Whatever Happened to Stem Cell Research? -- a Short History

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Whatever happened to stem cell research? Well, plenty. But it does not dominate our political conversation anymore. What’s more, it has moved into morally acceptable avenues. And for that we can thank President George W. Bush.

Ten years ago this week, he made his first prime time speech and, remarkably, it was about this wedge political issue, with much elite opinion stacked against him. Yet he remained firm.

The scientific and political communities were giddy about stem cells’ potential to treat and cure ever since they were discovered in 1998. Embryonic stem cells would allow us to grow whole organs. The lame would walk, the blind would see, the deaf would hear.

And then came George Bush, that Neanderthal Christian. All that was needed for medical miracles was federal funding. Everyone wanted it, Congress, the American people, Chris Matthews.

President Bush began protracted dialogue with experts from many different fields. He met with scientists, ethicists, theologians, medical doctors, and philosophers. To many, of course, this was a no-brainer: we should just use embryos left over from in vitro fertilization.

Bush stood before the microphones on the evening of August 9, 2001 and called embryonic stem cell research “one of the most profound (issues) of our time.” He added, “most scientists, at least today, believe that research on embryonic stem cells offers the most promise because these cells have the potential to develop in all of the tissues of the body.”

Bush then addressed the ethical problems, especially two main questions. “Are these frozen embryos human life and therefore something precious to be protected? And, if they are going to be destroyed anyway, shouldn’t they be used for a great good” He had received conflicting views on each question.

There was genuine tension at the time because no one knew what he would do. He said, “At its core, this issue forces us to confront the fundamental questions about the beginnings of life and the ends of science. It lives at a difficult moral intersection, juxtaposing the need to protect life in all its phases with the prospect of saving and improving life in all its stages.”

Near the end of this eloquent speech, Bush announced he would allow federal funding of research on sixty stem cell lines that already existed, that the U.S. government would not be about the killing of embryos. He would also fund federal research into alternative methods, and he would create a presidential commission to explore these issues and advise him.

The president speaks: August 9, 2001

The backlash was immediate, fierce, and long-lasting. Though relieved that Bush did not permit the death of hundreds of thousands of frozen embryos, even the Catholic Bishops complained that paying for experimentation on embryos already killed for their stem cells, still cooperated in evil. Many said Bush was gambling with his reelection.

His policy did not end the political controversy. Recall the speeches at the 2004 Democratic National Convention. Almost every one mentioned embryonic stem cell research. John Kerry announced he would fully fund it and received thundering applause. Even Ron Reagan Jr. was invited to speak in favor of embryo-destructive research. The Democratic Party was certain they had a social wedge issue all their own.

But something was already happening, something the Bush policy nurtured. William Hurlbut of Stanford was circulating an idea he called Altered Nuclear Transfer (ANT), a form of cloning he postulated would create pluripotent stem cells without a human embryo.

Hurlbut was invited onto the President’s Bioethics Commission, along with such stalwarts as Professor Robert George of Princeton, but also with opponents like Michael Sandel of Harvard and Michael Gazzaniga of UC-Santa Barbara. When Hurlbut presented ANT to the Commission, Gazzaniga mocked him, “So, we’re going to take the soul out and put it back in later?”

Hurlbut’s ethical proposal was not the only one. Donald Landry of Columbia University said we could medically recognize embryo death and then harvest their stem cells ethically, not unlike organ transplantation. At the same time, a whole host of scientists were having multiple successes with adult stem cells. Here were actual scientists grappling with profound ethical questions and working within ethical boundaries.

Often, a lack of rules results in wider chaos while narrow rules result in greater creativity – and even beauty. That is Bush’s great contribution. He encouraged scientists – and gave them room – to catch up to the ethics.

The political pressure remained, but Bush was at his bravest. Congress passed an embryo-destructive stem cell funding bill in 2006. Bush stood in the White House again, this time surrounded by “snow-flake babies,” children adopted as frozen embryos and implanted in adoptive mothers. He said, “These boys and girls are not spare parts.” A veto override was defeated the next day, largely owing to Hurlbut’s idea that embryonic stem cells could be derived ethically.

Not long after, Shinya Yamanaka announced that he had derived pluripotent stem cells (iPS) from the manipulation of adult stem cells that were reprogrammed into embryonic stem cells. The original discoverer of embryonic stem cells announced that embryos were no longer needed for research.

Game, set, match? Not by a long shot.

Hurlbut says many technical problems remain with ANT and with iPS. How could there not be? We are dusting for the finest fingerprints of our creation as humans. He says stem cells derived from embryos are still seen as the “gold standard” and that a biotech firm, Geron, has raised $200 million for such research.

