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.

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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

FREEPORT, The Bahamas (PRWEB) December 06, 2013

December 6, 2013 Matt Feshbach, CEO of Okyanos Heart Institute whose mission it is to bring a new standard of care and better quality of life to patients with coronary artery disease using cardiac stem cell therapy, acknowledges the Japanese legislature for its recent approval of a bill aimed at the treatment of certain chronic diseases using regenerative medicine strategies.

The legislation was passed in Japan on November 20th, 2013. The new regenerative medicine law emphasizes the importance of establishing patient safety in the use of adult stem cell therapies prior to being offered commercially. It also serves to support innovation in stem cell and regenerative medicine therapies by providing a framework by which such technologies may be granted new, limited approval paths for some biologics.

Japan has taken a leadership position globally for its passage of enlightened legislation for stem cell therapy, said Feshbach, who recognizes this development as an important milestone in its potential to benefit patients and the field of healthcare.

We applaud Japan as well as other countries including but not limited to Australia, Singapore, and New Zealand for approving stem cell processing devices and/or biologics (such as stem cells) for use in clinics today, he added. This legislation in Japan says that if a stem cell therapy protocol can demonstrate a strong safety profile, physicians have the option to offer it to patients, generally when other standard-of-care interventions have not proven effective and the patients have no other options available to them. Patients will have the choice to use their own stem cells to treat the condition. By tracking the progress of the patients over time, efficacy can be determined and the treatment may become another standard-of-care treatment option available to patients.

While this research is important over the long term, adult stem cell therapy is unique in that it takes advantage of the natural mechanisms of a persons own stem cells to repair the cells, tissues or organs damaged by disease or injury, stated Feshbach. The dawn of a new phase in the evolution of medicine has begun.

Additional countries such as The Bahamas, Panama, Argentina and Jordan have established regulations and legislation designed to both protect patient safety and give access to treatments which have the potential to help unmet needs such as heart failure and other diseases.

Japan represents the second-largest medical market in the world and remains a global leader in both adult stem cell and gene therapy trials. Dr. Shinya Yamanaka, professor and director for the Center for iPS Cell Research and Application (CiRA) at Kyoto University, was awarded a Nobel Prize in 2012 for the discovery of induced pluripotent stem cells (iPS). Click here to read more about the Japanese legislatures recent stem cell measures.

About Okyanos Heart Institute: (Oh key AH nos) Based in Freeport, The Bahamas, Okyanos Heart Institutes mission is to bring a new standard of care and a better quality of life to patients with coronary artery disease using cardiac stem cell therapy. Okyanos adheres to U.S. surgical center standards and is led by Chief Medical Officer Howard T. Walpole Jr., M.D., M.B.A., F.A.C.C., F.S.C.A.I. Okyanos Treatment utilizes a unique blend of stem and regenerative cells derived from ones own adipose (fat) tissue. The cells, when placed into the heart via a minimally-invasive catheterization, stimulate the growth of new blood vessels, a process known as angiogenesis. The treatment facilitates blood flow in the heart and supports intake and use of oxygen (as demonstrated in rigorous clinical trials such as the PRECISE trial). The literary name Okyanos (Oceanos) symbolizes flow. For more information, go to http://www.okyanos.com

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Okyanos Heart Institute CEO Matt Feshbach Congratulates Japan’s Legislators On Stem Cell Bill And Global Regulatory ...

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.

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

NBC News - 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.

They're 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 Hayley's and Bari's bodies. It's 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 don't 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 don't have any mutations, and there are no developmental issues. We have no idea how it happened. "

The girls need special schooling and physical therapy. They must wear diapers, and when they get a cold or the flu, they can develop dangerously low blood sugar. "When the kids get sick, get colds or flu, we have to get them to the hospital," Mogul said.

Hayley, 15, has a mutation in a gene called RAI1, which can cause Smith-Magenis syndrome. The syndrome affects 1 in 25,000 people and can disturb sleep patterns, cause obesity and behavioral issues. But Hayley's mutation is unique and puzzling. Bari, 9, has an RAI1 mutation and a similarly unique mutation in the GRIN2B gene, which can cause learning disabilities.

