Science That the Government Doesn't Want to Exist

Stem-cell research lurches along through roadblocks and red tape.

By Stephen S. Hall|Friday, October 19, 2007
RELATED TAGS: STEM CELL RESEARCH

On a Thursday afternoon earlier this year, Willy Lensch sat at his desk in the “nonpresidential” section of a seventh-floor laboratory at Children’s Hospital Boston and watched in dismay as one of the recent congressional debates about embryonic stem cell research streamed into his laptop. Employing the arch rhetoric that has typified stem cell politics since 1998, some members of Congress denounced the research because it requires the destruction of human embryos. Others trumpeted “alternative” techniques that promise the creation of embryonic stem cells without destroying embryos. Stem cell scientists like Lensch have heard it all before, and it never feels comfortable. “You feel the heat working on stem cells,” he said. “I’ve been working in labs for 20 years, and this is a different deal.”

While conservatives in Congress took turns echoing George W. Bush’s opposition to destroying human embryos for research, Lensch’s colleague Paul Lerou stepped into a small room behind a heavy black curtain to check up on a line of nonpresidential embryonic stem cells. These human cells were ineligible for federal research funds because they had been created after President Bush’s August 9, 2001, announcement freezing the number of government-approved stem cell lines. Every piece of equipment in the “nonpresidential suite”—the incubator, the microscopes, the boxes of gloves, and even the wastebaskets—carried a warning sticker reading “NP,” a brand intended to keep it separate from the items that are for federally funded hands only.

Lerou maneuvered the nonpresidential plastic dish under a nonpresidential microscope and adjusted the focus. “So that’s them,” he said, pointing out some of the nonpresidential embryonic stem cells that have been created and distributed among researchers since 2001.

When you glimpse these human cells in the lab, they make about as much of an impression as a black-and-white TV in the age of streaming video. Clumps of the cells floated, like wet pieces of dandruff, in a little plastic dish containing a fluid that looked a bit like watered-down pink mouthwash. Under magnification, each patch of the cells had a smooth, blobby surface. Yet each little scrap contained hundreds of cells that had the potential to grow into 200 distinct human tissues: heart tissue, neural tissue, liver, kidney, bone, muscle, and of particular interest in this laboratory, blood.

“And, like, that’s what all the fuss is about?” Lerou asked rhetorically.

In fact, these researchers are never far from the fuss—it follows them at meetings, in newspapers, on TV, and right into these balkanized labs, where certain scientists can use the equipment while others can’t. For some, the fuss is accompanied by a vague cloud of threat: Pictures of Kevin Eggan, a Harvard stem cell biologist, have appeared on antiabortion Web sites, where readers are urged “to stop madmen like Eggan.” And the fuss has mired cutting-edge science in a kind of bureaucratic sludge, bogging it down in an almost mindless series of administrative details. The questions that come up every day are so intricate, so Talmudic, that the National Institutes of Health (NIH) might as well be funding laboratories to have a rabbi on call.

In the research bay at Children’s Hospital where Lensch and Lerou conduct their experiments, for example, the NP sticker on an item distinguishes it from items purchased with the support of federal funds. To do experiments, these labs must purchase separate stocks of the most ordinary supplies—pens, pencils, clear plastic pipettes, household bleach, even Reynolds aluminum foil—and slap a sticker on them.

“If we run out of distilled water on this side of the bench,” Lensch explained, pointing to the narrow nonpresidential lab counter with supplies marked NP piled up to the ceiling, “I literally cannot reach across the bench and get it from the other side. Can I ask my colleague on the other side for advice? If he receives federal funding, does asking for advice violate federal policy? You just go down this rabbit hole. . . .”

The Harvard Stem Cell Institute is a loose-knit group of scientists in Boston and Cambridge who have opted to conduct this research in that rabbit hole, often without federal funding and despite political and logistical impediments the likes of which the public rarely glimpses. “The climate has become so burdensome in terms of regulation,” lamented George Daley, who heads the lab where Lerou and Lensch work. “The hurdles have become so much higher to get anything done, and it’s only the most intrepid people who push ahead.” Why? Because biologists like Daley are convinced that embryonic stem cells—the most generic, versatile type—may not only lead to dramatically different new treatments but can also uniquely illuminate the origins of disease in a way adult stem cells never will.

