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The story of mRNA: From a loose idea to a tool that may help curb Covid – STAT

By daniellenierenberg

ANDOVER, Mass. The liquid that many hope could help end the Covid-19 pandemic is stored in a nondescript metal tank in a manufacturing complex owned by Pfizer, one of the worlds biggest drug companies. There is nothing remarkable about the container, which could fit in a walk-in closet, except that its contents could end up in the worlds first authorized Covid-19 vaccine.

Pfizer, a 171-year-old Fortune 500 powerhouse, has made a billion-dollar bet on that dream. So has a brash, young rival just 23 miles away in Cambridge, Mass. Moderna, a 10-year-old biotech company with billions in market valuation but no approved products, is racing forward with a vaccine of its own. Its new sprawling drug-making facility nearby is hiring workers at a fast clip in the hopes of making history and a lot of money.

In many ways, the companies and their leaders couldnt be more different. Pfizer, working with a little-known German biotech called BioNTech, has taken pains for much of the year to manage expectations. Moderna has made nearly as much news for its stream of upbeat press releases, executives stock sales, and spectacular rounds of funding as for its science.

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Each is well-aware of the other in the race to be first.

But what the companies share may be bigger than their differences: Both are banking on a genetic technology that has long held huge promise but has so far run into biological roadblocks. It is called synthetic messenger RNA, an ingenious variation on the natural substance that directs protein production in cells throughout the body. Its prospects have swung billions of dollars on the stock market, made and imperiled scientific careers, and fueled hopes that it could be a breakthrough that allows society to return to normalcy after months living in fear.

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Both companies have been frequently name-checked by President Trump. Pfizer reported strong, but preliminary, data on Monday, and Moderna is expected to follow suit soon with a glimpse of its data. Both firms hope these preliminary results will allow an emergency deployment of their vaccines millions of doses likely targeted to frontline medical workers and others most at risk of Covid-19.

There are about a dozen experimental vaccines in late-stage clinical trials globally, but the ones being tested by Pfizer and Moderna are the only two that rely on messenger RNA.

For decades, scientists have dreamed about the seemingly endless possibilities of custom-made messenger RNA, or mRNA.

Researchers understood its role as a recipe book for the bodys trillions of cells, but their efforts to expand the menu have come in fits and starts. The concept: By making precise tweaks to synthetic mRNA and injecting people with it, any cell in the body could be transformed into an on-demand drug factory.

But turning scientific promise into medical reality has been more difficult than many assumed. Although relatively easy and quick to produce compared to traditional vaccine-making, no mRNA vaccine or drug has ever won approval.

Even now, as Moderna and Pfizer test their vaccines on roughly 74,000 volunteers in pivotal vaccine studies, many experts question whether the technology is ready for prime time.

I worry about innovation at the expense of practicality, Peter Hotez, dean of the National School of Tropical Medicine at Baylor College of Medicine and an authority on vaccines, said recently. The U.S. governments Operation Warp Speed program, which has underwritten the development of Modernas vaccine and pledged to buy Pfizers vaccine if it works, is weighted toward technology platforms that have never made it to licensure before.

Whether mRNA vaccines succeed or not, their path from a gleam in a scientists eye to the brink of government approval has been a tale of personal perseverance, eureka moments in the lab, soaring expectations and an unprecedented flow of cash into the biotech industry.

It is a story that began three decades ago, with a little-known scientist who refused to quit.

Before messenger RNA was a multibillion-dollar idea, it was a scientific backwater. And for the Hungarian-born scientist behind a key mRNA discovery, it was a career dead-end.

Katalin Karik spent the 1990s collecting rejections. Her work, attempting to harness the power of mRNA to fight disease, was too far-fetched for government grants, corporate funding, and even support from her own colleagues.

It all made sense on paper. In the natural world, the body relies on millions of tiny proteins to keep itself alive and healthy, and it uses mRNA to tell cells which proteins to make. If you could design your own mRNA, you could, in theory, hijack that process and create any protein you might desire antibodies to vaccinate against infection, enzymes to reverse a rare disease, or growth agents to mend damaged heart tissue.

In 1990, researchers at the University of Wisconsin managed to make it work in mice. Karik wanted to go further.

The problem, she knew, was that synthetic RNA was notoriously vulnerable to the bodys natural defenses, meaning it would likely be destroyed before reaching its target cells. And, worse, the resulting biological havoc might stir up an immune response that could make the therapy a health risk for some patients.

It was a real obstacle, and still may be, but Karik was convinced it was one she could work around. Few shared her confidence.

Every night I was working: grant, grant, grant, Karik remembered, referring to her efforts to obtain funding. And it came back always no, no, no.

By 1995, after six years on the faculty at the University of Pennsylvania, Karik got demoted. She had been on the path to full professorship, but with no money coming in to support her work on mRNA, her bosses saw no point in pressing on.

She was back to the lower rungs of the scientific academy.

Usually, at that point, people just say goodbye and leave because its so horrible, Karik said.

Theres no opportune time for demotion, but 1995 had already been uncommonly difficult. Karik had recently endured a cancer scare, and her husband was stuck in Hungary sorting out a visa issue. Now the work to which shed devoted countless hours was slipping through her fingers.

I thought of going somewhere else, or doing something else, Karik said. I also thought maybe Im not good enough, not smart enough. I tried to imagine: Everything is here, and I just have to do better experiments.

In time, those better experiments came together. After a decade of trial and error, Karik and her longtime collaborator at Penn Drew Weissman, an immunologist with a medical degree and Ph.D. from Boston University discovered a remedy for mRNAs Achilles heel.

The stumbling block, as Kariks many grant rejections pointed out, was that injecting synthetic mRNA typically led to that vexing immune response; the body sensed a chemical intruder, and went to war. The solution, Karik and Weissman discovered, was the biological equivalent of swapping out a tire.

Every strand of mRNA is made up of five molecular building blocks called nucleosides. But in its altered, synthetic form, one of those building blocks, like a misaligned wheel on a car, was throwing everything off by signaling the immune system. So Karikand Weissman simply subbed it out for a slightly tweaked version, creating a hybrid mRNA that could sneak its way into cells without alerting the bodys defenses.

That was a key discovery, said Norbert Pardi, an assistant professor of medicine at Penn and frequent collaborator. Karik and Weissman figured out that if you incorporate modified nucleosides into mRNA, you can kill two birds with one stone.

That discovery, described in a series of scientific papers starting in 2005, largely flew under the radar at first, said Weissman, but it offered absolution to the mRNA researchers who had kept the faith during the technologys lean years. And it was the starter pistol for the vaccine sprint to come.

And even though the studies by Karik and Weissman went unnoticed by some, they caught the attention of two key scientists one in the United States, another abroad who would later help found Moderna and Pfizers future partner, BioNTech.

Derrick Rossi, a native of Toronto who rooted for the Maple Leafs and sported a soul patch, was a 39-year-old postdoctoral fellow in stem cell biology at Stanford University in 2005 when he read the first paper. Not only did he recognize it as groundbreaking, he now says Karik and Weissman deserve the Nobel Prize in chemistry.

If anyone asks me whom to vote for some day down the line, I would put them front and center, he said. That fundamental discovery is going to go into medicines that help the world.

But Rossi didnt have vaccines on his mind when he set out to build on their findings in 2007 as a new assistant professor at Harvard Medical School running his own lab.

He wondered whether modified messenger RNA might hold the key to obtaining something else researchers desperately wanted: a new source of embryonic stem cells.

In a feat of biological alchemy, embryonic stem cells can turn into any type of cell in the body. That gives them the potential to treat a dizzying array of conditions, from Parkinsons disease to spinal cord injuries.

But using those cells for research had created an ethical firestorm because they are harvested from discarded embryos.

Rossi thought he might be able to sidestep the controversy. He would use modified messenger molecules to reprogram adult cells so that they acted like embryonic stem cells.

He asked a postdoctoral fellow in his lab to explore the idea. In 2009, after more than a year of work, the postdoc waved Rossi over to a microscope. Rossi peered through the lens and saw something extraordinary: a plate full of the very cells he had hoped to create.

