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Stem Cell Research: The
Quest Resumes Melton, his family, & the Harvard Stem Cell Institute) - - - January 30, 2009 Stem Cell Research: The Quest Resumes http://tinyurl.com/type1diabetesMeltonHarvard - - - Excerpts [with inserts, not part of original article, included in brackets]: Scientific inspiration can come from any- where - a person, an event, even an experi- ment gone awry. But perhaps nothing can drive innovation more powerfully than the passion born of tragedy. Or, in Douglas Melton's case, near tragedy. The co-director of the Harvard Stem Cell Institute (HSCI) is one of the leading figures in the search for cures for presently incur- able diseases, and his breakthrough work is challenging many long-held beliefs about the ways biology and human development work. But it was a very personal experience that brought Melton to stem cells, one that 17 years later he still finds difficult to discuss. When his son Sam was 6 months old, he became ill with what his parents thought was a cold. He woke up with projectile vomiting and before long began taking short, shallow breaths. After several hours, he started to turn gray, and Melton and his wife Gail brought the baby to the emergency room. For the rest of that afternoon, doctors performed test after test, trying to figure out what was wrong. "It was a horrific day," says Melton. It was not until that evening that a nurse thought to dip a testing strip into Sam's urine and they finally got a diagnosis. The boy's body was flooded with sugar; he had Type 1 diabetes. Then, as now, the disease had no cure, and patients like Sam need to perform for them- selves the duties their pancreas cannot - keeping track of how much glucose they consume and relying on an insulin pump to break down the sugars when their levels climb too high. The diagnosis changed not only Sam's life but the lives of his parents and older sister Emma as well. Throughout Sam's childhood, Gail would wake every few hours during the night to check his blood sugar and feed him sugar if his concentration fell too low or give him insulin if it was too high. "I thought, This is no way to live," says Mel- ton. "I decided I was not just going to sit around. I decided I was going to do some- thing." Trained as a molecular biologist in amphibian development, Melton began the work he pur- sues today: trying to find a way to make insulin- producing cells by using stem cells. "It was a courageous thing to do because he was at the pinnacle of his career," says Gail. "He brought home textbooks on the pancreas to figure it all out." Nearly two decades later, Melton is convinced that stem cells will be a critical part of new therapies that will treat and maybe cure not only diabetes but also other diseases for which there are no answers today. Melton's confidence is testament to the extra- ordinary advances in stem-cell science, some of which have brought the promise of break- through therapies for conditions like diabetes, Parkinson's and heart disease closer than ever before. The cells filling petri dishes in freezers and incubators in Melton's lab and others around the world are so vastly different - in proven- ance, programming and potential - from the stem cells of just two years ago that even the scientists leading this biological revolution marvel at the pace at which they are learning, and in some cases relearning, rules of devel- opment. Until recently, the field has revolved around either embryonic stem cells - a remarkably plastic class of cells extracted from an embryo that could turn into any of the body's 200 tis- sue types - or their more restricted adult cou- sins, cells taken from mature organs or skin that were limited to becoming only specific types of tissue. On Jan. 23, after nearly a decade of prepara- tion, the Food and Drug Administration ap- proved the first trial of an embryonic-stem- cell therapy for a handful of patients paralyzed by spinal-cord injuries. But today the field encompasses far more than just embryonic and adult stem cells; it has expanded into the broader field of regenerative medicine, and Melton's lab at Harvard is at the vanguard, bringing the newest type of stem cells, which do not rely on embryos at all, closer to the clinic, where patients will actu- ally benefit. Last summer, Melton stunned the scientific community with yet another twist, finding a way to generate new populations of cells by reprogramming one type of fully mature cell so it simply became another, bypassing stem cells altogether. "If I were in high school, I can't imagine any- thing more interesting than stem cells," says Melton. "This is so cool. It's so amazing that cells in the body have this potential that we can now unlock by asking question after ques- tion." A Battle Joined That hidden power in each of us did not become obvious until 1963, when Canadian researchers Ernest McCulloch and James Till first proved the existence of stem cells, in the blood. These cells possess the ability to divide and create progeny - some of which will eventually expire, others that are self-renewing. ... That discovery led, 35 years later, to James Thomson's isolation of the first human embry- onic stem cells, at the University of Wisconsin in 1998. And that milestone in turn inspired researchers to think about directing these cellu- lar blank slates to eventually replace cells that had been damaged or were depleted by disease. The key lay in finding just the right recipe of growth factors and nutrients to induce a stem cell to become a heart cell, a neuron, an insulin- making cell or something else. ... new therapies were sure to come. Then, in 2001, everything changed. ... Presi- dent Bush restricted federal funding for the study of human embryonic stem cells. ... The decision sent some leading scientists abroad, to Britain, Singapore and China, where the gov- ernments were more receptive to their work. ... Federally backed scientists, like Melton, who continued embryonic work were forced to adopt a byzantine system of labeling and cataloging their cell cultures and equipment so that gov- ernment money was not used to grow forbidden cells - and government microscopes were not even used to look at them. Those days may soon be over. Barack Obama campaigned on a promise to lift the research ban and support "responsible oversight" of the stem-cell field. For scientists, that means "we can stop the silliness," says Melton. ... Clearly, Melton does not shrink from a fight. As Washington's squeeze on stem-cell research tightened in the early part of this decade, he decided to take action, providing life support for what remained of the U.S. stem-cell com- munity. Not convinced that an entire field could make much progress relying on a few dozen cell