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Caution urged in new method for stem cells

Harvard sticks to cloning

Email|Print| Text size + By Colin Nickerson
Globe Staff / December 17, 2007

CAMBRIDGE - The stem cell wars are not over, say leading researchers at Harvard and other universities who believe that the cloning of human embryos still represents the key to developing effective treatments for an array of horrific diseases.

Recent weeks have seen spectacular breakthroughs in creating embryonic-like stem cells without making or destroying human embryos. Politicians, including President Bush, together with religious activists and some highly visible biologists have been quick to proclaim that the new technique for genetically "reprogramming" ordinary adult skin tissue into stem cells marks the moral high road to the future.

It is a route that bypasses thorny issues raised by the use of frozen or cloned human embryos, and is also technically simpler than cloning.

But researchers at Harvard, viewed by many as the world's leading center of stem cell research with some 750 lead scientists at 119 laboratories in the Boston area, are worried that a stampede to the new technique is a gamble that medicine can ill afford to make.

Although new reprogramming techniques are all but certain to yield giant advances in researching disease, they remain far too dangerous for actual treatment, the scientists say. The so-called induced pluripotent stem cells, or IPS, made by the process may never be safe for humans, making it vital to maintain the pace of research on more controversial fronts.

"For doing basic research on human cells, IPS as a method has won - it's huge," said Dr. George Q. Daley, a stem cell researcher at Children's Hospital Boston. "But for the ultimate goal of getting cells into a patient, it's a lot less clear. These cells may never be useful for direct therapy."

That is because the reprogramming technique, conceived by Japanese scientist Shinya Yamanaka, employs genetic alteration to turn back the clock on ordinary cells, making them regress to the desired "blank slate" stem cell form.

Four potent regulator genes are inserted in the adult cells to induce reprogramming. But this may also produce quirks in cells, like so many booby traps - making the reprogrammed stem cells far too unpredictable, for now, to use in human therapy. Moreover, several of the genes used to trigger the reprogramming process are known to cause cancer in mammals.

In what is even more of a lurking threat, the process uses retroviruses to carry the genes into cells. These viruses can disrupt the normal function of DNA and also can spur the birth of cancer cells.

Some proponents of reprogramming argue that problems from genetic modification and use of viruses are purely technical and easily surmountable. But other stem cell researchers are skeptical that reprogrammed cells or specialized cells produced from them will ever win approval for use in humans. "It will never be approved [by the FDA] to put these cells in a patient," said biologist Douglas A. Melton, codirector of the Harvard Stem Cell Institute. "The retrovirus can be a Trojan horse that can carry all sorts of problems."

That's why Harvard, with stem cell funding in excess of $60 million, intends to maintain full-throttle efforts to clone petri dish human embryos, from which to harvest stem cells. This work has so far not been successful, but Harvard scientists also will press ahead with creation of human stem cells from frozen embryos - most embryonic stem cell research around the world involves 42 "lines," or batches of stem cells, forged at Harvard from frozen embryos to bypass Bush's virtual ban on use of federal money for such research.

Bush and other opponents believe that human embryos possess the potential to become full human beings - and thus, scientists are committing murder when they destroy early-stage embryos in the process of culling stem cells. Most scientists acknowledge work with embryos raises difficult questions, but argue that the potential for medical good justifies their pursuit.

"There is a core of scientists, myself included, who deeply believe this an ethical and highly valuable area of research," Daley said.

Harvard is by no means ignoring reprogrammed cells. Several of its labs have made major findings in this area, and Melton, Daley and other Harvard scientists said they are intensifying their work with reprogrammed cells, which they see as likely to produce deeper understanding of cell function and the origins of disease, as well as providing the best realm for testing drugs and other therapies.

In fact, Daley's lab and another led by developmental biologist Kevin Eggan are the only two in the Harvard system pursuing the creation of human embryonic stem cells through cloning. The process, known as nuclear transfer, involves removing DNA from a patient's cell and inserting it into a donated egg, which forms an early embryo genetically matched to the patient - a crucial feature if stem cells are to be used for therapy. Worldwide, fewer than 10 universities and other research centers remain actively involved in the scientifically complex process.

The numbers may dwindle further as researchers - and, critically, funding sources - switch emphasis to reprogramming procedures. Since the technique of genetically manipulating workaday cells into functional embryonic-like stem cells is as simple as it is revolutionary, advanced stem cell research is now feasible for almost any biological lab.

The National Institutes of Health said earlier this month it is about to commit new money to spur work on reprogramming cells. "NIH will be releasing new program announcements soon," Story Landis, head of the institutes' Stem Cell Task Force, told the Globe by e-mail.

That's a big carrot for stem cell research labs across the country.

"A lot of bright scientists have already been carried away from the field - partly by the controversy, partly by lack of money," said Daley.

Harvard scientists, as well as biologists and ethicists from other institutions, argued forcefully that stem cells harvested from human embryos still represent the single best hope for ultimately treating humans with devastating ailments ranging from severed spinal cords to heart disease. Reprogrammed cells represent "a gigantic part of the future of stem cell research, but not the whole future," said Konrad Hochedlinger, a Massachusetts General Hospital lab leader and developmental biologist who has done cutting edge work on reprogrammed stem cells.

"Maybe in a few years all efforts will go in this direction," he said. "But right now that would be a very foolish and maybe tragic bet."

The intense scientific interest in embryonic stem cells lies in their ability to form any of the human body's 220 cell types. Thus, they might be coaxed to form nerve and bone tissue to heal a broken spine; pancreatic cells to treat diabetes; heart tissue to mend coronary artery disease - the potential appears limitless.

The view that efforts to secure stem cells from human embryos should stay on course is one expressed well beyond Harvard.

"It's very early days, the game isn't over," said Christopher Scott, director of Stanford University's Program on Stem Cells and Society. "It would be folly to shove other research in the drawer in favor of following this one new direction, however promising."

Said Ronald M. Green, professor of ethics at Dartmouth College: "Not to move forward with research" involving human embryos "would be grossly irresponsible. These still remain the most realistic routes to the end of the rainbow - that is, true healing therapies for flesh-and-blood patients."

Colin Nickerson can be reached at nickerson@globe.com.

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