Rossi excitedly informed his colleague Timothy Springer, another professor at Harvard Medical School and a biotech entrepreneur. Recognizing the commercial potential, Springer contacted Robert Langer, the prolific inventor and biomedical engineering professor at the Massachusetts Institute of Technology.

On a May afternoon in 2010, Rossi and Springer visited Langer at his laboratory in Cambridge. What happened at the two-hour meeting and in the days that followed has become the stuff of legend and an ego-bruising squabble.

Langer is a towering figure in biotechnology and an expert on drug-delivery technology. At least 400 drug and medical device companies have licensed his patents. His office walls display many of his 250 major awards, including the Charles Stark Draper Prize, considered the equivalent of the Nobel Prize for engineers.

As he listened to Rossi describe his use of modified mRNA, Langer recalled, he realized the young professor had discovered something far bigger than a novel way to create stem cells. Cloaking mRNA so it could slip into cells to produce proteins had a staggering number of applications, Langer thought, and might even save millions of lives.

I think you can do a lot better than that, Langer recalled telling Rossi, referring to stem cells. I think you could make new drugs, new vaccines everything.

Langer could barely contain his excitement when he got home to his wife.

This could be the most successful company in history, he remembered telling her, even though no company existed yet.

Three days later Rossi made another presentation, to the leaders of Flagship Ventures. Founded and run by Noubar Afeyan, a swaggering entrepreneur, the Cambridge venture capital firm has created dozens of biotech startups. Afeyan had the same enthusiastic reaction as Langer, saying in a 2015 article in Nature that Rossis innovation was intriguing instantaneously.

Within several months, Rossi, Langer, Afeyan, and another physician-researcher at Harvard formed the firm Moderna a new word combining modified and RNA.

Springer was the first investor to pledge money, Rossi said. In a 2012 Moderna news release, Afeyan said the firms promise rivals that of the earliest biotechnology companies over 30 years ago adding an entirely new drug category to the pharmaceutical arsenal.

But although Moderna has made each of the founders hundreds of millions of dollars even before the company had produced a single product Rossis account is marked by bitterness. In interviews with the Globe in October, he accused Langer and Afeyan of propagating a condescending myth that he didnt understand his discoverys full potential until they pointed it out to him.

Its total malarkey, said Rossi, who ended his affiliation with Moderna in 2014. Im embarrassed for them. Everybody in the know actually just shakes their heads.

Rossi said that the slide decks he used in his presentation to Flagship noted that his discovery could lead to new medicines. Thats the thing Noubar has used to turn Flagship into a big company, and he says it was totally his idea, Rossi said.

Afeyan, the chair of Moderna, recently credited Rossi with advancing the work of the Penn scientists. But, he said, that only spurred Afeyan and Langer to ask the question, Could you think of a code molecule that helps you make anything you want within the body?

Langer, for his part, told STAT and the Globe that Rossi made an important finding but had focused almost entirely on the stem cell thing.

Despite the squabbling that followed the birth of Moderna, other scientists also saw messenger RNA as potentially revolutionary.

In Mainz, Germany, situated on the left bank of the Rhine, another new company was being formed by a married team of researchers who would also see the vast potential for the technology, though vaccines for infectious diseases werent on top of their list then.

A native of Turkey, Ugur Sahin moved to Germany after his father got a job at a Ford factory in Cologne. His wife, zlem Treci had, as a child, followed her father, a surgeon, on his rounds at a Catholic hospital. She and Sahin are physicians who met in 1990 working at a hospital in Saarland.

The couple have long been interested in immunotherapy, which harnesses the immune system to fight cancer and has become one of the most exciting innovations in medicine in recent decades. In particular, they were tantalized by the possibility of creating personalized vaccines that teach the immune system to eliminate cancer cells.

Both see themselves as scientists first and foremost. But they are also formidable entrepreneurs. After they co-founded another biotech, the couple persuaded twin brothers who had invested in that firm, Thomas and Andreas Strungmann, to spin out a new company that would develop cancer vaccines that relied on mRNA.

That became BioNTech, another blended name, derived from Biopharmaceutical New Technologies. Its U.S. headquarters is in Cambridge. Sahin is the CEO, Treci the chief medical officer.

We are one of the leaders in messenger RNA, but we dont consider ourselves a messenger RNA company, said Sahin, also a professor at the Mainz University Medical Center. We consider ourselves an immunotherapy company.

Like Moderna, BioNTech licensed technology developed by the Pennsylvania scientist whose work was long ignored, Karik, and her collaborator, Weissman. In fact, in 2013, the company hired Karik as senior vice president to help oversee its mRNA work.

But in their early years, the two biotechs operated in very different ways.

In 2011, Moderna hired the CEO who would personify its brash approach to the business of biotech.

Stphane Bancel was a rising star in the life sciences, a chemical engineer with a Harvard MBA who was known as a businessman, not a scientist. At just 34, he became CEO of the French diagnostics firm BioMrieux in 2007 but was wooed away to Moderna four years later by Afeyan.

Moderna made a splash in 2012 with the announcement that it had raised $40 million from venture capitalists despite being years away from testing its science in humans. Four months later, the British pharmaceutical giant AstraZeneca agreed to pay Moderna a staggering $240 million for the rights to dozens of mRNA drugs that did not yet exist.

The biotech had no scientific publications to its name and hadnt shared a shred of data publicly. Yet it somehow convinced investors and multinational drug makers that its scientific findings and expertise were destined to change the world. Under Bancels leadership, Moderna would raise more than $1 billion in investments and partnership funds over the next five years.

Modernas promise and the more than $2 billion it raised before going public in 2018 hinged on creating a fleet of mRNA medicines that could be safely dosed over and over. But behind the scenes the companys scientists were running into a familiar problem. In animal studies, the ideal dose of their leading mRNA therapy was triggering dangerous immune reactions the kind for which Karik had improvised a major workaround under some conditions but a lower dose had proved too weak to show any benefits.

Moderna had to pivot. If repeated doses of mRNA were too toxic to test in human beings, the company would have to rely on something that takes only one or two injections to show an effect. Gradually, biotechs self-proclaimed disruptor became a vaccines company, putting its experimental drugs on the back burner and talking up the potential of a field long considered a loss-leader by the drug industry.

Meanwhile BioNTech has often acted like the anti-Moderna, garnering far less attention.

In part, that was by design, said Sahin. For the first five years, the firm operated in what Sahin called submarine mode, issuing no news releases, and focusing on scientific research, much of it originating in his university lab. Unlike Moderna, the firm has published its research from the start, including about 150 scientific papers in just the past eight years.

In 2013, the firm began disclosing its ambitions to transform the treatment of cancer and soon announced a series of eight partnerships with major drug makers. BioNTech has 13 compounds in clinical trials for a variety of illnesses but, like Moderna, has yet to get a product approved.

When BioNTech went public last October, it raised $150 million, and closed with a market value of $3.4 billion less than half of Modernas when it went public in 2018.

Despite his role as CEO, Sahin has largely maintained the air of an academic. He still uses his university email address and rides a 20-year-old mountain bicycle from his home to the office because he doesnt have a drivers license.

Then, late last year, the world changed.

Shortly before midnight, on Dec. 30, the International Society for Infectious Diseases, a Massachusetts-based nonprofit, posted an alarming report online. A number of people in Wuhan, a city of more than 11 million people in central China, had been diagnosed with unexplained pneumonia.

Chinese researchers soon identified 41 hospitalized patients with the disease. Most had visited the Wuhan South China Seafood Market. Vendors sold live wild animals, from bamboo rats to ostriches, in crowded stalls. That raised concerns that the virus might have leaped from an animal, possibly a bat, to humans.

After isolating the virus from patients, Chinese scientists on Jan. 10 posted online its genetic sequence. Because companies that work with messenger RNA dont need the virus itself to create a vaccine, just a computer that tells scientists what chemicals to put together and in what order, researchers at Moderna, BioNTech, and other companies got to work.

A pandemic loomed. The companies focus on vaccines could not have been more fortuitous.

Moderna and BioNTech each designed a tiny snip of genetic code that could be deployed into cells to stimulate a coronavirus immune response. The two vaccines differ in their chemical structures, how the substances are made, and how they deliver mRNA into cells. Both vaccines require two shots a few weeks apart.