"Bari doesn't talk," Mogul said. "She walks around, she gets around and lets you know what she wants. She is eating baby food and she is drinking from bottles."

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'Something positive for humankind': Girls lend cells to genetic study

Introduction

The announcement of the ability to produce embryonic cell-like lines from ordinary skin cells has the news media scrambling to get feedback about the possible efficacy of such lines in stem cell therapies. Many politicians have landed on one side or the other, with liberals saying that embryonic stem cell research is still necessary1 and conservatives claiming that all embryonic research should be halted. The marketplace of science will eventually weigh-in on which method(s) are used in real therapies.

Embryonic stem cell (ESC) research has been a hot topic, with conservatives saying that such research is morally unacceptable and liberals saying that conservatives value a clump of cells more than people who have serious disabling diseases. Several groups of medical researchers (including James Thomson, the first person to culture ESC) recently showed that normal skin cells can be reprogrammed to an embryonic state, producing what are now called induced pluripotent stem (iPS) cells. Originally performed in mice in June, 2007,2 researchers took four genes OCT3/4, SOX2, KLF4, and c-MYC and incorporated those genes into the nucleus of cells to induce pluripotency. Such lines could be expanded indefinitely and could differentiate to form numerous kinds of different tissues.

Just five months after the mouse study was published, the feat was repeated by three separate laboratories using human skin cells.3 One research group used the same genes as those used in the mouse study, whereas a second group used OCT3, SOX2, NANOG and LIN28. The techniques were efficient enough to generate one cell line for every 5-10 thousand cells treated. Although not extremely efficient, it is quite usable, since it is possible to obtain hundreds of thousands to millions of cells to carry out these kinds of studies. The technique was recently replicated for adult human skin cells,4 instead of skin cell lines, demonstrating that it could be used to generate patient-specific cell lines.

Studies using iPS cell lines have shown that those cells undergo similar changes compared to what is observed with embryonic stem cells. Cell populations grew at the same rate, telomerase (which preserves the ends of chromosomes) was present in both iPS and ESC. Severalgenes that are silenced in fibroblasts, but active in ESC, were also active in the iPS cells. The iPS cell lines could be differentiated into heart muscle and neuronal cells, in addition to basic cell types (ectoderm, mesoderm, and endoderm). Gene expression assays showed that 5,000 genes from iPS cells showed a five-fold difference in expression compared to those in fibroblasts, although 1,267 genes had a five-fold difference in expression between ESC and iPS cells. According to the James Thomson study, "The human iPS cells described here meet the defining criteria we originally proposed for human ES cells (14), with the significant exception that the iPS cells are not derived from embryos."3

Originally, the new technique is not without its own set of problems, although within two years, virtually all had been resolved. One of the original genes used for reprogramming (c-MYC) has been shown to produce tumors and cancers. Obviously, it would not be a good choice for patient therapy. However, this gene was eliminated in some of the later techniques.5 The second problem was that the genes were originally introduced through the use of a retrovirus that incorporates into the host cell DNA. Depending upon where the gene sequence inserts, it may cause trouble (including mutations and cancers). Those who watched the I am Legend movie will remember that a retrovirus-derived cancer treatment was responsible for turning the surviving members of the human race into an army of grotesque monsters. Although such a transformation is not possible, the initiation of cancer in even a small number of treated patients would make such treatments unusable for human therapy. Two years later the problem of using a retroviral system for reprogramming was solved by switching to a simple lentivirus reprogramming system.6 Within weeks, other researchers went a step further, eliminating viral reprogramming altogether by using reprogramming genes (OCT4, SOX2, NANOG, LIN28, c-Myc, and KLF4) cloned into a circular piece of DNA called a plasmid.7 Subsequent culture of of the iPS over a period of weeks resulted in the complete loss of the plasmid, but with continued pluripotency. The potential of iPS cells is so great that the researcher who first grew ESC in culture is now one of the leading proponents of iPS stem cell research.