Over the past nine months or so, the news for stem cell research has sounded deceptively positive. Last January, the House of Representatives voted, 253 to 174, to pass a bill, H.R. 3, that would allow researchers to use leftover embryos from in vitro fertilization (IVF) clinics to create new lines of embryonic stem cells, and in April, the Senate passed its version of the bill. But as long as the president vetoes such legislation, as he did in June, and as long as the current Congress is unable to override those vetoes, there is unlikely to be any change in federal stem cell policy.

Daley, one of the leading stem cell researchers in the country, feels as if he has been treading water for years. Wearing a crisp white shirt, pressed slacks, and a stethoscope, he paused in the cafeteria of Children’s Hospital Boston one day to grab lunch between seeing patients. Many of them were babies, and a few suffered from the hematologic disorders that have been the focus of Daley’s research—diseases like Fanconi’s anemia, thalassemia, sickle-cell anemia, and childhood leukemias. In 2002, Daley and his colleagues at MIT’s Whitehead Institute published research in which they created cloned embryonic stem cells and used them to treat a blood-based immunologic disorder in mice. But he is not even close to attempting a similar approach in humans, and he was still ornery about the latest example of how alternative approaches to isolating stem cells become exercises in politically twisted science.

Last January, days before a vote in the House of Representatives to loosen the rules on stem cell research, the journal Nature Biotechnology posted an article online, written by a group headed by Anthony Atala at Wake Forest University School of Medicine, reporting the discovery of stem cells isolated from amniotic fluid. These cells reportedly possessed many of the same characteristics of embryonic stem cells, without requiring the ethically problematic destruction of embryos. Atala’s group claimed the cells could be prodded into becoming neural, bone, muscle, fat, and liver tissue.

The White House quickly capitalized on the news. In a report called “Advancing Stem Cell Science Without Destroying Human Life,” the White House’s Domestic Policy Council hailed Atala’s work as “landmark” and part of what it called a growing consensus that embryonic stem cell lines were not necessary to scientific progress. (This report, which Harvard biologist Eggan calls the “Human Embryonic Stem Cell Misinformation Packet,” prompted a corrective letter from Harvard biologists, who claimed that the White House misrepresented their research for political reasons.) Syndicated columnist Charles Krauthammer, a former member of the President’s Council on Bioethics, declared the finding “revolutionary” and possibly even “the turning point in the evolution of stem cell research.”

The view from the basement cafeteria of Children’s Hospital was considerably more dubious, and probably more realistic. “It’s the same old bunkum,” Daley said, shoving a pile of oily potatoes around his plate. He argued that this tactic—hyping preliminary adult stem cell research and other alternative strategies at delicate political moments—has been a set piece in the national debate over stem cells since the Bush decision in 2001. “Every time a new paper comes out, this is the breakthrough that is going to solve the ethical problem and change the whole picture,” Daley said. “I’ve seen it time and time again.” He wore an expression beyond cynicism: battle fatigue. “C’mon,” he grumbled. “This is another in a long line of claims of alternative sources of stem cells that are going to chip away at the value of using embryonic stem cells.”

In 2002, Daley pointed out, a group headed by Catherine Verfaillie at the University of Minnesota had reported the existence of an adult stem cell that appeared to possess the same qualities as embryonic stem cells, and conservative opponents of embryonic stem cell research quickly embraced that development as a solution to the ethical quandary. “Five years later,” Daley said, “I still don’t know of any laboratory that has been able to culture those cells. At the least, that says that it’s not a robust platform that is easily generalizable to other labs.” (Earlier this year, researchers at Stanford finally reproduced a portion of Verfaillie’s work, but New Scientist magazine reported that Verfaillie’s original study contained significant flaws. The University of Minnesota has since launched an investigation.)

