, after meetings this year with leading cell biologists. The institute will study human induced pluripotent stem cells (cells coaxed into an embryonic stem-cell-like state) as they differentiate in the lab into two cell types: heart-muscle cells called cardiomyocytes; and the epithelial cells that line body cavities. These tissues were chosen as much for their relevance to disease cardiomyocytes malfunction in heart disease and most cancers arise in epithelial tissues as for the ease with which they can be reproducibly generated and grown in the lab.

The institutes plan is to engineer many different cell lines and determine how different cellular components respond to stimuli such as infection or exposure to a drug. These data will then guide the construction of computer models aimed at predicting how cells operate under various conditions, and all the information gained will be made available online. The institute will also distribute its cell lines so that other scientists can build on its work.

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Microsoft billionaire takes on cell biology