A more recent, but somewhat uncertain potential problem has been identified more recently. Since iPS cells are derived from adult tissues, they tend to harbor some of the same epigenetic profiles as those adult tissues from which they are derived. As cells age or differentiate, certain genes are turned on or off through methylation of those gene's promoters. The process prevents those cells from undergoing additional changes that might cause the cells to lose their differentiated properties. When adults cells are induced to pluripotency, some of those epigenetic profiles are retained in the iPS cells.8 How will these vestiges of adult cells affect iPS ability to differentiate into cells that are useful for disease models or therapy? At this point, we don't know for sure. However, my guess is that different ESC lines will exhibit different epigenetic profiles, as will specific isolates of iPS cells. Although researchers have found no problems in producing differentiated iPS lines, some of these epigenetic changes might interfere with the ultimate function of these cells as differentiated cell lines.

Even with these issues, research institutes are beginning to focus their stem cell research on iPS cells. Cedars-Sinai Medical Center recently opened its Induced Pluripotent Stem Cell Core Production Facility in late 2011, according to their press release.9

Induction of pluripotency to produce embryonic-like stem cells is the hot topic in stem cell research. The fact that human iPS cells have been produced in many different laboratories after the initial animal studies shows that the technique is robust and easily reproducible. In contrast, the competing technique, human somatic cell nuclear transfer (cloning), has never been transferred from animal studies to human application, despite years of attempts. At this point, it seems pretty certain that the iPS technique will soon replace ESC as the preferred means of generating human stem cell lines. However, the disadvantage of iPS cells is that the cell lines produced would be patient specific (only useful for the intended patient), whereas the establishment of ESC lines allows biotech companies to patent the lines in order to make lots of money.

http://www.godandscience.org/doctrine/reprogrammed_stem_cells.html Last Modified October 6, 2011

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Induced Pluripotent Stem Cells (iPS) from Human Skin: Probable ...

Somatic stem cells (also called adult stem cells) exist naturally in the body. They are important for growth, healing, and replacing cells that are lost through daily wear and tear.

Potential as therapy Stem cells from the blood and bone marrow are routinely used as a treatment for blood-related diseases. However, under natural circumstances somatic stem cells can become only a subset of related cell types. Bone marrow stem cells, for example, differentiate primarily into blood cells. This partial differentiation can be an advantage when you want to produce blood cells; but it is a disadvantage if you're interested in producing an unrelated cell type.

Special considerations Most types of somatic stem cells are present in low abundance and are difficult to isolate and grow in culture. Isolation of some types could cause considerable tissue or organ damage, as in the heart or brain. Somatic stem cells can be transplanted from donor to patient, but without drugs that suppress the immune system, a patient's immune system will recognize transplanted cells as foreign and attack them.

Ethical considerations Therapy involving somatic stem cells is not controversial; however, it is subject to the same ethical considerations that apply to all medical procedures.

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Stem Cell Quick Reference - Learn Genetics

Oct. 17, 2013

A Waisman Biomanufacturing specialist examines cells in a culture in the cell therapy clean room. The UW-Madison Waisman Center opened Waisman Biomanufacturing to ease the research and development of biological products and drugs.

Photo: Waisman Biomanufacturing

Developing a new drug takes enormous amounts of time, money and skill, but the bar is even higher for a promising stem-cell therapy. Many types of cells derived from these ultra-flexible parent cells are moving toward the market, but the very quality that makes stem cells so valuable also makes them a difficult source of therapeutics.

"The ability to form many types of specialized cells is at the essence of why we are so interested in stem cells, but this pluripotency is not always good," says Derek Hei, director of Waisman Biomanufacturing, a facility in the Waisman Center at UW-Madison.

"The cells we can make from stem cells cells for the heart, brain and liver have amazing potential, but you can also end up with the wrong type of cell. If the cells are not fully differentiated, they can end up differentiating into the wrong cell type," Hei says.

Derek Hei

Just like drugs, stem cells for clinical trials must be produced under a demanding regulatory regime called "good manufacturing practice," he says. That capacity is rare in labs in private business and universities, and this is the only one at UWMadison.

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Biomanufacturing center takes central role in developing stem ...

When pluripotent stem cells are made from a patients own cells, it may be also be possible to replace the faulty gene that caused their disease with a normal, healthy copy. The repaired stem cells could then be directed to form the tissue type needed, introduced into the body, allowed to divide, and used to reconstitute the diseased tissue. It's a treatment that should last a lifetime.