But we would not have had a chance if President Bush had not stood firm on that night ten years ago this week – and remained firm through the years. Without him, this fight for human dignity would have been lost a long time ago. It is still far from over, but thanks to him and many others, we stand a very good chance of winning. The Catholic Thing

Austin Ruse is the President of the New York and Washington, D.C.-based Catholic Family & Human Rights Institute (C-FAM), a research institute that focuses exclusively on international social policy. The opinions expressed here are Mr. Ruse’s alone and do not necessarily reflect the policies or positions of C-FAM.

MCCL Blog: Comment on Errors in Star Tribune's Article on Proposed Ban on Human Cloning in Minn.

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Wednesday, March 30, 2011

Star Tribune gets everything wrong about human cloning

It is difficult to point out all that is wrong with the Star Tribune's coverage today of the MCCL-backed human cloning ban (currently before the state Legislature). The reporter, Jenna Ross, is uneducated and obviously not qualified to be writing about this subject. Here are some of the mistakes in the order they appear.

The story starts by claiming that the bill would make human cloning a felony. False. The bill would make human cloning a misdemeanor. (Read the bill!)

Ross then writes:

The bill's advocates say it would still allow stem cell research that does not rely on destruction of embryos, including adult stem cells.

Actually, the bill would still allow not just research that doesn't destroy embryos, but also research that does rely on the destruction of embryos. All of the current embryonic stem cell research happening in the state would be unaffected, because it does not involve human cloning (according to testimony from the University of Minnesota's Stem Cell Institute).

Embryonic stem cell research (which requires the destruction of embryos) is not the same thing as human cloning, which is what the bill prohibits. Human cloning (via somatic cell nuclear transfer, or SCNT) is one possible way of producing embryos for use in research, but all the embryos currently used for research in Minnesota were not produced by cloning. Ross continues:

Opponents say the bill's language -- banning "human cloning" -- is purposely deceptive ...

Our use of "human cloning" -- using SCNT to produce a genetically virtually identical human organism, as precisely defined in the legislation itself -- has been the standard use. It is opponents of the bill who are shamelessly misleading by redefining cloning so that it includes only so-called "reproductive" cloning -- that is, allowing the resulting cloned embryo to live and grow, rather than kill it for research (so-called therapeutic cloning).

The U emphasizes that it has not and will not attempt to clone a human being, a process called reproductive cloning. Think Dolly the sheep, the first cloned mammal. "We have been crystal clear on this," said Dr. Aaron Friedman, the U's vice president for health sciences and medical school dean.

Again, the University has redefined human cloning. The University does support cloning human beings -- it simply opposes letting them live very long. Dolly the sheep was cloned by exactly the same technique that this bill prohibits.

Minnesota Citizens Concerned for Life's broader definition of "human cloning" also includes one kind of stem cell research called therapeutic cloning. In that process, a scientist would extract stem cells from a 5-day-old embryo and then destroy it in a test tube. This bill would ban that too.

The author seems hopelessly confused. Destroying an embryo for its stem cells is not the same thing as therapeutic cloning. Cloning is simply one possible means of creating an embryo for use in destructive research. Generally embryos destroyed for their stem cells are not produced by cloning, but are the result of in vitro fertilization. The bill does not affect this research.

But "there are reasons why I might want to do [therapeutic cloning] in the future," said Dr. John Wagner, clinical director of the Stem Cell Institute, who uses adult stem cells to treat a fatal skin condition in children. Therapeutic cloning offers the possibility of merging a patient's cells with embryonic cells, so there's less risk of rejection, he said.

"Merging a patient's cells with embryonic cells"? Perhaps Dr. Wagner didn't explain it very well. Therapeutic cloning offers the possibility of producing embryonic stem cells genetically matched to the patient, so theoretically there might be no rejection problems. Why are they genetically matched? Because they are derived from the embryo, which is a genetic clone of the patient.

What Dr. Wagner has not explained is what possible benefits therapeutic cloning could offer that (ethically uncontroversial) induced pluripotent stem cells (iPSCs) do not also offer. Indeed, iPSCs seem superior: they are also pluripotent (functionally identical to embryonic stem cells) and genetically matched, but they already exist, they are less expensive, and they are easier to produce. This is why some leading scientists like Dr. Ian Wilmut have switched from therapeutic cloning to iPSC research. And I imagine this is why the University of Minnesota is currently working with iPSCs but not with therapeutic cloning.