The biotechs were competing against dozens of other groups that employed varying vaccine-making approaches, including the traditional, more time-consuming method of using an inactivated virus to produce an immune response.

Moderna was especially well-positioned for this moment.

Forty-two days after the genetic code was released, Modernas CEO Bancel opened an email on Feb. 24 on his cellphone and smiled, as he recalled to the Globe. Up popped a photograph of a box placed inside a refrigerated truck at the Norwood plant and bound for the National Institute of Allergy and Infectious Diseases in Bethesda, Md. The package held a few hundred vials, each containing the experimental vaccine.

Moderna was the first drug maker to deliver a potential vaccine for clinical trials. Soon, its vaccine became the first to undergo testing on humans, in a small early-stage trial. And on July 28, it became the first to start getting tested in a late-stage trial in a scene that reflected the firms receptiveness to press coverage.

The first volunteer to get a shot in Modernas late-stage trial was a television anchor at the CNN affiliate in Savannah, Ga., a move that raised eyebrows at rival vaccine makers.

Along with those achievements, Moderna has repeatedly stirred controversy.

On May 18, Moderna issued a press release trumpeting positive interim clinical data. The firm said its vaccine had generated neutralizing antibodies in the first eight volunteers in the early-phase study, a tiny sample.

But Moderna didnt provide any backup data, making it hard to assess how encouraging the results were. Nonetheless, Modernas share price rose 20% that day.

Some top Moderna executives also drew criticism for selling shares worth millions, including Bancel and the firms chief medical officer, Tal Zaks.

In addition, some critics have said the government has given Moderna a sweetheart deal by bankrolling the costs for developing the vaccine and pledging to buy at least 100 million doses, all for $2.48 billion.

That works out to roughly $25 a dose, which Moderna acknowledges includes a profit.

In contrast, the government has pledged more than $1 billion to Johnson & Johnson to manufacture and provide at least 100 million doses of its vaccine, which uses different technology than mRNA. But J&J, which collaborated with Beth Israel Deaconess Medical Centers Center for Virology and Vaccine Research and is also in a late-stage trial, has promised not to profit off sales of the vaccine during the pandemic.

Over in Germany, Sahin, the head of BioNTech, said a Lancet article in January about the outbreak in Wuhan, an international hub, galvanized him.

We understood that this would become a pandemic, he said.

The next day, he met with his leadership team.

I told them that we have to deal with a pandemic which is coming to Germany, Sahin recalled.

He also realized he needed a strong partner to manufacture the vaccine and thought of Pfizer. The two companies had worked together before to try to develop mRNA influenza vaccines. In March, he called Pfizers top vaccine expert, Kathrin Jansen.

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The story of mRNA: From a loose idea to a tool that may help curb Covid - STAT

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Probing Psychoses – Harvard Magazine

By JoanneRUSSELL25

Andrew LeClerc knew something was wrong when he heard voices when no one else was around. Some were those of people he knew, others were unfamiliar, but all had the authentic mannerisms of real people, not his imagination. He was in his early twenties, unsure of his direction in life, and had been taking synthetic marijuana to ease stress from past traumas. Disturbed by the voices, he sought help in an emergency room and voluntarily admitted himself to a psychiatric hospital, not realizing he would be kept there for six days. He was diagnosed with psychosis, but had little interaction with a therapist. You mostly sit around with coloring books, he says. It felt like a punishment, when all he wanted was help.

Afterward, he contacted therapists, but many were booked. An online search led him to a research study at Beth Israel Deaconess Medical Center in Boston for people newly diagnosed with psychotic disorders. In January 2014, he entered a two-year study that compared two approaches to psychotherapy to help manage cognitive impairments and other symptoms. He was also prescribed an antipsychotic medication.

Eventually he was diagnosed with schizophrenia. Now, about four years later, at 26, LeClerc is learning to live with the condition. Its hard for a person whos diagnosed with schizophrenia to be told somethings not real when they think its real, he says. He continues to take antipsychotic medications that help control his hallucinations and lives in an apartment below his parents in Middleton, Massachusetts. Hes hoping to start a small business, putting his love of gardening to work as a landscaper.

But more importantly, hes learned to make peace with his mind. He likes to say: I dont hear voices, I hear my own brain. When voices do appear, he recognizes them as a product of an aberrant auditory cortex, and he thinks about engaging his prefrontal cortexthe decision-making part of the brainto help him distinguish fact from fiction. I have tools to pull myself back to the moment, he says.

Not everyone who struggles with schizophrenia is able to find such stability. The illness takes many forms; symptoms may include hallucinations and delusions, lack of motivation, and cognitive problems similar to dementia. It tends to strike in the late teens and early twenties, robbing young people of their mental stability just as theyre entering adulthood, beginning careers, or pursuing a college degree. Some improve, while others experience a long mental decline.

The treatments that we have are useful but not great, says Matcheri Keshavan, Cobb professor of psychiatry at Harvard Medical School (HMS) and the leader of the study that LeClerc participated in. The medications used to treat schizophrenia are decades old, and only ameliorate symptoms. Like other psychiatric illnesses, schizophrenia has suffered from a lack of investment from pharmaceutical companies. Says Keshavan, We need better medications that really address the underlying cause of this illness.

But those causes are still mysterious. What scientists do know is that schizophrenia tends to run in families. About 70 percent to 80 percent of a persons risk of developing the illness, Keshavan says, can be explained by genetic factors. Recently, theres been a surge of effort to capitalize on that fact. Advances in genetics have made it possible to search not only for clues about schizophrenia and other psychiatric illnesses hidden within thousands of human genomesbut also for potential new treatments.

As a result, theres been a renaissance in research on schizophrenia and other psychiatric disorders, and some cautious optimism. Its been possible to make real if still early progress in understanding what genes and molecules influence these illnesses, says Steven McCarroll, Flier associate professor of biomedical science and genetics. At Harvard, the leading force is the Stanley Center for Psychiatric Disease Research at the Broad Institute, which is pouring new funding and resources into amassing data on the genetics of mental illness.

Bringing the power of genomics to psychiatric disease fulfills a long-held goal for the Stanley Centers director, Steven Hyman, professor of stem cell and regenerative biology. An HMS professor of psychiatry before becoming head of the National Institute of Mental Health (NIMH) in 1996, Hyman was frustrated by the sluggish progress on the science of psychiatric disorders, as research on illnesses like cancer, heart disease, and diabetes marched ahead. Schizophrenia in particular is challenging to study because its uniquely human. Scientists can study limited aspects of psychiatric illness in animals if they can measure an observable behavior, such as avoiding social interactions or grooming excessively. But psychosis is a problem of thinking; animals, as far as is known, dont experience it in any way we can measure. Its also challenging because brain tissue is so inaccessible. We were really hampered, Hyman says, and I, frankly, didnt know all that much more when I was at NIMH in the late 1990s than careful observers knew at the turn of the twentieth century.

Steven Hyman, director of the Stanley Center for Psychiatric Disease Research Photograph by Stu Rosner

When he left the position, Hyman was interested in researching psychiatric disease but didnt see a rigorous path to do so; instead, he accepted a position as Harvards provosttaking what he now refers to as a 10-year timeout. During that time, a revolution occurred. Genetic technologies and vastly expanded computer power opened new paths for studying the biological basis of complex diseases.

The Broad Institute launched the Stanley Center in 2007 under inaugural director Edward Scolnick, thanks to an initial $100 million in private funding from philanthropists Ted and Vada Stanley, aiming to bring much-needed innovation to treatments for psychiatric disease by harnessing the power of genomics. (The Stanleys provided another $650 million in 2014, an unprecedented gift for psychiatric research.) Partly as a result, the center has gathered the worlds largest collection of DNA samples for studying not only psychiatric diseasesincluding schizophrenia, autism, ADHD, and bipolar disorderbut also healthy control subjects. The resulting data are freely available to the public.

The human genome has started to give us a really powerful way into the problem, Steven McCarroll explains, because the key source of scientific leverage that we have is we know that schizophrenia and other psychiatric illnesses are heritablethey aggregate in families. Their molecular secrets are almost certainly hidden in the way our genomes vary from person to person.