Boston Childrens Hospital researcher George Q. Daley, MD, PhD, then at the Whitehead Institute, was the first to demonstrate, in 2002, that pluripotent stem cells could successfully treat a disease. Working with mice that possess a genetic defect caused by an immune deficiency, the research team created genetically-matched embryonic stem cells through nuclear transfer, introduced corrective genes, then derived healthy blood stem cells and infused them into the mice, partially restoring their immune function. Daley, Director of Stem Cell Transplantation at Childrens, would like to do the same for his patients with blood diseases.

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Combining Stem Cell Therapy with Gene Therapy | Boston ...

1. Introduction

Neuromuscular disease is a very broad term that encompasses many diseases and aliments that either directly, via intrinsic muscle pathology, or indirectly, via nerve pathology, impair the functioning of the muscles. Neuromuscular diseases affect the muscles and/or their nervous control and lead to problems with movement. Many are genetic; sometimes, an immune system disorder can cause them. As they have no cure, the aim of clinical treatment is to improve symptoms, increase mobility and lengthen life. Some of them affect the anterior horn cell, and are classified as acquired (e.g. poliomyelitis) and hereditary (e.g. spinal muscular atrophy) diseases. SMA is a genetic disease that attacks nerve cells, called motor neurons, in the spinal cord. As a consequence of the lost of the neurons, muscles weakness becomes to be evident, affecting walking, crawling, breathing, swallowing and head and neck control. Neuropathies affect the peripheral nerve and are divided into demyelinating (e.g. leucodystrophies) and axonal (e.g. porphyria) diseases. Charcot-Marie-Tooth (CMT) is the most frequent hereditary form among the neuropathies and its characterized by a wide range of symptoms so that CMT-1a is classified as demyelinating and CMT-2 as axonal (Marchesi & Pareyson, 2010). Defects in neuromuscular junctions cause infantile and non-infantile Botulism and Myasthenia Gravis (MG). MG is a antibody-mediated autoimmune disorder of the neuromuscular junction (NMJ) (Drachman, 1994; Meriggioli & Sanders, 2009). In most cases, it is caused by pathogenic autoantibodies directed towards the skeletal muscle acetylcholine receptor (AChR) (Patrick & Lindstrom, 1973) while in others, non-AChR components of the postsynaptic muscle endplate, such as the muscle-specific receptor tyrosine kinase (MUSK), might serve as targets for the autoimmune attack (Hoch et al., 2001). Although the precise origin of the autoimmune response in MG is not known, genetic predisposition and abnormalities of the thymus gland such as hyperplasia and neoplasia could have an important role in the onset of the disease (Berrih et al., 1984; Roxanis et al., 2001).

Several diseases affect muscles: they are classified as acquired (e.g. dermatomyositis and polymyositis) and hereditary (e.g. myotonic disorders and myopaties) forms. Among the myopaties, muscular dystrophies are characterized by the primary wasting of skeletal muscle, caused by mutations in the proteins that form the link between the cytoskeleton and the basal lamina (Cossu & Sampaolesi, 2007). Mutations in the dystrophin gene cause severe form of hereditary muscular diseases; the most common are Duchenne Muscular Dystrophy (DMD) and Becker Muscular Dystrophy (BMD). DMD patients suffer for complete lack of dystrophin that causes progressive degeneration, muscle wasting and death into the second/third decade of life. Beside, BMD patients show a very mild phenotype, often asymptomatic primarily due to the expression of shorter dystrophin mRNA transcripts that maintain the coding reading frame. DMD patients muscles show absence of dystrophin and presence of endomysial fibrosis, small fibers rounded and muscle fiber degeneration/regeneration. Untreated, boys with DMD become progressively weak during their childhood and stop ambulation at a mean age of 9 years, later with corticosteroid treatment (12/13 yrs). Proximal weakness affects symmetrically the lower (such as quadriceps and gluteus) before the upper extremities, with progression to the point of wheelchair dependence. Eventually distal lower and then upper limb weakness occurs. Weakness of neck flexors is often present at the beginning, and most patients with DMD have never been able to jump. Wrist and hand muscles are involved later, allowing the patients to keep their autonomy in transfers using a joystick to guide their wheelchair. Musculoskeletal contractures (ankle, knees and hips) and learning difficulties can complicate the clinical expression of the disease. Besides this weakness distribution in the same patient, a deep variability among patients does exist. They could express a mild phenotype, between Becker and Duchenne dystrophy, or a really severe form, with the loss of deambulation at 7-8 years. Confinement to a wheelchair is followed by the development of scoliosis, respiratory failure and cardiomyopathy. In 90% of people death is directly related to chronic respiratory insufficiency (Rideau et al., 1983). The identification and characterization of dystrophin gene led to the development of potential treatments for this disorder (Bertoni, 2008). Even if only corticosteroids were proven to be effective on DMD patient (Hyser and Mendell, 1988), different therapeutic approaches were attempted, as described in detail below (see section 7).