Minnesota Citizens Concerned for Life argues that scientists should abandon embryonic stem cells in favor of adult stem cells -- in particular, a process of reprogramming adult stem cells to mimic the flexible properties of their embryonic counterparts.

"In adult stem cell research, money is flowing like a river," Scott Fischbach said. "Money going into embryonic stem cell research is resulting in nothing but dead embryos."

But researchers argue that those methods are far from ready and might never work for certain diseases.

Actually, the process (for iPSCs) is to reprogram regular adult cells, not stem cells, to make them into pluripotent stem cells, just like embryonic stem cells. iPSCs seem to make obsolete the therapeutic justification for embryonic stem cell research and therapeutic cloning.

It's true that iPSCs, like embryonic stem cells, have not succeeded in treating anyone. But "iPSC research" does not equal "adult stem cell research," as the author apparently believes. Adult stem cell research is the only kind of stem cell research that actually is ready and actually has successfully treated medical conditions -- dozens of them. It is therapeutic cloning, and embryonic stem cell research more broadly, that is "far from ready and might never work."

A reporter should not write a story when she knows so little and gets so much wrong. And the Star Tribune is terribly at fault for publishing this. MCCL Blog (Minnesota Citizens Concerned for Life)

Treating Traumatic Brain Injuries in Children Using Adult Stem Cells

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Use of adult stem cells to treat traumatic brain injury in children appears safe and effective. .Scientists at the University of Texas Health Science Center at Houston have published preliminary results of a Phase I clinical trial showing the safety of bone marrow adult stem cells in treating traumatic brain injury in children. A total of ten children between the age of 5 and 14 years old were treated within 48 hours of their injury with their own adult stem cells; the cells were collected from their bone marrow, processed and returned to them intravenously. Using the patient’s own adult stem cells avoids potential complications of cell rejection, graft versus host disease, and blood-borne disease transfer.

Over 2.5 million Americans live with the devastating consequences of traumatic brain injury, and children who survive such an injury often have serious long-term problems. Six months after their adult stem cell treatment, all of the children showed significant improvement and seven of the 10 children had a “good outcome,” meaning no or only mild disability. The medical team is also testing use of cord blood stem cells for treatment of traumatic brain injury.

According to Dr. Charles S. Cox, Jr., lead author:

“Our data demonstrate that the acute harvest of bone marrow and infusion of bone marrow mononuclear cells to acutely treat severe TBI in children is safe.”

The results are published in the journal Neurosurgery.

Family Research Council

Embryonic Stem Cell Research: Rare Hits and Heaps of Misses to Pay For

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Research, in any field of science, is not the risk-free business that might easily be supposed from the confident promises of scientific spokesmen or the daily reports of new advances.

Nature yields her secrets with the greatest unwillingness, and in basic research most experiments contribute little to further progress, as judged by the rarity with which most scientific reports are cited by others.

Basic research, the attempt to understand the fundamental principles of science, is so risky, in fact, that only the federal government is willing to keep pouring money into it. It is a venture that produces far fewer hits than misses. . . .

This is why it was such a risk for California to earmark $3 billion specifically for stem cell research over the next 10 years. Stem cells are just one of many promising fields of biomedical research. They could yield great advances, or become an exercise in sustained failure, as gene therapy has so far been. By allocating so much money to a single field, California is placing an enormous bet on a single horse, and the chances are substantial that its taxpayers will lose their collective shirt.

Stem cell researchers have created an illusion of progress by claiming regular advances in the 12 years since human embryonic stem cells were first developed. But a notable fraction of these claims have turned out to be wrong or fraudulent, and many others have amounted to yet another new way of getting to square one by finding better methods of deriving human embryonic stem cells.

The major advances in stem cell biology have come from molecular biologists who study transcription factors, the master control switches that govern the cell’s operations. The Japanese biologist Shinya Yamanaka showed that with a mere four of these factors, which he cleverly guessed, he could force an ordinary cell to walk back to embryonic state.

But the finding illustrates what stem cell research is really about. It’s not about therapies and quick cures, it’s about understanding the basic nature of human cells and what makes one type different from another even though all have the identical genome. In other words, it’s a basic research program with little likelihood of producing therapeutic gains in the near future. Stem cell scientists, while generally avoiding rash promises themselves, have allowed politicians to portray stem cells as a likely cure for all the major diseases. . . . New York Times

Skin Cells Turned Directly Into Human Blood

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Scientists have used a modified version of the induced pluripotent stem cell process to create blood cells out of skin cells–without going through the pluripotent stage. This could be big. From the story:

Mick Bhatia, scientific director of McMaster’s Stem Cell and Cancer Research Institute in the Michael G. DeGroote School of Medicine, and his team of researchers have also shown that the conversion is direct. Making blood from skin does not require the middle step of changing a skin stem cell into a pluripotent stem cell that could make many other types of human cells, then turning it into a blood stem cell. “We have shown this works using human skin. We know how it works and believe we can even improve on the process,” said Bhatia. “We’ll now go on to work on developing other types of human cell types from skin, as we already have encouraging evidence.” The discovery was replicated several times over two years using human skin from both young and old people to prove it works for any age of person.