Much of the research on genetics and disease has focused on what McCarroll calls genetic sledgehammersgenes that when mutated would almost certainly make you sick. But schizophrenia, like most common diseases, is genetically complex. The hereditary component of the disease may be a product of tens to hundreds of genetic nudges, variations that dont cause disease by themselves, but together make people vulnerable to illness.

Studying genetic nudges requires amassing large numbers of DNA samples to achieve the statistical power to find subtle variations that may contribute to disease, a project thats taken enormous collaborative effort by many scientists and institutions around the world. The Psychiatric Genomics Consortiumthe largest scientific collaboration involving psychiatric diseaseformed in 2007 and comprises hundreds of investigators in 38 countries and nearly a million genetic samples. The Stanley Center has served as the hub for data sharing, aggregation, and analysis to further the consortiums discoveries.

One of the key tools for uncovering the genetic basis of disease is the genome-wide association study (GWAS)a way of quickly sorting through the common variations in genomes to find those that are more common in people with a given trait or disease than in those without. Associate professor of medicine Mark Daly, who leads the analytic hub of the consortium, says that scientists originally thought such studies might uncover a handful or two of DNA variants that could be statistically correlated with schizophrenia. But rather than identifying a few standouts, the consortiums Schizophrenia Working Group found a crowd of genetic associations, each contributing just a tiny amount of risk. A landmark paper published in 2014 in the journal Nature, led by Michael ODonovan of Cardiff University, described 108 different locations in the genome that harbored variants associated with schizophrenia.

GWAS studies can identify only stretches of DNA: like flags on a zoomed-out map of a city, they provide a neighborhood, not the exact address. We know where the variants are, one of which is likely to be the causal variant, but cant say for sure which one, says assistant professor of medicine Ben Neale, who is developing methods to analyze genomic data. Another approach is to sift through genomes in finer-grained detail by directly reading each letter of the DNA sequence. Such work is time-consuming, but it can help uncover rare genetic differences that are linked to disease, many of which have a stronger effect than common variants. Work by the consortium has also analyzed areas of DNA that are deleted or duplicated, called copy number variations. People with schizophrenia tend to have more such variations overall, and the genes they affect can provide clues to the diseases origins.

Meanwhile, the Stanley Center and other institutions are working to collect thousands more DNA samples from people with schizophrenia and other psychiatric disorders, hoping to identify even more genetic associations of risk. Hyman doesnt see such data-gathering as an endless project. We should kill this problem, he says, meaning in some reasonable number of yearsseven to 10we should have proceeded so far in the genetics of schizophrenia, bipolar disorders, autism, perhaps some other disorders, that weve reached diminishing returns in terms of biological information.

But so far, the picture is still incomplete. The vast majority of genetic samples, for instance, come from people of European ancestry. From a purely scientific point of view, it means were missing a large proportion of the worlds genetic diversity, says Karesten Koenen, professor of psychiatric epidemiology at the Harvard T.H. Chan School of Public Health. Most of that diversity is in Africa: There is much more diversity in African genomes than in those of people from other parts of the world.

Koenen is leading an effort through the Stanley Center to launch genetic research on psychiatric disease in Ethiopia, Uganda, Kenya, and South Africa. Their researchers are partnering with researchers and academic and clinical institutions in those countries and will be gathering DNA samples and clinical information from people diagnosed with schizophrenia. We really want to build local capacity, she says, and develop sustainable research programs that can be led by local scientists and clinicians. The center also plans to extend the effort to Latin America, beginning in Mexico.

This effort will help fill in the genetic picture of psychiatric illness, and will also help correct a vast imbalance. Geneticists are beginning to use data to classify patients based on their risk of developing complex diseases, including schizophrenia. But these risk profiles, Koenen says, lose accuracy when applied to people of African descent. As this kind of profiling makes its way into medicine, she says, Theres a risk that if we dont extend this research to Africa, the health disparity and treatment gap will widen.

What will all this data amount to? Theres a misconception, McCarroll says, that the goal of this research is to conjure up a crystal ball genetic test that will give people personalized treatments based on their unique portfolio of genes. Thats not the aim. Our goal, he says, is to understand the core biological processes in the illnesses, so that innovative treatments can be developed that can treat anyone. Scientists hope that the dizzying array of schizophrenia-related genes will converge onto a few basic processes in the brain, once the function of those genes is understood.

But even as scientists have made dramatic leaps in discovering genetic risk factors of complex diseases, the task of understanding how those genes work is a different, and slower, task.

Researchers from Harvard and the Broad Institute have grown human brain organoids, three-dimensional organ models cultured from stem cells, to study the genetics of psychiatric illness. This series shows (clockwise from upper left) growth at 1, 3, 6, and 9 months, with development of synapses indicated in green. Quadrato et al./Nature 2017

McCarroll was lead author of a study making one of the strongest links between a specific genetic variant and its role in schizophrenia. Working with Aswin Sekar (then a graduate student, now a research fellow), he focused on the most powerful signal of risk in GWAS studies to date, a stretch of DNA in chromosome 6 that was known to harbor many genes involved in the immune system. They focused on one called C4, which has a high degree of variability in humans: each of its different forms may be present in multiple copies in one individual. By using both genetic data and postmortem brain tissue, they found that people with schizophrenia are more likely to have variants of the C4 gene that lead to higher levels of one gene product, C4A, in brain cells.

C4A is one of several proteins involved in a type of immunity called the complement pathway, which helps clear damaged cells and harmful microbes from the body. As part of their study, McCarroll and Sekar collaborated with associate professor of neurology Beth Stevens, whose previous research with mice clarified an ingenious connection between the complement pathway and the brain. Scientists know that as the brain develops, it churns out new cells, which form billions of connections called synapses. In adolescence and early adulthood, some of these connections are pared back, a process called synaptic pruning. In mice, Stevens has found, this pruning is mediated by the complement pathway, which triggers immune cells called microglia to attack neural connections: literally nibbling at synapses.

Sekar, McCarroll, and Stevens also worked with professor of pediatrics Michael Carroll, who had developed mice with varying copies of the C4 gene, and showed that too much C4 activity in the animals can lead to excess pruning. Its too much of a good thing, Stevens says. Their finding suggests that schizophrenia, in some cases, may be caused by loss of synapses in adolescencean especially promising result because it supports clinical observations: synaptic pruning coincides with the age when schizophrenia typically emerges, and brain imaging shows that many people with schizophrenia experience a thinning of the prefrontal cortex in the early stages of disease.

Steven McCarroll, Flier associate professor of biomedical science and genetics Photograph by Stu Rosner

McCarroll emphasizes that the C4A variation contributes only a small amount of risk of disease, but may collude with other variants to tip the brain past a threshold. There are a lot of genetic findings that map to synapses, says Hyman, so some of those other variants may contribute to a larger disruption in how synapses are formed and maintained. But other processes are likely at work in schizophrenia as well. Some genetic risk variants relate to a chemical signal in the brain called glutamate, and others to ion channels, proteins that determine how electrical signals propagate in brain cells. There are also others, Hyman adds, that, frankly, just have us scratching our heads.

The work on C4 offers an example of how genetics is beginning to help neuroscience move forward. Its opened up a ton of new directions and strategies for our group, says Stevens. Across Harvard and the Stanley Center, a growing community is launching collaborative projects with the goal of taking psychiatric disease research into new territories.

One priority is developing new models for teasing out the role of genes in the brain. Scientists have been able to study some behaviors that relate to mental illness in animals, but there is no animal model for schizophrenia. Michael Carroll is now working to extend the C4 study by creating humanized mice that carry human C4 genes, which may make it possible to study their function in a living brain.

Other researchers are trying to develop new ways to study psychiatric disease in humans. Paola Arlotta, professor of stem cell and regenerative biology, explains that when scientists are able to get samples of human brain tissuefrom patients undergoing surgery, postmortem donations, or even tissue from fetusesthe cells die quickly. They cant be propagated and studied in a laboratory, so there is no renewable source of the actual endogenous tissue.