The identification and characterization of the genes whose mutations caused the most common neuromuscular diseases led to the development of potential treatments for those disorders. Gene therapy for neuromuscular disorders embraced several concepts, including replacing and repairing a defective gene or modifying or enhancing cellular performance, using gene that is not directly related to the underlying defect (Shavlakadze et al., 2004). As an example, the finding that DMD pathology was caused by mutations in the dystrophin gene allowed the rising of different therapeutic approaches including growth-modulating agents that increase muscle regeneration and delay muscle fibrosis (Tinsley et al., 1998), powerful antisense oligonucleotides with exon-skipping capacity (Mc Clorey et al., 2006), anti-inflammatory or second-messenger signal-modulating agents that affect immune responses (Biggar et al., 2006), agents designed to suppress stop codon mutations (Hamed, 2006). Viral and non-viral vectors were used to deliver the full-length - or restricted versions - of the dystrophin gene into stem cells; alternatively, specific antisense oligonucleotides were designed to mask the putative splicing sites of exons in the mutated region of the primary RNA transcript whose removal would re-establish a correct reading frame. In parallel, the biology of stem cells and their role in regeneration were the subject of intensive and extensive research in many laboratories around the world because of the promise of stem cells as therapeutic agents to regenerate tissues damaged by disease or injury (Fuchs and Segre, 2000; Weissman, 2000). This research constituted a significant part of the rapidly developing field of regenerative biology and medicine, and the combination of gene and cell therapy arose as one of the most suitable possibility to treat degenerative disorders. Several works were published in which stem cell were genetically modified by ex vivo introduction of corrective genes and then transplanted in donor dystrophic animal models.

Stem cells received much attention because of their potential use in cell-based therapies for human disease such as leukaemia (Owonikoko et al., 2007), Parkinsons disease (Singh et al., 2007), and neuromuscular disorders (Endo, 2007; Nowak and Davies, 2004). The main advantage of stem cells rather than the other cells of the body is that they can replenish their numbers for long periods through cell division and, they can produce a progeny that can differentiate into multiple cell lineages with specific functions (Bertoni, 2008). The candidate stem cell had to be easy to extract, maintaining the capacity of myogenic conversion when transplanted into the host muscle and also the survival and the subsequent migration from the site of injection to the compromise muscles of the body (Price et al., 2007). With the advent of more sensitive markers, stem cell populations suitable for clinical experiments were found to derive from multiple region of the body at various stage of development. Numerous studies showed that the regenerative capacity of stem cells resided in the environmental microniche and its regulation. This way, it could be important to better elucidate the molecular composition cytokines, growth factors, cell adhesion molecules and extracellular matrix molecules - and interactions of the different microniches that regulate stem cell development (Stocum, 2001).

Several groups published different works concerning adult stem cells such as muscle-derived stem cells (Qu-Petersen et al., 2002), mesoangioblasts (Cossu and Bianco, 2003), blood- (Gavina et al., 2006) and muscle (Benchaouir et al., 2007)-derived CD133+ stem cells. Although some of them are able to migrate through the vasculature (Benchaouir et al., 2007; Galvez et al., 2006; Gavina et al., 2006) and efforts were done to increase their migratory ability (Lafreniere et al., 2006; Torrente et al., 2003a), poor results were obtained.