“Then there were fat stem cells,” Daley continued, reciting a litany of alternative ways to tap into the therapeutic potential of embryonic stem cells. “And mesenchymal [bone marrow] stem cells. Tooth stem cells. Cord blood stem cells.” He paused to shake his head. “Even if we can make other cells to look like embryonic stem cells, ES cells allow you to investigate unique aspects of human embryonic development.”

In the past few months, researchers in the United States and Japan have described a promising way of deriving embryonic stem cells from skin cells (of mice) without destroying embryos—the “Holy Grail of biotechnology,” as The Times of London put it. But it can take years to transfer those technologies to human cells, and as the Verfaillie story suggests, five years can transpire before researchers discover they may have driven into a cul-de-sac.

Daley’s scientific frustration stems from more than just the distraction of alternative techniques. In November 2003, he transferred his large lab group from the Whitehead Institute to Children’s Hospital, with hopes of investigating human cells as soon as possible, and the lab has made progress—in mice. The group produced a splash last December when it reported results of experiments exploring what news stories described as a “virgin birth” technique. Beginning with mouse egg cells, Daley and his team tricked these egg cells, or oocytes, into thinking they had been fertilized (a process called parthenogenesis) and managed to isolate embryonic stem cells from the subsequent early mouse embryos. They view this as a test run for creating human embryonic stem cells in the same way (and according to the team, South Korean biologist Hwang Woo Suk seems to have accidentally accomplished this feat while executing his famously fraudulent human cloning experiment).

But while scientists are able to make great strides with tiny four-legged rodents, regulatory hurdles and institutional caution have slowed parallel human work to a crawl. To Daley, the delays caused by the Bush administration’s opposition to stem cell research are as much of an ethical issue as the handling of human embryos themselves, because it actively impedes progress on research that might benefit millions of Americans. The atmosphere of hypersensitivity surrounding the research, he says, has resulted in local institutions creating layer upon layer of oversight committees. “The sensitivities have really been ratcheted up,” he said.

Daley knows, because for several years his lab has been seeking approval to collect human eggs and embryos from several Harvard-affiliated institutions. As a result of the hypersensitivity, each medical center is a regulatory player, with its own institutional review board to oversee human biomedical research and its own embryonic stem cell review and oversight committee to monitor the ethical conduct of this controversial research. Mindful of public sensitivities, Daley opted to pursue experiments using what he considers the least controversial human materials to create new nonpresidential stem cell lines—poor quality embryos and oocytes that, in his words, “otherwise would have been disposed of as medical waste.”

Despite the low quality of this starting material, Lerou has made reasonably good progress. But the scientific challenge has been only part of the problem. “Every time concern is raised about one sentence on the consent form, it has to go back to four or five committees to get approval,” Daley said. “If the climate was different, if the president had said this is the science of the future, believe me, everyone all the way down the line would have been more comfortable getting this work moving. The president’s stance has had an incredible chilling effect on the pace of the research.”

Weissman of Stanford argues that the political and bureaucratic delays imposed upon stem cell research have interfered with a medical scientist’s ability to honor the Hippocratic oath, which places the health of patients above all other concerns. He has been making that point since 2004, when in testimony to the U.S. Senate, he warned embryonic stem cell opponent Sam Brownback of Kansas, “Those in a position of advice or authority who participate in the banning or enforced delays of biomedical research that could lead to the saving of lives and the amelioration of suffering are directly and morally responsible for the lives made worse or lost due to the ban, or even of a moratorium that would deny such treatments in that short window of time when it could help or save them.” It is “morally unacceptable,” he said in a recent interview, to make patients wait in order to satisfy religious and political opposition.

If delay is a moral issue, it is one that has been built into the stem cell debate from the beginning. Michael Sandel, a Harvard professor of political science who served for four years on President Bush’s bioethics panel, said the committee’s prolonged discussion of alternative methods of isolating embryonic stem cells could be viewed as an effort to diminish public support for the research.

