How Important Is the Latest Cloning Feat?

Scientists at Stemagen, a small biotechnology company in La Jolla, CA, reported yesterday that they have for the first time generated cloned human blastocysts--early-stage embryos--from adult skin cells. This is the first step in generating stem cell lines matched to individuals, which are crucial for creating new cellular models of disease and potentially important for future tissue replacement therapies. (See "Next Steps for Stem Cells" and "The Real Stem Cell Hope".) The new findings also confirm that access to fresh eggs from healthy young donors is a key part of successful cloning. Lack of access to human eggs has been the major barrier in the field. (See "Human Therapeutic Cloning at a Standstill".)

Cloned blastocysts have been generated before, but from embryonic stem cells rather than from adult cells. Scientists theorize that embryonic stem cells are easier to turn into blastocysts because of their earlier developmental stage.

Experts in the field have had a mixed reaction to the new work. "It's a nice achievement, but in my view, they haven't crossed the bar," says Evan Snyder, director of the Stem Cells and Regenerative Medicine Program at the Burnham Institute in La Jolla. "The real test will be, can you generate cell lines that are stable and self-renewing and normal?" Others applaud the confirmation of the feasibility of human cloning. "The fact that it can be done is important," says Jeanne Loring, a stem cell scientist at the Scripps Research Institute in La Jolla. "It wipes away that blot on our scientific integrity," she says, referring to a massive fraud unveiled in 2005 in which South Korean scientist Woo Suk Hwang claimed to have generated stem cell lines from cloned human embryos. (See "Stem Cells Reborn".)

To clone an embryo, a process also called nuclear transfer, scientists first strip an egg of its genetic material. Then they insert DNA from an adult cell, such as a skin cell, into the egg. Through an unknown process, the egg turns back the clock on the adult DNA and begins to develop as a normally fertilized egg would. From the embryo, researchers could theoretically collect a specialized ball of cells that can be coaxed to turn into stem cells. So far, however, no one has successfully performed this feat.

Stemagen, a relatively unknown player in the field, probably owes its success to access to human eggs through a close association with a local fertility clinic. (The company was founded by a fertility specialist at the Reproductive Sciences Center in La Jolla.) "We were able to get access to high-quality oocytes and have them in the incubator within one to two hours," says Andrew French, Stemagen's chief scientific officer.

Egg donors and the intended parents gave eggs in excess of those needed for in vitro fertilization to the Stemagen scientists for research. Regulations in many states prohibit compensation for donated eggs for ethical reasons, a requirement that has slowed other cloning efforts.

Starting with 25 fresh oocytes, French and colleagues generated five blastocysts--five- to six-day-old embryos consisting of 30 to 70 cells. Rather than attempting to generate stem cell lines from the embryos, the researchers sent them to an independent company for genetic confirmation of their results. "They showed we had completely removed the DNA from the egg donor and replaced it with DNA from the skin-cell donor," says French. One blastocyst was confirmed as a clone via two DNA-fingerprinting methods, while genetic analysis of two others indicated the likelihood that they were clones.

The next crucial step will be generating stem cell lines from cloned embryos, which many stem cell scientists speculate will be the most challenging step. "That's likely where Hwang failed," says Synder.

French and colleagues are planning such experiments, with results potentially in the next eight to twelve months. "The quality of our blastocysts improved with each experiment," says French. Based on the success rate of previous attempts to make stem cells from regular embryos, he estimates that Stemagen will be able to generate a stem cell line from between five and ten cloned embryos and report the results in the next year. The company aims to sell or license the lines to pharmaceutical companies and others who would use them to test new drugs or develop new therapies.

While human therapeutic cloning has always been an ethically contentious area of research--partly because it requires the creation and destruction of human embryos--it has recently come under greater fire. After the announcement of new techniques for reprogramming adult cells so that they turn into stem cells without first forming embryos, some opponents called for a halt on embryonic-stem-cell research. (See "Stem Cells without the Embryos".)

However, researchers in the field emphasize the need to pursue all reprogramming techniques. "Even though there are other techniques to reprogram a cell that have gotten a lot of press, we still don't know how those compare with the reprogramming you actually see with nuclear transfer," says Snyder. "My feeling is, if we understand nuclear transfer better, we will be able to do the other kind of reprogramming more efficiently."

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Killing Skin-Cancer Stem Cells

Harvard Medical School researchers have identified a class of cells that initiates skin-cancer melanomas; they are also developing a therapy that specifically targets these cells. In a major study, the researchers characterized these cells and linked them to disease progression in humans. They also demonstrated that an antibody targeting these cells slows tumor growth in mice. The work may lead to new treatments for resistant melanoma. It also has broader implications for cancer biology.

There is a growing consensus amongst cancer biologists that not all cancer cells are equal. There is a hierarchy of cells inside a tumor, and only a few cells, called cancer stem cells, are capable of generating new tumors. Such tumor-initiating cells have been identified in many cancers, including those of the colon, brain, and breast. These cells are also thought to play an important role in chemotherapy resistance and cancer recurrence.

Previously, researchers had connected the presence of cancer stem cells with breast-cancer patient outcomes. Now the Harvard team has demonstrated a second important connection between cancer stem cells and clinical impacts, linking the presence of such cells with the speed at which the disease progresses in humans.

"We've defined for the first time a direct link between cancer stem cells and cancer progression," says Markus Frank, an assistant professor at Harvard Medical School, who led the melanoma research.

This research grew out of Frank's study of a protein made by some melanomas that confers resistance to chemotherapy. In a paper published today in the journal Nature, Frank and his colleagues at Harvard Medical School and Brigham and Women's Hospital, in Boston, report that human melanoma cells that make this protein can be characterized as cancer stem cells because they generate tumors when implanted in mice. Examining melanoma biopsies, they found that tumors expressing this protein were more aggressive.

Frank's group also demonstrated that an antibody specifically targeting the melanoma stem-cell protein slowed tumor growth in mice. Many other researchers are working on therapies that attack cancer stem cells, but Frank believes that his group is the first to develop such an antibody.

"Most current therapies target the bulk cells of the tumor," he says. "Resistant stem cells are left behind," allowing the tumor to come back after therapy seems to be progressing. Frank and other researchers hope that therapies that specifically target cancer stem cells can completely eradicate tumors.

Robert Weinberg, a founding member of the Whitehead Institute for Biomedical Research, in Cambridge, MA, and director of the Ludwig Center for Molecular Oncology at MIT, agrees that the Harvard work adds to the growing evidence of cancer stem cells' importance. "We don't really understand how tumors renew themselves, or how to treat many tumors," he says. Some researchers remain unconvinced, Weinberg says, but he and many others think that cancer stem cells may hold the answers to these questions. Cancer stem cells are "going to be very important," he predicts. Slowly but surely, he believes, the evidence is building.

Frank says that much remains to be learned about the newly identified melanoma stem cells. It's not clear, for example, whether the protein that the Harvard researchers have been focusing on causes the cells to act as cancer stem cells, or whether this protein is simply a marker for these cells. Further studies of their gene-expression patterns will tell the researchers more about what makes them different from normal melanoma cells. In the meantime, the Harvard researchers will continue to develop their antibody in hopes of taking it to human trials.

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