Embryonic and adult stem cells differ significantly in regard to their differentiation potential and in vitro expansion capability. While adult stem cells constitute a reservoir for tissue regeneration throughout the adult life, they are tissue-specific and possess limited capacity to be expanded ex vivo. Embryonic Stem (ES) cells are derived from the inner cell mass of blastocyst embryos and, by definition, are capable of unlimited in vitro self-renewal and have the ability to differentiate into any cell type of the body (Darabi et al., 2008b). ES cells, together with recently identified iPS cells, are now broadly and extensively studied for their applications in clinical studies.

Embryonic stem cells are pluripotent cells derived from the early embryo that are characterized by the ability to proliferate over prolonged periods of culture remaining undifferentiated and maintaining a stable karyotype (Amit and Itskovitz-Eldor, 2002; Carpenter et al., 2003; Hoffman and Carpenter, 2005). They are capable of differentiating into cells present in all 3 embryonic germ layers, namely ectoderm, mesoderm, and endoderm, and are characterized by self-renewal, immortality, and pluripotency (Strulovici et al., 2007).

hESCs are derived by microsurgical removal of cells from the inner cell mass of a blastocyst stage embryo (Fig. 1). The ES cells can be also obtained from single blastomeres. This technique creates ES cells from a single blastomere directly removed from the embryo bypassing the ethical issue of embryo destruction (Klimanskaya et al., 2006). Although maintaining the viability of the embryo, it has to be determined whether embryonic stem cell lines derived from a single blastomere that does not compromise the embryo can be considered for clinical studies. Cell Nuclear Transfer (SCNT): Nuclear transfer, also referred to as nuclear cloning, denotes the introduction of a nucleus from an adult donor cell into an enucleated oocyte to generate a cloned embryo (Wilmut et al., 2002).

ESCs differentiation. Differentiation potentiality of human embryonic stem cell lines. Human embryonic stem cell pluripotency is evaluated by the ability of the cells to differentiate into different cell types.

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Stem Cell Therapy for Neuromuscular Diseases | InTechOpen

Regenerative medicine is the process of replacing or regenerating human cells, tissues or organs to restore or establish normal function.[1] This field holds the promise of regenerating damaged tissues and organs in the body by replacing damaged tissue and/or by stimulating the bodys own repair mechanisms to heal previously irreparable tissues or organs.

Regenerative medicine also includes the possibility of growing tissues and organs in the laboratory and safely implant them when the body cannot heal itself This can potentially solves the problem of the shortage of organs available for donation, and the problem of organ transplant rejection if the organs cells are derived from the patients own tissue or cells.[2][3][4]

Widely attributed to having first been coined by William Haseltine (founder of Human Genome Sciences),[5] the term Regenerative Medicine was first found in a 1992 article on hospital administration by Leland Kaiser. Kaisers paper closes with a series of short paragraphs on future technologies that will impact hospitals. One such paragraph had Regenerative Medicine as a bold print title and went on to state, A new branch of medicine will develop that attempts to change the course of chronic disease and in many instances will regenerate tired and failing organ systems.[6][7]

Regenerative medicine refers to a group of biomedical approaches to clinical therapies that may involve the use of stem cells.[8] Examples include the injection of stem cells or progenitor cells (cell therapies); the induction of regeneration by biologically active molecules administered alone or as a secretion by infused cells (immunomodulation therapy); and transplantation of in vitro grown organs and tissues (Tissue engineering).[9][10]

A form of regenerative medicine that recently made it into clinical practice, is the use of heparan sulfate analogues on (chronic) wound healing. Heparan sulfate analogues replace degraded heparan sulfate at the wound site. They assist the damaged tissue to heal itself by repositioning growth factors and cytokines back into the damaged extracellular matrix.[11][12][13] For example, in abdominal wall reconstruction (like inguinal hernia repair), biologic meshes are being used with some success.