Those alternatives have included an attempt, encouraged by panel member William Hurlbut of Stanford University, to create genetically maimed embryos that, because they were incapable of developing, could not technically be killed. In 2005, Rudolf Jaenisch’s laboratory at Whitehead reported preliminary success with this strategy, using mouse cells. But religious conservatives did not appear to be morally mollified by this technique, and even many scientists have taken a dim view of the experiments. In an editorial in The New England Journal of Medicine, developmental biologist Davor Solter dismissed such efforts, saying “manipulating science for the sake of politics is usually a waste of time.”

In his recently published book, The Case Against Perfection, Sandel concluded that President Bush’s stem cell policy does not even make ethical sense. “It is morally inconsistent to condemn the destruction of embryos in stem cell research,” Sandel said, “while permitting the destruction of embryos in the IVF clinics.” In contrast, Sandel argues that the opposition to stem cell research voiced by people like Richard Doerflinger of the United States Conference of Catholic Bishops is “morally consistent and principled” because they oppose any activity that promotes the destruction of human embryos, including in vitro fertilization. (IVF procedures inevitably create embryos that will later be discarded; there are an estimated 400,000 such “spare” human embryos in the United States alone.)

If the president’s philosophy—to restrict federal funding to research on cell lines created prior to August 9, 2001—lacks a principled moral basis that amplifies the view that the governmental obstacles imposed on stem cell research, and the delays they have caused, themselves represent an ethical problem. “The delay created by the president’s policy carries great costs that can only be justified if the right-to-life position is morally correct,” Sandel said. “But if it is not, then delaying the progress of stem cell research is morally indefensible.”

At any rate, Sandel believes that both the scientific community and the public at large have mostly come to a different moral conclusion than the Bush administration. “Despite the Bush veto, the opponents of embryonic stem cell research have lost the national debate,” he said. “It is virtually certain that the next president, Democrat or Republican, will ease the restrictions on funding.”

Even if that is true, it is little consolation for patients right now. George Daley, speaking of potential therapeutic testing of parthenote-derived stem cells (the sort that his lab reported isolating last December), said it was “reasonable” to assume that the technology wouldn’t be ready for human testing for another seven years.

Doing good science may turn out to be the best revenge of scientists struggling against these political impediments. Even as Congress lurches to and fro in its efforts to emancipate stem cell research, biologists continue to weave through the obstacles.

Kevin Eggan’s lab in Cambridge has been busy demonstrating the clinical potential of the research—and finding novel ways to create stem cells. Last May in Nature Neuroscience, his lab and a team at Columbia University reported that embryonic stem cells could be used to shed light on the origins of amyotrophic lateral sclerosis (ALS), the progressive neurodegenerative disease in which motor neurons in the brain die. Using embryonic stem cells, Eggan and his colleagues demonstrated that, at least in some cases of ALS, the affected neurons do not self-destruct but rather are poisoned by neighboring neural cells known as astrocytes.

Eggan has also been itching to use cloning technology to create embryonic stem cells that could be used to model the development of various diseases, especially diabetes and ALS. The idea is that, by placing an adult cell from a diabetic, for example, into a human egg cell, the egg cell could turn back the clock of the adult DNA, or reprogram it, to its initial, pristine state. In this way, the development of the disease, too, could be traced back to its genesis. These cloning experiments (known as somatic cell nuclear transfer), in addition to being unambiguously nonpresidential, require a rare and precious starting material: healthy human egg cells. And those cells have been hard to come by.

In May 2006, Eggan’s lab received approval from Harvard to seek healthy human eggs from female donors, a first step toward using research cloning to create new stem cell lines. As soon as the lab got the green light, advertisements began to appear in The Boston Globe, The Harvard Crimson, and other local publications, seeking egg donors. The ads stimu­lated lots of inquiries, but actual donors? When asked recently, Eggan maneuvered his thumb and index finger into a big, fat zero. After nearly a year of recruitment efforts, not a single woman consented to donate her eggs for stem cell research.