This breakthrough could do away with need for bone marrow donations in blood diseases. . . .
First Things

And yet millions continue to be spent by stubborn researchers attempting to find even one use for embryonic stem cells, at the cost of much human life.

U of MN Scientists use bone marrow stem cells to treat rare skin disease

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Scientists from the University of Minnesota Medical School, working with their counterparts from Oregon, the United Kingdom and Japan, have found a way to use stem cells from bone marrow to treat a deadly skin disease called recessive dystrophic epidermolysis bullosa. The disease causes the skin to flake off easily, resulting in extreme pain. Stem cell therapies have shown to significantly repair damage to the skin of those inflicted with the disease. MinnPost

Researchers find that adult stem cells can rebuild heart tissue

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Researchers at the Mayo Clinic, working together with Belgium experts, have demonstrated in lab tests that adult stem cells from bone marrow can repair and rebuild damaged heart tissue. The discovery was published yesterday in the Journal of the American College of Cardiology.

Stem cells that have been isolated from patients generally have a limited capacity to repair heart tissue, explained the Mayo Clinic in a press release. However, the technology used in this particular study yielded significant results by programming these cells to acquire a profile similar to cardiac cells.

In order to carry out the tests, researchers obtained bone marrow-derived stem cells from patients with heart disease during coronary bypass surgery.

The Mayo Clinic reported that stem cells from two of the 11 individuals demonstrated an unusual capacity to repair heart tissue. The researchers then used techniques to introduce the same molecular signature into the stem cells of the other patients in order to “program” their capacity to repair heart tissue.

These kinds of cells, called Mesenchymal stem cells, were injected into rats with heart disease and resulted in significant recovery of heart function, as well as an improved survival rate after one year, in contrast with rats infused with stem cells not guided by researchers.

According to Andre Terzic of the Mayo Clinic, the main author of the study, “These findings provide proof-of-principle that "smart" adult stem cells have added benefit in repairing the heart.” Catholic News Agency

Windpipes made with Adult Stem Cells Help Cancer Patients

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from Family Research Council Blog by David Prentice

Italian doctors have announced the use of patients’ own adult stem cells to fabricate new tracheas for two cancer patients. The surgical team was led by Dr. Paolo Macchiarini, has used this technique in prior surgeries, though not for cancer patients. The two patients were a 31-year-old Czech woman with a 6-month-old son, and a 19-year-old British woman. The surgeries took place on July 3 and 13, and both patients are in good condition and have been released from the hospital in Florence just weeks after the surgery. The hospital said that the British woman was speaking after only three or four days.

To grow a new trachea, the doctors started with a donor trachea and removed all of the cells. The cartilage scaffold left after the procedure was then bathed in the patient’s bone marrow adult stem cells prior to transplantation. Over a period of 2-3 months the adult stem cells cover the scaffold with new tissue, grown within the body of the patient. Using the patient’s own adult stem cells removes any problems with tissue rejection. According to Dr. Walter Giovannini, director of the AOU Careggi hospital where the surgeries took place:

“This is a unique solution for a problem that had none, except the death of the patient.”

Dr. Macchiarini told the press conference in Florence that the procedure could in the future be applied to other organs.

“I’m thinking about the larynx or surgeries involving lungs.”

Have Stem Cells Become Passé?

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Fr. Thomas Berg, Executive Director of the Westchester Institute for Ethics and the Human Person.
An update on stem cell research June 15, 2010

I last wrote an update on stem cell research in December. On that occasion I explained that the National Institutes of Health (NIH) had announced the approval of thirteen new lines of human embryonic stem cells for use in NIH-funded research under the new NIH Guidelines for Human Stem Cell Research published in July of 2009.

What has been happening in stem cell science over the past six months to a year?