lines of questionable quality, in 2004 he used funds HSCI receives from the Juvenile Diabetes Research Foundation and the Howard Hughes Medical Institute, as well as from Harvard alumni, and developed a more streamlined method for generating stem-cell lines from embryos. He created more than 70 new ones and has since distributed 3,000 copies to scientists around the country for free. "Doug drew a line in the sand," says Alan Trounson, president of the California Insti- tute of Regenerative Medicine, the organi- zation charged with dispensing state money for embryonic-stem-cell research. "He turned the tables on an Administration that was incredibly negative toward stem cells and showed [it] we are not going to tolerate being put out of this field by ideo- logical views that we don't think are correct." Melton's motivation was, again, both pro- fessional and intensely personal. Two months after Bush announced his ban, Melton's daugh- ter Emma, then 14, also received a diagnosis of Type 1 diabetes. ... In 2004, voters in California approved a mea- sure providing $3 billion in state funding to embryonic-stem-cell research. That threatened to draw scientists in the stem-cell community west, and Melton took pains to foster a "band of brothers" mentality. "I tried to create a cocoon here," he says, "and tell people that your job is to focus on the sci- ence. Don't worry what the politicians say." By then, Melton's team was one of only a hand- ful in the country working on embryonic stem cells and was making headway in teasing apart the myriad critical steps needed to guide these impressionable cells into becoming insulin- generating cells. Both as a scientist and as a father, Melton re- mained convinced that the federal restrictions simply could not survive. He continued to insist that "the science is so significant that it will change the policy." ... The true power of reprogramming ... does not stop with the stem cell. This summer, Melton flirted with the rules of biology once again when he generated another batch of history-making cells, switching one type of adult pancreatic cell, which does not produce insulin, to a type that does - without using stem cells at all. Why, he thought, do we need to erase a mature cell's entire genetic memory? If it's possible to reprogram cells back to the embryo, wouldn't it be more efficient in some cases to go back only part of the way and simply give them an extreme makeover? Using mouse cells, Melton did just that, creating the insulin-producing pancreatic cells known as islets. "The idea now is that you can view all cells, not just stem cells, as a potential thera- peutic opportunity," says Scadden. "Every cell can be your source." Realizing that potential - and with it, the pros- pect of successful treatments for conditions like Parkinson's or diabetes - may still be a few years away. ... Even if iPS cells do not prove as stable and as versatile as embryonic stem cells when they're transplanted into patients, they remain a power- ful research tool. And if nothing else, they will have opened our eyes to the remarkable plasti- city of biology and made possible new ways of thinking about repairing and replacing dam- aged tissues so we may consider not only treat- ing but also curing disease. "It's a wonderful time," says Scadden. "Keep your seat belt on, because this ride is going to be wild." For patients like Sam and Emma Melton, that ride carries with it the possibility of being free [of a chronic disease and the risk of premature death and the fact they have to manually replace a body function that's critical for life, with 24by 7by365, 366 every leap year, walking on a tight rope] ... they endure to keep their blood sugar under control [manually, as if that's even possi- ble without becoming a human pin cushion ob- sessed with trying to manually be like 'normal' (an oxymoron -and- an impossibility, currently) and at the same time acting as if everything is fine aside from that manually taking over a cri- tical body function thing]. "I definitely think about how my life would be different if there is a cure," says Sam. His father is keenly aware that the ability of stem cells and reprogramming science to provide that cure is far from guaranteed. But his initial confidence in the power of the technology hasn't waned. "Everything we learned about stem cells tells us this was a really powerful approach," he says. "It would be a great shame if we let it wither and just go away." Melton, for one, is determined not to let that happen. Science in Steps A decade of conflicts and breakthroughs 1998 James Thomson, U of Wisconsin, isolates human embryonic stem cells 2001 President Bush restricts federal funding for research on human embryonic stem cells 2004 Douglas Melton of Harvard creates more than 70 embryonic-stem-cell lines using private funding and distributes free copies of the cells to researchers around the world 2006 Shinya Yamanaka, Kyoto University, turns back the clock on mouse skin cells to create the first induced pluripotent stem (iPS) cells, or stem cells made without the use of embryos. He uses only four genes, which are inserted into a skin cell's genome using retrovirus vectors 2007 Yamanaka and Thomson separately create the first human iPS cells 2008 July Kevin Eggan at Harvard generates the first patient-specific cells from iPS cells - motor neurons from two elderly women with ALS August Melton bypasses stem cells altogether and transforms a type of mouse pancreatic cell that does not produce insulin into one that does September Konrad Hochedlinger at Harvard creates iPS cells in mice using the common-cold virus rather than retrovirus vectors - an important step in making the technology safer for human use October Melton's team makes human iPS cells by replacing two of the four genes, known to cause cancer, with chemicals. All four must be swapped out before iPS-generated cells can be transplanted into people October Yamanaka creates mouse iPS cells using safer plasmids of DNA instead of retrovirus vectors Read Stem Cells: The Hope and The Hype. http://tinyurl.com/StemCellsHopeHype-Jan2009 Excerpt: ... Scientists who are having surprising success with adult stem cells find their progress being used by activists to argue that embryo research is not just immoral but also unnecessary. But to those in the field, the only answer is to press ahead on all fronts. "There are camps for adult stem cells and embry- onic stem cells," says Douglas Melton, a co-dir- ector of the Harvard Stem Cell Institute. "But these camps only exist in the political arena. There is no disagreement among scientists over the need to aggressively pursue both in order to solve important medical problems." ... - - - end excerpt - - -
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