Were they morally opposed to the research? Hardly, Eggan says. The problem, he believes, is that Harvard Stem Cell Institute researchers, following ethics guidelines, decided not to pay women to donate their eggs for research. Paying for human eggs, many bioethicists argue, commodifies a human resource; Sandel, for example, a proponent of both research cloning and embryonic stem cell research, opposes the idea of financial inducement for what he calls “human reproductive capacity.”

But this bioethically correct approach has run straight into a buzz saw of market economics. Fertility clinics typically pay women $5,000 or more to donate their egg cells, in a procedure that is time-consuming, medically arduous, and not without health risks. “People respond to our ad, but they don’t move forward,” Eggan admitted. “It seems like people really want to do it, but don’t feel they can justify the amount of time it would take without compensation. Needless to say, that’s been a source of considerable frustration.”

Faced with this litany of obstacles, you might think that Eggan’s lab represents another variation on the theme of delay. But that would underestimate the scientific ingenuity in solving problems. On the same day last January that conservatives in the House of Representatives tried unsuccessfully to criminalize the very experiments Eggan wants to do, he tapped his fingers on a thick manuscript sitting on his desk. “This is going out tomorrow,” he said, of a paper that ultimately made the cover of Nature last June. Its news was outlined, in schematic form, on the huge whiteboard in Eggan’s office. The drawing depicted a stunningly unexpected way to create embryonic stem cells—without using or needing an unfertilized egg.

“Everyone thinks we need oocytes to do somatic cell nuclear transfer,” Eggan said. Biologists have assumed that an adult cell could be “reprogrammed”—that is, cloned—only by an egg cell.

But Eggan and his colleagues went on to perform experiments suggesting that the mysterious elixir responsible for reprogramming was not geographically static but instead moved around inside the cell, depending on the phase of cell division. It tended to be sequestered in the nucleus but migrated out into the cell’s gelatinous exurbs, or cytoplasm, when the cell was about to divide. “Maybe at the one-cell or two-cell stage,” Eggan and his colleagues reasoned, “there’s still some of that stuff in there. . . .” And if they picked the right moment of cell division, when these powerful reprogramming factors were still floating around in the periphery of the cell, they might be able to use drugs to temporarily freeze the cell in the middle of division, stick in the needle of a micromanipulator to suck out the embryonic DNA, squirt in DNA from an adult animal, and then kick-start the process of reprogramming—hours, perhaps even days after an egg had been fertilized.

That is exactly what the team has demonstrated in mice, creating cloned animals from a fertilized egg. “You can [both] clone animals and make embryonic stem cell lines using this technique,” said Eggan, who is now testing the technique—nonpresidentially, of course—in human cells.

Eggan paused to write a number on the whiteboard: 90,000. “There are 90,000 IVF procedures every year in the United States,” he said. “Let’s say there are, conservatively, five oocytes from each cycle. That is maybe 450,000 eggs, right? A large proportion of those oocytes will get too much sperm. We’ll say it’s 5 percent.” He then paused to write another number on the board: 20,000. In IVF clinics, these overfertilized eggs are routinely culled after inspection and thrown away; their chromosomal irregularities make them unsuitable for implantation. “That’s like between 20,000 and 25,000 eggs that get thrown away in the U.S. every year at that stage,” Eggan continued. “They have abnormal numbers of chromosomes, and they would develop abnormally, and so you can’t use them. Even God doesn’t want these. But our method would allow them to be used. Twenty-five thousand eggs every year . . . ”

Each one, formerly doomed to be tossed away as medical waste, could be used to clone embryonic stem cells that might tell stories about common diseases and how they get started. As he headed out the door of the lab that day, Eggan barely contained his excitement. “It could,” he said, “change everything.”

That phrase, lamentably, has been used repeatedly during the six-year debate on alternative strategies. But it was nice, for a change, to hear it not from a politician or a pundit but from a scientist actually doing stem cell research.

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