For the better part of the past two years, scientific attention has focused on comparing the traits and capabilities of induced pluripotent stem cells (iPSCs) with the putative “gold standard” human embryonic stem cells (hESCs). Unlike hESCs, which are obtained by destroying live embryos, iPSCs are made directly from adult cells—such as skin cells—by adding a small number of factors to these cells in the laboratory. These factors remodel the mature cells and convert them into stem cells that are functionally identical to stem cells obtained from embryos. No human eggs are required and no human embryos are generated or destroyed in the process.

Several recent side-by side comparison studies of both hES cells and iPS cells have been conducted to evaluate which types of stem cells might be best suited to which tissue-generating tasks. The most recent research has brought to light two potential hurdles for the use of iPS cells. On the one hand, because iPS cells are derived from adult—which is to say, fully determined—cells, they often “remember” their cell-type of origin and revert back to it. Another recent study suggested that iPS cells may actually have an entire series of genetic switches turned “off” and that this might explain why they sometimes fail to robustly generate more specific types of tissues.

Since 2007, there has been steady progress in using iPS cells as models for the study of diseases. iPS cells derived from both animals and human adults have been isolated which bear the phenotypes (structural characteristics) found in several diseases including Alzheimers, Parkinson’s, Huntington’s, Multiple Sclerosis, Type 1 Diabetes and Sickle Cell Anemia. Because these lines of cells exhibit disease-specific phenotypes, researchers are able to study disease mechanisms, and use them for drug screening.

Another important inroad in iPS research has been continued confirmation by independent teams of scientists that the reprogramming of adult cells can be accomplished without having recourse to viruses as vehicles for transporting the reprogramming agents into the cells. Rather than having to manipulate the genome itself by inserting viruses into the cells to be reprogrammed—hazardous to humans—researchers have identified ways to turn on the pluripotency genes in those cells simply by manipulating the chemical environment of the culture surrounding the cells. In 2009, researchers were also able to reduce the number of reprogramming factors necessary for accomplishing the task down to only one from the original four used by Dr. Yamanaka in 2007.

Yet, the biggest stem cell news seems to be that stem cells have largely disappeared from the news. Two factors have contributed to the dearth of headline grabbing stem cell news of late. Despite advances summarized above, the most recent progress is cloaked in such technical complexity that, understandably, journalists have been unusually challenged to make the news accessible to the average reader.

The second factor, more notably, is that stem cell fervor has waned and public frustration over the lack of tangible progress in stem cell science is growing.

To be sure, criticism of the lack of progress in the translation of stem cell research to therapies has arisen from surprising sources. In March of 2009 Dr. Bernadine Healy, director of the National Institutes of Health under the first Bush adminstration, wrote in her U.S. News & World Report column that "embryonic stem cells, once thought to hold the cure for Alzheimer's, Parkinson's and diabetes, are obsolete." An editorial last January in Investor’s Business Daily angrily criticized California’s Proposition 71. This was the 2004 State law which allotted $6 billion of California taxpayer money to primarily embryo-destructive stem cell research over the next decade, an initiative that rode a tremendous wave of hyped advocacy for embryonic stem cell research. “Five years after a budget-busting $3 billion was allocated to embryonic stem cell research,” wrote the editors, “there have been no cures, no therapies and little progress.” Writing earlier this month in the Los Angeles Times, one science reporter felt it was time to offer her own mea culpa: don’t blame the scientists for hyping the potential of hESC research; blame us, the reporters.

Adult Stem Cells Reverse Blindness Caused by Burns

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AP – This image from an Italian study published online
Wednesday, June 23, 2010 by the New England Journal …

Slideshow:Stem Cell Research

Dozens of people who were blinded or otherwise suffered severe eye damage when they were splashed with caustic chemicals had their sight restored with transplants of their own stem cells — a stunning success for the burgeoning cell-therapy field, Italian researchers reported Wednesday.

The treatment worked completely in 82 of 107 eyes and partially in 14 others, with benefits lasting up to a decade so far. One man whose eyes were severely damaged more than 60 years ago now has near-normal vision.

"This is a roaring success," said ophthalmologist Dr. Ivan Schwab of the University of California, Davis, who had no role in the study — the longest and largest of its kind.

Stem cell transplants offer hope to the thousands of people worldwide every year who suffer chemical burns on their corneas from heavy-duty cleansers or other substances at work or at home.

The approach would not help people with damage to the optic nerve or macular degeneration, which involves the retina. Nor would it work in people who are completely blind in both eyes, because doctors need at least some healthy tissue that they can transplant.

In the study, published online by the New England Journal of Medicine, researchers took a small number of stem cells from a patient's healthy eye, multiplied them in the lab and placed them into the burned eye, where they were able to grow new corneal tissue to replace what had been damaged. Since the stem cells are from their own bodies, the patients do not need to take anti-rejection drugs.

