This is the first part of a five-part series.
Two weeks ago, members of Congress held a press conference to demand Senate ratification of H.R. 810, a bill to expand federal funding of human embryonic stem-cell (or hES) research. Alternative schemes to get stem cells without killing embryos would take too long, they argued. "There is only one bill which may quickly open the door to medical solutions. That is H.R. 810," said the bill's sponsor, Rep. Michael Castle, R-Del. He pointed to the glut of embryos left over from fertility treatments and concluded, "It simply makes no sense at all not to take advantage of what is already immediately available."
But the Castle bill isn't the quickest way to open the door to medical solutions. If we're going to take advantage of what's already available, the quickest way is to open a different door. The Castle bill, which has already passed the House, would open a door President Bush closed on Aug. 9, 2001, when he agreed to fund hES research on cell lines derived before that date but not afterward. Research proponents dismiss Bush's rule as irrational. At the press conference, Michael J. Fox asked, "Once you say we can do this much of it, what's the difference?"
The other door, the one that's blocking more-immediate help, has been closed by research proponents themselves. To get transplantable tissue your body won't reject, cells from somebody else—the cells you'd get from the Castle bill—won't do. You need cells with your DNA. You need a clone. This is why most senators support legislation sponsored by Sens. Orrin Hatch, R-Utah, and Dianne Feinstein, D-Calif., that would ban cloning for procreation but keep it legal for research. The cloning bill forbids preservation of cloned embryos beyond two weeks. "After 14 days, an unfertilized blastocyst begins differentiating into a specific type of cell such as a heart or brain cell and is no longer useful for the purposes of embryonic stem cell research," Feinstein told her colleagues.
But if the goal is tissue, clones aren't less useful after 14 days. They're more useful, precisely because they're differentiating into the cell types that patients need. Why stop research at 14 days? Once you say we can do this much of it, what's the difference?
Four years ago, a team led by John Gearhart, one of the field's top researchers, published a study of cells "derived and cultured from 5-, 6-, 7-, and 11-week postfertilization primordial germ cells." The derived cells, unlike hES cell lines from embryos before 14 days, caused no tumors when they were injected into mice. Gearhart's team found that the derived cells "may be useful … as a resource for cellular transplantation therapies." When Gearhart testified before the President's Council on Bioethics in April 2002, he was asked, "Would it in fact be the greatest advantage if a patient's own cell line could be derived from primordial germ cells?" He replied:
Oh, boy, this committee would—well, wow. Now, think what this means. It means that you would be generating an embryo, and having it implanted. Now, what you don't know is that our fetal tissue comes from 5-to-9 weeks post-fertilization. These are therapeutic abortions. And which means now that you are way beyond—I mean, the point of where a blastocyst is, and obviously way beyond I think anyone subscribing to that approach.
In other words, ethics said no, but science said yes. And science was just beginning to speak. Three weeks before Gearhart testified, a team featuring two other top researchers, George Daley and Rudolf Jaenisch, reported development of a therapeutic cloning system that included "differentiation of [cloned] ES cells in vivo" prior to transplantation. "In vivo" meant that the cells differentiated—matured into specific tissues—in a living organism. When the researchers fixed a gene in mouse ES cells, derived embryos from the cells, and grew the embryos into 1-month-old mice, "bone marrow cells derived from the 'repaired' ES cell mice were able to fully function after transplantation" into the mice that had been cloned. But when the researchers tried "in vitro differentiation of the repaired ES cells instead of in vivo formation of normal bone marrow," they ran into "unanticipated biological principles" that thwarted transplantation.
Something crucial had happened during differentiation in vivo but not in vitro. What was it? As more data came in, the problem persisted. In July 2002, a team led by Robert Lanza and Michael West of Advanced Cell Technology reported data in cows that suggested "cloned cells and tissues … can be grafted back into the nuclear donor organism without destruction by the immune system." Unfortunately, said the team, "bovine ES cells capable of differentiating into specified tissue in vitro have not yet been isolated. It was therefore necessary in the present study to generate an early-stage bovine embryo." The team took "cardiac and skeletal tissue" from "five- to six-week-old cloned and natural fetuses" and derived kidney cells from "seven- to eight-week-old cloned and natural fetuses." (Cow gestation takes a bit longer than human gestation, so equivalent human fetuses would be younger than eight weeks.) The authors concluded, "This strategy could not be applied in humans, as ethical considerations require that preimplantation embryos not be developed in vitro beyond the blastocyst stage."
Transplantation forged ahead, but differentiation lagged. Until scientists could grow the necessary tissues in the lab, they would have to enlist nature. Six to seven weeks of embryonic development seemed to do the trick. In 2003, Israeli researchers published a study showing that "when human and pig kidney precursors are obtained from 7- to 8-week human or 3.5- to 4-week pig gestation and transplanted into immunodeficient mice, they survive, grow and undergo complete nephrogenesis, forming a functional organ able to produce urine. Embryonic renal cells of earlier origin fail to mature into the desired professional cell fate." The authors wrote, "Our data pinpoint a window of human and pig embryogenesis that may be optimal for transplantation in humans."
Last year, Lanza, West, and colleagues reported that they had used cloned tissue to repair heart-attack damage in mice. "Stem cells derived from cloned embryos are sufficiently normal to repair damaged tissue in vivo," they announced. But the mouse embryos they used had gestated for 11 to 13 days—the equivalent of about five months in humans. Again, they cautioned, "the approach used in this study cannot be applied clinically because the cells were obtained from fetuses and ethical principles require that preimplantation embryos not be allowed to grow beyond the blastocyst stage." A third study by the Lanza-West group, published last month, found that liver stem cells from 4-month-old fetal calves "showed a 10-fold competition advantage" over comparable adult cow stem cells as transplant material.
So, here's the dilemma: We've proved we can transplant differentiated tissue into animals. We've proved they won't reject it if it's cloned. We've proved it can rebuild their organs or cure them of genetic diseases. What we haven't proved is that we can grow all this tissue in vitro. Why not? Can we afford to wait, or should we grow it in vivo? Tomorrow we'll talk about the science. Then we'll talk about the ethics.