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Left: Sean Morrison, HHMI investigator; Stuart Orkin, HHMI investigator. HHMI scientists and others are exploring the possibilities and limitations of stem cells to understand tissue development with hopes of curing disease.
To achieve cellular repair in mice, a team led by senior colleague Rudolf Jaenisch and Daley, when he was at the Whitehead Institute, took the nucleus from the cell of an adult mouse with a genetic defect and inserted it into a mouse egg. (An egg cell can reprogram its nucleus to create a cell with the potential to produce any part of the body.) If the egg is grown to a blastocyst—an early stage embryo—researchers can harvest stem cells from it. Daley's team did that and more. They repaired the defective gene in the cultured stem cells, coaxed the repaired cells to become blood stem cells in a Petri dish, transplanted the healthy blood cells into diseased mice, and partially restored immune function in the animals; they published the results in 2002 in Cell.
This is the ultimate promise of stem cell research—fixing illnesses at the genetic level and then using the modified cells to treat patients. No one has yet succeeded in creating human stem cell lines with the technique Daley's team used in mice, called somatic cell nuclear transfer or therapeutic cloning. Researchers have created human stem cell lines from embryos donated by in vitro fertilization patients, but these cell lines are not patient specific.
There are groups with ethical or religious concerns that consider the use of embryos destruction of human life or a step toward reproductive cloning. President George W. Bush agrees, and announced in 2001 that the U.S. government would fund research only with human embryonic stem cell lines created before August 9, 2001. Researchers like Daley cannot apply for National Institutes of Health (NIH) grants, or any other federal funds, to support development of new human embryonic stem cells, nor can they use equipment funded by federal grants to work with newer stem cell lines.
Voters in some states as well as private donors have provided a few alternatives. In 2004, Californians passed Proposition 71, authorizing $3 billion in state bonds to fund stem cell research through a granting agency called the California Institute for Regenerative Medicine. A handful of other states followed, with much smaller amounts. For its part, Harvard relied on private philanthropic donations to create the Harvard Stem Cell Institute, which now encompasses labs at the medical school, other parts of the university, and 11 teaching hospitals. Daley, a member of the Stem Cell Institute along with several HHMI colleagues, lined up private funding to support his embryonic stem cell work, supplemented in February 2008 when he became an HHMI investigator.
However, the administration's position on human embryonic stem cells is seen as a barrier, as many researchers limit themselves to projects that are eligible for funding from the NIH.
“I have a junior investigator in my lab who's a driving force behind our human ES research, which uses all private funding,” says Daley. “As he's trying to get an independent faculty position, other mentors are saying, you need an NIH grant, you better focus on a mouse program.”
At the end of 2007, a new door swung open. Scientists in Japan and Wisconsin, and Daley at Harvard, reported that they had successfully turned human adult skin cells into stem cells. In November, researchers in the lab of Shinya Yamanaka at Kyoto University documented in Cell, and, separately, a team led by James Thomson at the University of Wisconsin reported in Science, that they had created stem cells by inserting four genes into human adult skin cells. The genes appeared to perform the same function that insertion into an egg does in other animals: resetting the cell's genetic state back to day one.
Photos: Morrison: Donna Terek; Orkin: Marie Palardy / Orkin lab