Adult stem cells have been used for decades to cure blood cancers such as leukemia and diseases like sickle cell anemia. But fixing a problem like damaged eyes is a relatively new use. Researchers have been studying cell therapy for a host of other diseases, including diabetes and heart failure, with limited success.

Adult stem cells, which are found around the body, are different from embryonic stem cells, which come from human embryos and have stirred ethical concerns because removing the cells requires destroying the embryos.

Currently, people with eye burns can get an artificial cornea, a procedure that carries such complications as infection and glaucoma, or they can receive a transplant using stem cells from a cadaver, but that requires taking drugs to prevent rejection.

The Italian study involved 106 patients treated between 1998 and 2007. Most had extensive damage in one eye, and some had such limited vision that they could only sense light, count fingers or perceive hand motions. Many had been blind for years and had had unsuccessful operations to restore their vision.

The cells were taken from the limbus, the rim around the cornea, the clear window that covers the colored part of the eye. In a normal eye, stem cells in the limbus are like factories, churning out new cells to replace dead corneal cells. When an injury kills off the stem cells, scar tissue forms over the cornea, clouding vision and causing blindness.

In the Italian study, the doctors removed scar tissue over the cornea and glued the laboratory-grown stem cells over the injured eye. In cases where both eyes were damaged by burns, cells were taken from an unaffected part of the limbus.

Researchers followed the patients for an average of three years and some as long as a decade. More than three-quarters regained sight after the transplant. An additional 13 percent were considered a partial success. Though their vision improved, they still had some cloudiness in the cornea.

Patients with superficial damage were able to see within one to two months. Those with more extensive injuries took several months longer.

"They were incredibly happy. Some said it was a miracle," said one of the study leaders, Graziella Pellegrini of the University of Modena's Center for Regenerative Medicine in Italy. "It was not a miracle. It was simply a technique."

The study was partly funded by the Italian government.

Researchers in the United States have been testing a different way to use self-supplied stem cells, but that work is preliminary.

One of the successful transplants in the Italian study involved a man who had severe damage in both eyes as a result of a chemical burn in 1948. Doctors grafted stem cells from a small section of his left eye to both eyes. His vision is now close to normal.

In 2008, there were 2,850 work-related chemical burns to the eyes in the United States, according to the Bureau of Labor Statistics.

Schwab of UC Davis said stem cell transplants would not help those blinded by burns in both eyes because doctors need stem cells to do the procedure.

"I don't want to give the false hope that this will answer their prayers," he said.

Dr. Sophie Deng, a cornea expert at the UCLA's Jules Stein Eye Institute, said the biggest advantage was that the Italian doctors were able to expand the number of stem cells in the lab. This technique is less invasive than taking a large tissue sample from the eye and lowers the chance of an eye injury.

"The key is whether you can find a good stem cell population and expand it," she said. Yahoo News

Do ya suppose God is smarter than scientists? Maybe He DID create mankind in His Image and Likeness.

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A Decade Later, Genetic Map Yields Few New Cures: The Genome at 10

Ten years after President Bill Clinton announced that the first draft of the human genome was complete, medicine has yet to see any large part of the promised benefits.

For biologists, the genome has yielded one insightful surprise after another. But the primary goal of the $3 billion Human Genome Project — to ferret out the genetic roots of common diseases like cancer and Alzheimer’s and then generate treatments — remains largely elusive. Indeed, after 10 years of effort, geneticists are almost back to square one in knowing where to look for the roots of common disease.

One sign of the genome’s limited use for medicine so far was a recent test of genetic predictions for heart disease. A medical team led by Nina P. Paynter of Brigham and Women’s Hospital in Boston collected 101 genetic variants that had been statistically linked to heart disease in various genome-scanning studies. But the variants turned out to have no value in forecasting disease among 19,000 women who had been followed for 12 years.

The old-fashioned method of taking a family history was a better guide, Dr. Paynter reported this February in The Journal of the American Medical Association.

In announcing on June 26, 2000, that the first draft of the human genome had been achieved, Mr. Clinton said it would “revolutionize the diagnosis, prevention and treatment of most, if not all, human diseases.”

At a news conference, Francis Collins, then the director of the genome agency at the National Institutes of Health, said that genetic diagnosis of diseases would be accomplished in 10 years and that treatments would start to roll out perhaps five years after that.

“Over the longer term, perhaps in another 15 or 20 years,” he added, “you will see a complete transformation in therapeutic medicine.”