Stem cells have emerged as a way around that problem. Scientists can now take cells from the skin or hair and transform them into induced pluripotent stem (iPS) cells that are capable of becoming other cell types, including brain cells. (At the Stanley Center, Arlotta and other scientists are exploring how to transform iPS cells into specific types of brain cells.) The iPS cells allow scientists to study how cells derived from a person of one genetic background differ from those of another person. Scientists can also use the genome-editing tool CRISPR-Cas9 to introduce specific genetic changes and study their effects.

But theres very little that can be learned about psychiatric disease from isolated cells: brain activity depends on the constant chatter of many cells that are intricately connected. Arlotta has been investigating whether neural stem cells can be spun into something that behaves more like human brain tissue. So-called organoidsclusters of millions of cells up to a few millimeters in diametercan be formed from growing stem cells in a nutrient-rich solution. Organoids have already been used to study events that happen in early development: last year, a team of researchers used them to study the effects of the Zika virus on developing brains.

But since psychiatric diseases like schizophrenia emerge later in life, Arlotta wants to make organoids grow larger and live longer, and to understand whether they can mimic some of the properties of an older brain. This is a new tissue were making, she says, and so the questions that we want to answer are: can we develop them for a very long time, can we understand the cellular composition, can we see if these organoids make actual networks and communicate with each other?

To better characterize these cell-based models, Arlotta and her colleague Kevin Eggan, a fellow professor of stem cell and regenerative biology, are collaborating with McCarroll to apply a technology his lab developedDropSeqthat makes it possible to analyze gene activity in individual cells. The technology will provide a detailed, cell-by-cell understanding of what these models may reveal. In a Nature paper published in April, Arlottas team demonstrated that its possible to cultivate human brain organoids for nine months or more. Analysis revealed that the organoids are filled with a diverse mix of brain-cell types, and that these cells actually form interconnected networks, suggesting they may begin to function in ways that brains do.

But how much meaningful information about psychiatric disorders can be gleaned by studying individual cells or clusters of artificial tissue remains unclear. And an even bigger question is how to use these models to study the effects of genetic nudges. Disease genetics, typically, has been studied by altering or removing genes, one at a time, in an animal. Studying a whole suite of subtle genetic variations in a model system is a completely new idea.

There is no playbook, says Hyman. He acknowledges that the work is risky; many of these projects are possible only because the Stanley Centers open-ended funding makes it easier for labs to work together to pursue new ideas. We spend many tens of millions of dollars a year, and were accountable only at the end of the year to our scientific advisory board, and we tell them our strategy, he says. It gives us enormous flexibility, but its an enormous responsibility.

Some scientists and clinicians believe that gathering genetic data and studying cells is a misguided strategy for alleviating psychiatric illness. They see it as reductionist, and argue that it emphasizes the inborn biological origins of illnesses rather than other factorslike abuse, trauma, drug use, and emotional stressthat are known to play a role in their development. Hyman answers, Genes are not fate, but genes have an awful lot to say. Genetics and the environment both undoubtedly contribute to disease, but both ultimately must act on the brainand genetics happens to be a more tractable way to study whats happening in the brain.

Genetics is already providing insights that could help alter the way psychiatric disorders are defined. People have studied disorders with a box around them, says Elise Robinson, assistant professor of epidemiology, who has analyzed genetic differences within and between disorders such as schizophrenia, bipolar disorder, depression, and autism, which are usually defined by clinical categories outlined in the Diagnostic and Statistical Manual of Mental Disorders. But Robinson says the idea of distinct boundaries separating these disorders is not necessarily consistent with biology. Genetically, psychiatric disorders look more like Venn diagrams with large overlaps. People with schizophrenia share 60 percent to 70 percent of genome-wide variation with those who suffer bipolar disorder, and about 25 percent with autism.

Similarly, there is no simple dividing line between people who have a psychiatric illness and those who dont. Genetic risk for schizophrenia is not something you either have or dont have, she says. Theres a little bit of risk in all of us. Natural variations in many different genes, she explains, have been shown to relate to the way people perform on tests of cognitive or emotional skills. Schizophrenia may emerge from some combination of factors that are part of normal variation in the development and functioning of the human brain. This is true for other complex diseases and many normal traits, she adds: height, for instance, is largely determined by genetics, but theres no single geneor even handful of genesthat controls it. Its a quality that emerges from many genetic inputs.

Robinson believes that scientists could learn more about these disorders by cutting across diagnostic boxes and studying genetic variants that are linked to multiple traits and disorders. Only by understanding how these variants affect the brain can researchers begin to understand how they contribute both to normal brain function and to the risk of disease.

Such research could help demystify the experiences of people like Andrew LeClerc. He has learned to talk about his schizophrenia as something he struggles with, not something that defines him. He describes his condition as a mental difference.

LeClerc also appreciates that not all the voices in his head are negative: he sometimes hears words of encouragement or helpful warnings. As he speaks, his thoughts dont always follow the linear paths of normal conversation, but they can take him into deeper places; he has a keen understanding of how humans brains create their own realities. He sees an analogy to his condition in the once-expensive glass pieces he has begun collecting from his local dump. Glass that seems like trash, he says, can be reused or recycled, so it isnt really broken. He describes himself the same way: Im fragile, not broken.

It may take decades before genetic research on schizophrenia yields new treatments for people like LeClerc, but clues about the biological underpinnings of schizophrenia could help in other ways. Patients with psychiatric disorders get blamed for those disorders in our culture in a way that people with diseases in other organs dont, says McCarroll. If this research can provide a firmer biological understanding of whats happening in the brain, he says, I would hope that we could generate more empathy.

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Stem Cell Tourism Is the Controversial Subject of a New Cannes Documentary – Vogue.com

By raymumme

A fascinating documentary that is making the rounds at film festivals like Tribeca and Cannes gives a rare view of a controversial treatment that more and more Americans are paying up to $50,000 to receive. Stem cell therapy is widely considered to be the next big hope in medicine, with researchers everywhere from Stanford to Johns Hopkins investigating the technologys potential to treat seemingly every ailment known to mankindAlzheimers, cancer, joint injuries, even basic signs of aging. The only hitch: With one tiny exception, it isnt legal in the United States.

We all know the stem cell revolution is occurring outside the U.S., says Brian Mehling, M.D., a Manhattan-based orthopedic surgeon who is certainly doing his part to foment the insurgency. A coproducer of the film, as well as its charismatic recurring subject, Mehling is bringing stem cell tourism into the spotlight and determined to lift the curtain on a medical field that remains mysterious to most. His Blue Horizon medical clinics, with locations in China and Slovakiaand three more set to open in Mexico, Israel, and Jamaicacater to American tourists looking to cutting-edge therapy for help when traditional medicine fails.

Stem cells are the undifferentiated cells that abound in newborns and have the ability to transform into blood, nerve, or muscle cells and aid the body in self-repair. Proselytizers like Mehling say they constitute the latest in holistic medicine, allowing the body to healwithout drugs, surgery, or side effects. At clinics such as Mehlings, doctors either inject the cells, which are generally obtained from umbilical cords during C-sections, into a patients spinal cord (much like an epidural), or administer them via IV drip. The process is alarmingly quick, and patients can typically check out of the facility by the end of the day. One of the few stem-cell therapies approved for use in the United States is one used to treat the blood disease known as beta thalassemia; in that instance, the treatment replaces damaged blood in the immune system and saves tens of thousands of lives each year. Few other stem cell applications, however, have been proven effective in the rigorous clinical trials the Food and Drug Administration requires before signing off on any treatment.

In fact, stem cell clinics remain completely unregulated, and there have been incidents of related troubles. In one recent report , Jim Gass, a resident of San Diego who traveled to stem cell clinics in Mexico, China, and Argentina to help recover from a stroke, later discovered a sizable tumor on his spinal columnand the cancerous cells belonged to somebody else. Troubling cases also emerged at a loosely regulated clinic in Sunrise, Florida where, earlier this spring, three women suffering macular degeneration reported further loss of vision after having stem cells, extracted from their belly fat via liposuction, injected into their eyes. Though, on the whole, reports of treatments at clinics gone awry remain relatively few.