At the Wake Forest Institute for Regenerative Medicine, in North Carolina, Dr. Anthony Atala and his colleagues have successfully extracted muscle and bladder cells from several patients bodies, cultivated these cells in petri dishes, and then layered the cells in three-dimensional molds that resembled the shapes of the bladders. Within weeks, the cells in the molds began functioning as regular bladders which were then implanted back into the patients bodies.[14] The team is currently[when?] working on re-growing over 22 other different organs including the liver, heart, kidneys and testicles.[15]

From 1995 to 1998 Michael D. West, PhD, organized and managed the research between Geron Corporation and its academic collaborators James Thomson at the University of Wisconsin-Madison and John Gearhart of Johns Hopkins University that led to the first isolation of human embryonic stem and human embryonic germ cells.[16]

Dr. Stephen Badylak, a Research Professor in the Department of Surgery and director of Tissue Engineering at the McGowan Institute for Regenerative Medicine at the University of Pittsburgh, developed a process for scraping cells from the lining of a pigs bladder, decellularizing (removing cells to leave a clean extracellular structure) the tissue and then drying it to become a sheet or a powder. This cellular matrix powder was used to regrow the finger of Lee Spievak, who had severed half an inch of his finger after getting it caught in a propeller of a model plane.[17][18][19][dubious discuss] As of 2011, this new technology is being employed by the military to U.S. war veterans in Texas, as well as to some civilian patients. Nicknamed pixie-dust, the powdered extracellular matrix is being used success to regenerate tissue lost and damaged due to traumatic injuries.

In June 2008, at the Hospital Clnic de Barcelona, Professor Paolo Macchiarini and his team, of the University of Barcelona, performed the first tissue engineered trachea (wind pipe) transplantation. Adult stem cells were extracted from the patients bone marrow, grown into a large population, and matured into cartilage cells, or chondrocytes, using an adaptive method originally devised for treating osteoarthritis. The team then seeded the newly grown chondrocytes, as well as epithileal cells, into a decellularised (free of donor cells) tracheal segment that was donated from a 51 year old transplant donor who had died of cerebral hemorrhage. After four days of seeding, the graft was used to replace the patients left main bronchus. After one month, a biopsy elicited local bleeding, indicating that the blood vessels had already grown back successfully.[20][21]

In 2009 the SENS Foundation was launched, with its stated aim as the application of regenerative medicine defined to include the repair of living cells and extracellular material in situ to the diseases and disabilities of ageing. [22]

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MD Supervised Stem Cell Therapy

In 2006, Shinya Yamanaka of Kyoto University in Japan was the first to disprove the previous notion that reversible cell differentiation of mammals was impossible. He reprogrammed a fully differentiated mouse cell into a pluripotent stem cell by introducing four genes, Oct-4, SOX2, KLF4, and Myc, into the mouse fibroblast through gene-carrying viruses. With this method, he and his coworkers created induced pluripotent stem cells (iPS cells), the key component in this experiment.[1] Scientists have been able to conduct experiments that show the ability of iPS cells to treat and even cure diseases. In this experiment, tests were run on mice with inherited sickle cell anemia.Skin cells were turned into cells containing genes that transformed the cells into iPS cells. These replaced the diseased sickled cells, curing the test mice. The reprogramming of the pluripotent stem cells in mice was successfully duplicated with human pluripotent stem cells within about a year of the experiment on the mice.

Sickle cell anemia is a disease in which the body produces abnormally shaped red blood cells. Red blood cells are flexible and round, moving easily through the blood vessels. Infected cells are shaped like a crescent or sickle (the namesake of the disease). As a result of this disorder the hemoglobin protein in red blood cells is faulty. Normal hemoglobin bonds to oxygen, then releases it into cells that need it. The blood cell retains its original form and is cycled back to the lungs and re-oxygenated.

Sickle cell hemoglobin, however, after giving up oxygen, cling together and make the red blood cell stiff. The sickle shape also makes it difficult for the red blood cell to navigate arteries and causes blockages.[2] This can cause intense pain and organ damage. The sickled red blood cells are fragile and prone to rupture. When the number of red blood cells decreases from rupture (hemolysis), anemia is the result. Sickle cells also die in 1020 days as opposed to the traditional 120-day lifespan of a normal red blood cell.