The pharmaceutical industry has spent billions of dollars to reap genomic secrets and is starting to bring several genome-guided drugs to market. While drug companies continue to pour huge amounts of money into genome research, it has become clear that the genetics of most diseases are more complex than anticipated and that it will take many more years before new treatments may be able to transform medicine.

“Genomics is a way to do science, not medicine,” said Harold Varmus, president of the Memorial Sloan-Kettering Cancer Center in New York, who in July will become the director of the National Cancer Institute.

The last decade has brought a flood of discoveries of disease-causing mutations in the human genome. But with most diseases, the findings have explained only a small part of the risk of getting the disease. And many of the genetic variants linked to diseases, some scientists have begun to fear, could be statistical illusions.

The Human Genome Project was started in 1989 with the goal of sequencing, or identifying, all three billion chemical units in the human genetic instruction set, finding the genetic roots of disease and then developing treatments. With the sequence in hand, the next step was to identify the genetic variants that increase the risk for common diseases like cancer and diabetes.

It was far too expensive at that time to think of sequencing patients’ whole genomes. So the National Institutes of Health embraced the idea for a clever shortcut, that of looking just at sites on the genome where many people have a variant DNA unit. But that shortcut appears to have been less than successful.

The theory behind the shortcut was that since the major diseases are common, so too would be the genetic variants that caused them. Natural selection keeps the human genome free of variants that damage health before children are grown, the theory held, but fails against variants that strike later in life, allowing them to become quite common. In 2002 the National Institutes of Health started a $138 million project called the HapMap to catalog the common variants in European, East Asian and African genomes.

With the catalog in hand, the second stage was to see if any of the variants were more common in the patients with a given disease than in healthy people. These studies required large numbers of patients and cost several million dollars apiece. Nearly 400 of them had been completed by 2009. The upshot is that hundreds of common genetic variants have now been statistically linked with various diseases.

But with most diseases, the common variants have turned out to explain just a fraction of the genetic risk. It now seems more likely that each common disease is mostly caused by large numbers of rare variants, ones too rare to have been cataloged by the HapMap.

Defenders of the HapMap and genome-wide association studies say that the approach made sense because it is only now becoming cheap enough to look for rare variants, and that many common variants do have roles in diseases.

At this point, some 850 sites on the genome, most of them near genes, have been implicated in common diseases, said Eric S. Lander, director of the Broad Institute in Cambridge, Mass., and a leader of the HapMap project. “So I feel strongly that the hypothesis has been vindicated,” he said.

But most of the sites linked with diseases are not in genes — the stretches of DNA that tell the cell to make proteins — and have no known biological function, leading some geneticists to suspect that the associations are spurious.

Many of them may “stem from factors other than a true association with disease risk,” wrote Jon McClellan and Mary-Claire King, geneticists at the University of Washington, Seattle, in the April 16 issue of the journal Cell. The new switch among geneticists to seeing rare variants as the major cause of common disease is “a major paradigm shift in human genetics,” they wrote.

The only way to find rare genetic variations is to sequence a person’s whole genome, or at least all of its gene-coding regions. That approach is now becoming feasible because the cost of sequencing has plummeted, from about $500 million for the first human genome completed in 2003 to costs of $5,000 to $10,000 that are expected next year.

But while 10 years of the genome may have produced little for medicine, the story for basic science has been quite different. Research on the genome has transformed biology, producing a steady string of surprises. First was the discovery that the number of human genes is astonishingly small compared with those of lower animals like the laboratory roundworm and fruit fly. The barely visible roundworm needs 20,000 genes that make proteins, the working parts of cells, whereas humans, apparently so much higher on the evolutionary scale, seem to have only 21,000 protein-coding genes.

The slowly emerging explanation is that humans and other animals have much the same set of protein-coding genes, but the human set is regulated in a much more complicated way, through elaborate use of DNA’s companion molecule, RNA.

Little, if any, of this research could have been done without having the human genome sequence available. Every gene and control element can now be mapped to its correct site on the genome, enabling all the working parts of the system to be related to one another.

“Having a common scaffold on which one can put all the information has dramatically accelerated progress,” Dr. Lander said.

The genome sequence has also inspired many powerful new techniques for exploring its meaning. One is chip sequencing, which gives researchers access to the mysterious and essential chromatin, the complex protein machinery that both packages the DNA of the genome and controls access to it.

The data from the HapMap has also enabled population geneticists to reconstruct human population history since the dispersal from Africa some 50,000 years ago. They can pinpoint which genes bear the fingerprints of recent natural selection, which in turn reveals the particular challenges to which the populations on different continents have had to adapt.