In his film, Stem Cells: The Next Frontier , which is set to appear at Cannes Film Festival this month, Mehling offers a persuasive side of the story, with rapturous testimonials from patients, some of whom who have regained the ability to walk after their stem cell vacations. Added bonus: They come home with better skin, bigger sex drive, and (in the case of at least one balding patient) more hair.

However compelling, there is scant evidence that the injections actually make a difference, and most American doctors caution against buying into the hype. Stem cell researcher Jaime Imitola, M.D. and Ph.D, director of the progressive multiple sclerosis clinic research program at Ohio State University, says he is impressed by the evidence that stem cells can help with neurological disorders in animals. But the question is how can you translate it into clinical trials? We still dont know what were doing when we put stem cells in people.

David Scadden, a professor of medicine and stem cell and regenerative biology at Harvard, and the director of Harvards Stem Cell Institute, says that stem cell tourism is a waste of money for the time being. A world-renowned expert in stem cell science, he remains optimistic about its future applications. Researchers are currently looking into reprogramming, for instance, which effectively converts a mature cell into a stem cell. You rewind its history so it forgets its a blood cell or a skin cell and it rewinds back in time and it can become any cell type, he says. Youd be able to test drugs on these cells, and it could be used to reverse Type 1 diabetes.

For now, though, he does not recommend experimenting with stem cells before we understand them well enough to properlyand safelyharness their benefits. People call me about it all the timethey say, I have this knee thats bugging me, Im going to one of these clinics, he says. His response? For the most part they dont do harm. But nobody Ive spoken with has come back to me and said, You Harvard docs have to get on this . . . . Not yet.

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Stem-cell therapy – Wikipedia

By NEVAGiles23

This article is about the medical therapy. For the cell type, see Stem cell.

Stem-cell therapy is the use of stem cells to treat or prevent a disease or condition.

Bone marrow transplant is the most widely used stem-cell therapy, but some therapies derived from umbilical cord blood are also in use. Research is underway to develop various sources for stem cells, and to apply stem-cell treatments for neurodegenerative diseases and conditions such as diabetes, heart disease, and other conditions.

Stem-cell therapy has become controversial following developments such as the ability of scientists to isolate and culture embryonic stem cells, to create stem cells using somatic cell nuclear transfer and their use of techniques to create induced pluripotent stem cells. This controversy is often related to abortion politics and to human cloning. Additionally, efforts to market treatments based on transplant of stored umbilical cord blood have been controversial.

For over 30 years, bone marrow has been used to treat cancer patients with conditions such as leukaemia and lymphoma; this is the only form of stem-cell therapy that is widely practiced.[1][2][3] During chemotherapy, most growing cells are killed by the cytotoxic agents. These agents, however, cannot discriminate between the leukaemia or neoplastic cells, and the hematopoietic stem cells within the bone marrow. It is this side effect of conventional chemotherapy strategies that the stem-cell transplant attempts to reverse; a donor's healthy bone marrow reintroduces functional stem cells to replace the cells lost in the host's body during treatment. The transplanted cells also generate an immune response that helps to kill off the cancer cells; this process can go too far, however, leading to graft vs host disease, the most serious side effect of this treatment.[4]

Another stem-cell therapy called Prochymal, was conditionally approved in Canada in 2012 for the management of acute graft-vs-host disease in children who are unresponsive to steroids.[5] It is an allogenic stem therapy based on mesenchymal stem cells (MSCs) derived from the bone marrow of adult donors. MSCs are purified from the marrow, cultured and packaged, with up to 10,000 doses derived from a single donor. The doses are stored frozen until needed.[6]

The FDA has approved five hematopoietic stem-cell products derived from umbilical cord blood, for the treatment of blood and immunological diseases.[7]

In 2014, the European Medicines Agency recommended approval of Holoclar, a treatment involving stem cells, for use in the European Union. Holoclar is used for people with severe limbal stem cell deficiency due to burns in the eye.[8]

In March 2016 GlaxoSmithKline's Strimvelis (GSK2696273) therapy for the treatment ADA-SCID was recommended for EU approval.[9]

Stem cells are being studied for a number of reasons. The molecules and exosomes released from stem cells are also being studied in an effort to make medications.[10]

Research has been conducted on the effects of stem cells on animal models of brain degeneration, such as in Parkinson's, Amyotrophic lateral sclerosis, and Alzheimer's disease.[11][12][13] There have been preliminary studies related to multiple sclerosis.[14][15]

Healthy adult brains contain neural stem cells which divide to maintain general stem-cell numbers, or become progenitor cells. In healthy adult laboratory animals, progenitor cells migrate within the brain and function primarily to maintain neuron populations for olfaction (the sense of smell). Pharmacological activation of endogenous neural stem cells has been reported to induce neuroprotection and behavioral recovery in adult rat models of neurological disorder.[16][17][18]

Stroke and traumatic brain injury lead to cell death, characterized by a loss of neurons and oligodendrocytes within the brain. A small clinical trial was underway in Scotland in 2013, in which stem cells were injected into the brains of stroke patients.[19]

Clinical and animal studies have been conducted into the use of stem cells in cases of spinal cord injury.[20][21][22]

The pioneering work[23] by Bodo-Eckehard Strauer has now been discredited by the identification of hundreds of factual contradictions.[24] Among several clinical trials that have reported that adult stem-cell therapy is safe and effective, powerful effects have been reported from only a few laboratories, but this has covered old[25] and recent[26] infarcts as well as heart failure not arising from myocardial infarction.[27] While initial animal studies demonstrated remarkable therapeutic effects,[28][29] later clinical trials achieved only modest, though statistically significant, improvements.[30][31] Possible reasons for this discrepancy are patient age,[32] timing of treatment[33] and the recent occurrence of a myocardial infarction.[34] It appears that these obstacles may be overcome by additional treatments which increase the effectiveness of the treatment[35] or by optimizing the methodology although these too can be controversial. Current studies vary greatly in cell-procuring techniques, cell types, cell-administration timing and procedures, and studied parameters, making it very difficult to make comparisons. Comparative studies are therefore currently needed.

Stem-cell therapy for treatment of myocardial infarction usually makes use of autologous bone-marrow stem cells (a specific type or all), however other types of adult stem cells may be used, such as adipose-derived stem cells.[36] Adult stem cell therapy for treating heart disease was commercially available in at least five continents as of 2007.[citation needed]

Possible mechanisms of recovery include:[11]

It may be possible to have adult bone-marrow cells differentiate into heart muscle cells.[11]

The first successful integration of human embryonic stem cell derived cardiomyocytes in guinea pigs (mouse hearts beat too fast) was reported in August 2012. The contraction strength was measured four weeks after the guinea pigs underwent simulated heart attacks and cell treatment. The cells contracted synchronously with the existing cells, but it is unknown if the positive results were produced mainly from paracrine as opposed to direct electromechanical effects from the human cells. Future work will focus on how to get the cells to engraft more strongly around the scar tissue. Whether treatments from embryonic or adult bone marrow stem cells will prove more effective remains to be seen.[37]

In 2013 the pioneering reports of powerful beneficial effects of autologous bone marrow stem cells on ventricular function were found to contain "hundreds" of discrepancies.[38] Critics report that of 48 reports there seemed to be just five underlying trials, and that in many cases whether they were randomized or merely observational accepter-versus-rejecter, was contradictory between reports of the same trial. One pair of reports of identical baseline characteristics and final results, was presented in two publications as, respectively, a 578 patient randomized trial and as a 391 patient observational study. Other reports required (impossible) negative standard deviations in subsets of patients, or contained fractional patients, negative NYHA classes. Overall there were many more patients published as having receiving stem cells in trials, than the number of stem cells processed in the hospital's laboratory during that time. A university investigation, closed in 2012 without reporting, was reopened in July 2013.[39]

One of the most promising benefits of stem cell therapy is the potential for cardiac tissue regeneration to reverse the tissue loss underlying the development of heart failure after cardiac injury.[40]

Initially, the observed improvements were attributed to a transdifferentiation of BM-MSCs into cardiomyocyte-like cells.[28] Given the apparent inadequacy of unmodified stem cells for heart tissue regeneration, a more promising modern technique involves treating these cells to create cardiac progenitor cells before implantation to the injured area.[41]

The specificity of the human immune-cell repertoire is what allows the human body to defend itself from rapidly adapting antigens. However, the immune system is vulnerable to degradation upon the pathogenesis of disease, and because of the critical role that it plays in overall defense, its degradation is often fatal to the organism as a whole. Diseases of hematopoietic cells are diagnosed and classified via a subspecialty of pathology known as hematopathology. The specificity of the immune cells is what allows recognition of foreign antigens, causing further challenges in the treatment of immune disease. Identical matches between donor and recipient must be made for successful transplantation treatments, but matches are uncommon, even between first-degree relatives. Research using both hematopoietic adult stem cells and embryonic stem cells has provided insight into the possible mechanisms and methods of treatment for many of these ailments.[citation needed]

Fully mature human red blood cells may be generated ex vivo by hematopoietic stem cells (HSCs), which are precursors of red blood cells. In this process, HSCs are grown together with stromal cells, creating an environment that mimics the conditions of bone marrow, the natural site of red-blood-cell growth. Erythropoietin, a growth factor, is added, coaxing the stem cells to complete terminal differentiation into red blood cells.[42] Further research into this technique should have potential benefits to gene therapy, blood transfusion, and topical medicine.