Sickle cell anemia is inherited as an autosomal (meaning that the gene is not linked to a sex chromosome) recessive condition.[2] This means that the gene can be passed on from a carrier to his or her children. In order for sickle cell anemia to affect a person, the gene must be inherited from both the mother and the father, so that the child has two recessive sickle cell genes (a homozygous inheritance). People who inherit one sickle cell gene from one parent and one normal gene from the other parent, i.e. heterozygous patients, have a condition called sickle cell trait. Their bodies make both sickle hemoglobin and normal hemoglobin. They may pass the trait on to their children.

The effects of sickle cell anemia vary from person to person. People who have the disease suffer from varying degrees of chronic pain and fatigue. With proper care and treatment, the quality of health of most patients will improve. Doctors have learned a great deal about sickle cell anemia since its discovery in 1979. They know its causes, its effects on the body, and possible treatments for complications. Sickle cell anemia has no widely available cure. A bone marrow transplant is the only treatment method currently recognized to be able to cure the disease, though it does not work for every patient. Finding a donor is difficult and the procedure could potentially do more harm than good. Treatments for sickle cell anemia are generally aimed at avoiding crises, relieving symptoms, and preventing complications. Such treatments may include medications, blood transfusions, and supplemental oxygen.

During the first step of the experiment, skin cells (also known as fibroblasts) were collected from infected test mice and put in a culture. The fibroblasts were reprogrammed by infecting them with retroviruses that contained genes common to embryonic stem cells. These genes were the same four used by Yamanaka (Oct-4, SOX2, KLF4, and Myc) in his earlier study. The investigators were trying to produce cells with the potential to differentiate into any type of cell needed (i.e. pluripotent stem cells). As the experiment continued, the fibroblasts multiplied into identical copies of iPS cells. The cells were then treated to form the mutation needed to reverse the anemia in the mice. This was accomplished by restructuring the DNA containing the defective globin gene into DNA with the normal gene through the process of homologous recombination. The iPS cells then differentiated into blood stem cells, or hematopoietic stem cells. The hematopoietic cells were injected back into the infected mice, where they proliferate and differentiate into normal blood cells, curing the mice of the disease.[3][4][verification needed]

To determine whether the mice were cured from the disease, the scientists checked for the usual symptoms of sickle cell disease. They examined the blood for mean corpuscular volume (MCV) and red cell distribution width (RDW) and urine concentration defects. They also checked for sickled red blood cells. They examined the DNA through gel electrophoresis, checking for bands that display an allele that causes sickling. Compared to the untreated mice with the disease, which they used as a control, the treated animals had marked increases in RBC counts, healthy hemoglobin, and packed cell volume levels.[5]

Researchers examined the urine concentration defect, which results from RBC sickling in renal tubules and consequent reduction in renal medullary blood flow, and the general deteriorated systemic condition reflected by lower body weight and increased breathing.[5] They were able to see that these parts of the body of the mice had healed or improved. This indicated that all hematological and systemic parameters of sickle cell anemia improved substantially and were comparable to those in control mice.[5] They cannot say if this will work in humans because a safe way to inject the genes for the induced pluripotent cells is still needed.[citation needed]

The reprogramming of the induced pluripotent stem cells in mice was successfully duplicated in humans within a year of the successful experiment on the mice. This reprogramming was done in several labs and it was shown that the iPS cells in humans were almost identical to original embryonic stem cells (ES cells) that are responsible for the creation of all structures in a fetus.[1] An important feature of iPS cells is that they can be generated with cells taken from an adult, which would circumvent many of the ethical problems associated with working with ES cells. These iPS cells also have potential in creating and examining new disease models and developing more efficient drug treatments.[6] Another feature of these cells is that they provide researchers with a human cell sample, as opposed to simply using an animal with similar DNA, for drug testing.

One major problem with iPS cells is the way in which the cells are reprogrammed. Using gene-carrying viruses has the potential to cause iPS cells to develop into cancerous cells.[1] Also, an implant made using undifferentiated iPS cells, could cause a teratoma to form. Any implant that is generated from using these iPS cells would only be viable for transplant into the original subject that the cells were taken from. In order for these iPS cells to become viable in therapeutic use, there are still many steps that must be taken.[5][7]

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IPS Cell Therapy - Genetherapy