As more people have their entire genomes decoded, the roots of genetic disease may eventually be understood, but at this point there is no guarantee that treatments will follow. If each common disease is caused by a host of rare genetic variants, it may not be susceptible to drugs.

“The only intellectually honest answer is that there’s no way to know,” Dr. Lander said. “One can prefer to be an optimist or a pessimist, but the best approach is to be an empiricist.” New York Times

The Waterloo for Embryonic Stem Cell Research

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The battle over embryonic stem cell research is over. A few skirmishes will no doubt continue—perhaps even for years—and some ESCR advocates will refuse to acknowledge defeat. But they have decisively lost. Years from now, when we look back in astonishment at having been fleeced for billions to pay for therapeutically worthless research, we’ll recognize that California was the Waterloo for ESCR.

In 2004, California approved Proposition 71, a ballot measure that would allow the state to borrow $3 billion for ESCR. At best the measure would have been an epic boondoggle: pharmaceutical companies would have been able to profit off the taxpayer-funded research without the state sharing any of the profits or even obtaining any of the developed drugs at a cheaper cost. But because it was considered a “progressive” measure (ESCR has always been a stalking horse for abortion rights) it received the support from a long list of billionaires, Silicon Valley tycoons, Nobel laureates, and Hollywood celebrities. Convinced that the only thing standing between science and cures was time and money, the citizens of California opened the state’s coffers.

But five years later, the hype has died down and ESCR has provided no cures, no therapies, no progress, and no hope. Investor’s Business Daily notes,

The California Institute for Regenerative Medicine, the state agency created to, as some have put it, restore science to its rightful place, is diverting funds from ESCR to research that has produced actual therapies and treatments: adult stem cell research. It not only has treated real people with real results; it also does not come with the moral baggage ESCR does.

To us, this is a classic bait-and-switch, an attempt to snatch success from the jaws of failure and take credit for discoveries and advances achieved by research Prop. 71 supporters once cavalierly dismissed. We have noted how over the years that when funding was needed, the phrase “embryonic stem cells” was used. When actual progress was discussed, the word “embryonic” was dropped because ESCR never got out of the lab.

Advocates of ESCR preyed on the scientific and ethical illiteracy of the general public to support the massive funding of this speculative research. The complexity of the issue and the peculiar terminology used often prevented many citizens from developing a fully informed opinion on the matter. They relied on the “experts” and the ESCR supporters took full advantage of this trust by making claims that had no basis in reality. As Ronald D.G. McKay, a stem cell researcher at the National Institute of Neurological Disorders and Stroke, said in 2004 about the claims that ESCR could lead to cures for Alzheimer’s, “To start with, people need a fairy tale. Maybe that’s unfair, but they need a story line that’s relatively simple to understand.”

The truth about ESCR wasn’t unknown to researchers and scientists. The only legitimate practical (though it remained unethical) reason for pursuing ESCR has always been basic research. Researchers know, however, that you’ll never get a grant for millions of dollars because you find stem cells intriguing and want to spend your life studying them in a lab. So they stretched the truth by downplaying the fact that the barriers to therapeutic applications were all but insurmountable. They’ve always known, as MIT researcher James Sherley says, that, “Figuring out how to use human embryonic stem cells directly by transplantation into patients is tantamount to solving the cancer problem.”

Fortunately, the misinformation and false promises seem to be on the wane. Some politicians still continue to tout the benefits of ESCR, of course, because their ignorance is often as limitless as their willingness to talk about issues they know nothing about. (Digression: Several years ago I presented testimony on ESCR and cloning before the Illinois legislature. A Chicago Democrat told me I was wrong about ESCR because he knew that people had already been cured by injecting “embryos into a patient’s spinal cord.”) Scientists and researchers, however, appear to be less vocal than they were a few years ago. Perhaps the Climategate scandal has served as a warning that trust in science is destroyed when they are willing to deceive the public.

This doesn’t mean that they will be honest about their deception, of course. And we shouldn’t expect the “ESCR has proven to be a failure” theme to be carried by the media. Despite the fact that adult stem cell research has provided 73 treatments for everything from heart disease to brain cancer while ESCR has never produced any results at all, ESCR will still be considered a “promising approach.” Like climate change, stem cell research is often more about politics than science, so as long as gullible politicians are willing to hand over millions in funding, supporters won’t admit defeat.

Still, while the people of California may continue to throw their money away on the research, the real debate about the promise of ESCR is over. Whether they realize it or not, ESCR advocates have lost—and ethical research has won.

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