In 2004, scientists at King's College London discovered a way to cultivate a complete tooth in mice[43] and were able to grow bioengineered teeth stand-alone in the laboratory. Researchers are confident that the tooth regeneration technology can be used to grow live teeth in human patients.

In theory, stem cells taken from the patient could be coaxed in the lab turning into a tooth bud which, when implanted in the gums, will give rise to a new tooth, and would be expected to be grown in a time over three weeks.[44] It will fuse with the jawbone and release chemicals that encourage nerves and blood vessels to connect with it. The process is similar to what happens when humans grow their original adult teeth. Many challenges remain, however, before stem cells could be a choice for the replacement of missing teeth in the future.[45][46]

Research is ongoing in different fields, alligators which are polyphyodonts grow up to 50 times a successional tooth (a small replacement tooth) under each mature functional tooth for replacement once a year.[47]

Heller has reported success in re-growing cochlea hair cells with the use of embryonic stem cells.[48]

Since 2003, researchers have successfully transplanted corneal stem cells into damaged eyes to restore vision. "Sheets of retinal cells used by the team are harvested from aborted fetuses, which some people find objectionable." When these sheets are transplanted over the damaged cornea, the stem cells stimulate renewed repair, eventually restore vision.[49] The latest such development was in June 2005, when researchers at the Queen Victoria Hospital of Sussex, England were able to restore the sight of forty patients using the same technique. The group, led by Sheraz Daya, was able to successfully use adult stem cells obtained from the patient, a relative, or even a cadaver. Further rounds of trials are ongoing.[50]

In April 2005, doctors in the UK transplanted corneal stem cells from an organ donor to the cornea of Deborah Catlyn, a woman who was blinded in one eye when acid was thrown in her eye at a nightclub. The cornea, which is the transparent window of the eye, is a particularly suitable site for transplants. In fact, the first successful human transplant was a cornea transplant. The absence of blood vessels within the cornea makes this area a relatively easy target for transplantation. The majority of corneal transplants carried out today are due to a degenerative disease called keratoconus.

The University Hospital of New Jersey reports that the success rate for growth of new cells from transplanted stem cells varies from 25 percent to 70 percent.[51]

In 2014, researchers demonstrated that stem cells collected as biopsies from donor human corneas can prevent scar formation without provoking a rejection response in mice with corneal damage.[52]

In January 2012, The Lancet published a paper by Steven Schwartz, at UCLA's Jules Stein Eye Institute, reporting two women who had gone legally blind from macular degeneration had dramatic improvements in their vision after retinal injections of human embryonic stem cells.[53]

In June 2015, the Stem Cell Ophthalmology Treatment Study (SCOTS), the largest adult stem cell study in ophthalmology ( http://www.clinicaltrials.gov NCT # 01920867) published initial results on a patient with optic nerve disease who improved from 20/2000 to 20/40 following treatment with bone marrow derived stem cells.[54]

Diabetes patients lose the function of insulin-producing beta cells within the pancreas.[55] In recent experiments, scientists have been able to coax embryonic stem cell to turn into beta cells in the lab. In theory if the beta cell is transplanted successfully, they will be able to replace malfunctioning ones in a diabetic patient.[56]

Human embryonic stem cells may be grown in cell culture and stimulated to form insulin-producing cells that can be transplanted into the patient.

However, clinical success is highly dependent on the development of the following procedures:[11]

Clinical case reports in the treatment orthopaedic conditions have been reported. To date, the focus in the literature for musculoskeletal care appears to be on mesenchymal stem cells. Centeno et al. have published MRI evidence of increased cartilage and meniscus volume in individual human subjects.[57][58] The results of trials that include a large number of subjects, are yet to be published. However, a published safety study conducted in a group of 227 patients over a 3-4-year period shows adequate safety and minimal complications associated with mesenchymal cell transplantation.[59]

Wakitani has also published a small case series of nine defects in five knees involving surgical transplantation of mesenchymal stem cells with coverage of the treated chondral defects.[60]

Stem cells can also be used to stimulate the growth of human tissues. In an adult, wounded tissue is most often replaced by scar tissue, which is characterized in the skin by disorganized collagen structure, loss of hair follicles and irregular vascular structure. In the case of wounded fetal tissue, however, wounded tissue is replaced with normal tissue through the activity of stem cells.[61] A possible method for tissue regeneration in adults is to place adult stem cell "seeds" inside a tissue bed "soil" in a wound bed and allow the stem cells to stimulate differentiation in the tissue bed cells. This method elicits a regenerative response more similar to fetal wound-healing than adult scar tissue formation.[61] Researchers are still investigating different aspects of the "soil" tissue that are conducive to regeneration.[61]

Culture of human embryonic stem cells in mitotically inactivated porcine ovarian fibroblasts (POF) causes differentiation into germ cells (precursor cells of oocytes and spermatozoa), as evidenced by gene expression analysis.[62]

Human embryonic stem cells have been stimulated to form Spermatozoon-like cells, yet still slightly damaged or malformed.[63] It could potentially treat azoospermia.

In 2012, oogonial stem cells were isolated from adult mouse and human ovaries and demonstrated to be capable of forming mature oocytes.[64] These cells have the potential to treat infertility.

Destruction of the immune system by the HIV is driven by the loss of CD4+ T cells in the peripheral blood and lymphoid tissues. Viral entry into CD4+ cells is mediated by the interaction with a cellular chemokine receptor, the most common of which are CCR5 and CXCR4. Because subsequent viral replication requires cellular gene expression processes, activated CD4+ cells are the primary targets of productive HIV infection.[65] Recently scientists have been investigating an alternative approach to treating HIV-1/AIDS, based on the creation of a disease-resistant immune system through transplantation of autologous, gene-modified (HIV-1-resistant) hematopoietic stem and progenitor cells (GM-HSPC).[66]

On 23 January 2009, the US Food and Drug Administration gave clearance to Geron Corporation for the initiation of the first clinical trial of an embryonic stem-cell-based therapy on humans. The trial aimed evaluate the drug GRNOPC1, embryonic stem cell-derived oligodendrocyte progenitor cells, on patients with acute spinal cord injury. The trial was discontinued in November 2011 so that the company could focus on therapies in the "current environment of capital scarcity and uncertain economic conditions".[67] In 2013 biotechnology and regenerative medicine company BioTime (NYSEMKT:BTX) acquired Geron's stem cell assets in a stock transaction, with the aim of restarting the clinical trial.[68]

Scientists have reported that MSCs when transfused immediately within few hours post thawing may show reduced function or show decreased efficacy in treating diseases as compared to those MSCs which are in log phase of cell growth(fresh), so cryopreserved MSCs should be brought back into log phase of cell growth in invitro culture before these are administered for clinical trials or experimental therapies, re-culturing of MSCs will help in recovering from the shock the cells get during freezing and thawing. Various clinical trials on MSCs have failed which used cryopreserved product immediately post thaw as compared to those clinical trials which used fresh MSCs.[69]

Research currently conducted on horses, dogs, and cats can benefit the development of stem cell treatments in veterinary medicine and can target a wide range of injuries and diseases such as myocardial infarction, stroke, tendon and ligament damage, osteoarthritis, osteochondrosis and muscular dystrophy both in large animals, as well as humans.[70][71][72][73] While investigation of cell-based therapeutics generally reflects human medical needs, the high degree of frequency and severity of certain injuries in racehorses has put veterinary medicine at the forefront of this novel regenerative approach.[74] Companion animals can serve as clinically relevant models that closely mimic human disease.[75][76]

There is widespread controversy over the use of human embryonic stem cells. This controversy primarily targets the techniques used to derive new embryonic stem cell lines, which often requires the destruction of the blastocyst. Opposition to the use of human embryonic stem cells in research is often based on philosophical, moral, or religious objections.[110] There is other stem cell research that does not involve the destruction of a human embryo, and such research involves adult stem cells, amniotic stem cells, and induced pluripotent stem cells.

Stem-cell research and treatment was practiced in the People's Republic of China. The Ministry of Health of the People's Republic of China has permitted the use of stem-cell therapy for conditions beyond those approved of in Western countries. The Western World has scrutinized China for its failed attempts to meet international documentation standards of these trials and procedures.[111]

Since 2008 many universities, centers and doctors tried a diversity of methods; in Lebanon proliferation for stem cell therapy, in-vivo and in-vitro techniques were used, Thus this country is considered the launching place of the Regentime[112] procedure. http://www.researchgate.net/publication/281712114_Treatment_of_Long_Standing_Multiple_Sclerosis_with_Regentime_Stem_Cell_Technique The regenerative medicine also took place in Jordan and Egypt.[citation needed]

Stem-cell treatment is currently being practiced at a clinical level in Mexico. An International Health Department Permit (COFEPRIS) is required. Authorized centers are found in Tijuana, Guadalajara and Cancun. Currently undergoing the approval process is Los Cabos. This permit allows the use of stem cell.[citation needed]

In 2005, South Korean scientists claimed to have generated stem cells that were tailored to match the recipient. Each of the 11 new stem cell lines was developed using somatic cell nuclear transfer (SCNT) technology. The resultant cells were thought to match the genetic material of the recipient, thus suggesting minimal to no cell rejection.[113]

As of 2013, Thailand still considers Hematopoietic stem cell transplants as experimental. Kampon Sriwatanakul began with a clinical trial in October 2013 with 20 patients. 10 are going to receive stem-cell therapy for Type-2 diabetes and the other 10 will receive stem-cell therapy for emphysema. Chotinantakul's research is on Hematopoietic cells and their role for the hematopoietic system function in homeostasis and immune response.[114]

Today, Ukraine is permitted to perform clinical trials of stem-cell treatments (Order of the MH of Ukraine 630 "About carrying out clinical trials of stem cells", 2008) for the treatment of these pathologies: pancreatic necrosis, cirrhosis, hepatitis, burn disease, diabetes, multiple sclerosis, critical lower limb ischemia. The first medical institution granted the right to conduct clinical trials became the "Institute of Cell Therapy"(Kiev).

Other countries where doctors did stem cells research, trials, manipulation, storage, therapy: Brazil, Cyprus, Germany, Italy, Israel, Japan, Pakistan, Philippines, Russia, Switzerland, Turkey, United Kingdom, India, and many others.

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Stem-cell therapy - Wikipedia

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BioTimes Subsidiary Cell Cure Neurosciences Receives FDA Authorization to Initiate Phase I/IIa Trial of Embryonic …

By Sykes24Tracey

OpRegen consists of animal product-free retinal pigment epithelial (RPE) cells with high purity and potency that were derived from human embryonic stem cells (hESCs). Cell Cure will conduct the trial in Israel where OpRegen will be transplanted as a single dose into the subretinal space of the eye to test the safety and efficacy of the product. Patient enrollment is expected to begin in 2014 following approval of the trial by the Israel Ministry of Health.

About the OpRegenClinical Trial

Cell Cures Phase I/IIa clinical trial is a dose escalation safety and preliminary efficacy study of hESC-derived Retinal Pigment Epithelial (RPE) cells transplanted subretinally in patients with advanced dry-form AMD called geographic atrophy. The open-label, single center, nonrandomized trial will evaluate three different dose regimens of 50,000 to 500,000 cells. A total of 15 patients will be enrolled. The patients will be 55 years of age and older, with non-neovascular (dry-AMD) who have funduscopic findings of GA in the macula with absence of additional concomitant ocular disorders. The eye most affected by the disease will be treated with the contralateral eye being the control. Following transplantation, the patients will be followed for 12 months at specified intervals, to evaluate the safety and tolerability of OpRegen. A secondary objective of the clinical trial will be to examine the ability of transplanted OpRegen to engraft, survive, and induce changes in visual acuity. In addition to thorough characterization of visual function, a battery of defined ophthalmic imaging modalities will be used to quantify structural changes and rate of GA expansion. The study will be performed at Hadassah Ein Kerem Medical Center in Jerusalem, Israel.

The FDAs acceptance of our IND for the Phase I/IIa trial of OpRegen is a significant milestone for our company, and in the broader development of therapies based on human embryonic stem cells for the treatment of major diseases, said Benjamin Reubinoff, MD, PhD, Chief Scientific Officer of Cell Cure and Chairman of Obstetrics and Gynecology and Director of the Hadassah Human Embryonic Stem Cell Research Center at Hadassah Medical Center, Jerusalem, Israel. We look forward to initiating this first-of-its-kind study, and to continuing the clinical development of OpRegen.

Cell Cures Phase I/IIa study of OpRegen has been designed to provide preliminary, objective functional and structural data on the ability of hESC-RPE cell transplantation to slow the progression of geographic atrophy, in addition to safety data, added Prof. Eyal Banin, Head of the Center for Retinal and Macular Degenerations at the Department of Ophthalmology of Hadassah University Medical Center, Jerusalem, Israel who together with Prof. Reubinoff helped develop this novel treatment over the last decade. We are truly excited that this unique, hESC-based therapy will finally be tested in patients with dry-AMD which severely impacts the quality of life of the elderly, and for which no approved therapy yet exists, Dr. Banin stated.

Information about the trial will be made available at ClinicalTrials.gov website of the National Institutes of Health http://www.clinicaltrials.gov/ct2/home. Additional information will be made available on Cell Cures website at http://www.cellcureneurosciences.com/.

About Age-Related Macular Degeneration

Age-related macular degeneration (AMD) is one of the major diseases of aging and is the leading eye disease responsible for visual impairment of older persons in the US, Europe and Australia. AMD affects the macula, which is the part of the retina responsible for sharp, central vision that is important for facial recognition, reading and driving. There are two forms of AMD. The dry form (dry-AMD) advances slowly and painlessly but may progress to geographic atrophy (GA) in which RPE cells and photoreceptors degenerate and are lost. Once the atrophy involves the fovea (the center of the macula), patients lose their central vision and may develop legal blindness. There are about 1.6 million new cases of dry-AMD in the US annually, and as yet there is no effective treatment for this condition. The yearly economic loss to the gross domestic product in the United States from dry-AMD has been estimated to be $24.4 billion. The market opportunity for a treatment for GA has been estimated at over $5 billion globally. About 10% of patients with dry-AMD develop wet (or neovascular) AMD, the second main form of this disease, which usually manifests acutely and can lead to severe visual loss in a matter of weeks. Wet-AMD can be treated with currently marketed VEGF inhibitors. However, such products typically require frequent repeated injections in the eye, and patients often continue to suffer from continued progression of the underlying dry-AMD disease process. Current annual sales of VEGF inhibitors for the treatment of the wet form of AMD are estimated to be about $7 billion worldwide.

The root cause of the larger problem of dry-AMD is believed to be the dysfunction of RPE cells. Therefore, one of the most exciting new therapeutic strategies for dry-AMD is the transplantation of healthy young RPE cells to support and replace those lost with age. Pluripotent stem cells, such as hESCs, can potentially provide a means of manufacturing such healthy RPE cells on an industrial scale.

About OpRegen

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