Cloning Capsized?

Biopharmaceutical researchers fear how pending federal legislation outlawing the cloning of human cells will restrict their abilities to find cures for major degenerative diseases.1,2 Some also see lawmakers impinging on established nonhuman cloning techniques essential for the discovery of new drugs and therapies. The source of all this worry? The US House of Representatives passed July 31 by a wide margin a bill (H.R. 2505) sponsored by Reps. David Weldon (R-Fla.) and Bart Stupak (D-Mich.) that would ban the cloning of human cells for reproduction as well as for research. Of particular concern to scientists, the bill outlaws somatic cell nuclear transfer (SCNT) using human cells, a mechanism required in the new field of regenerative medicine. Potential uses for such therapeutic cloning include creating immune-compatible replacement tissue for diseased organs, such as the heart and pancreas, and treatments for neurodegenerative diseases, such as Parkinson's and Alzheimer's. Scientists, ethicists, and politicians agree that human reproductive cloning should not be permitted. Therapeutic cloning is another matter, however. While most researchers in the field argue that human therapeutic cloning through SCNT will result in medical breakthroughs, some ethicists assert it must be banned because it will inevitably lead to reproductive cloning. Anthony Canamucio President George W. Bush, who opposes human cloning, praised the House anti-cloning legislation. He recently decided to allow federal funding for research on human embryonic stem cells (ESCs) but limited it to 60 preexisting cell lines. The stem cell decision "allows us to explore the promise and potential of stem cell research without crossing a fundamental moral line," because the embryos were previously destroyed, Bush said. While technically distinct, the cloning issue has become intertwined with the human ESC research because both involve the discarding of human embryos. Current federal law prohibits the government from directly or indirectly financing research that results in the destruction of human embryonic material. The House bill would make human SCNT research a crime punishable by fines and imprisonment whether done with private or public funding. The bill "is completely antithetical to two decades of US policy to support biomedical research," says Michael Werner, director of government relations for the Biotechnology Industry Organization (BIO), a Washington-based trade group representing more than 950 biotech companies. The new legislation from Congress and regulatory guidance from the administration may not be directed at established cloning techniques, but scientists still fear the consequences. Some researchers have contemplated moving their work abroad to Europe or Asia. A day after the House voted, a Japanese Cabinet panel authorized human stem cell research. "Obviously, we are watching this whole cloning debate very carefully and very closely," says Jeff Trewhitt, spokesman for the Pharmaceutical Research and Manufacturers of America, a Washington-based trade association for major pharmaceutical and biotechnology companies. "There's a lot at stake for us." Biotechs Skirt Ethical Logjam While Congress legislates and Bush deliberates, many biopharmaceutical companies and institutions may be wor-rying, but they have not been waiting. Using private funds to forge ahead with stem cell research and with cloning involving both human and animal cells, the firms hope to create breakthroughs in drugs and therapies. "The potential for the field of regenerative medicine is enormous," says Werner. "It's a new paradigm in medicine that could lead to treating currently untreatable conditions, including heart attack, stroke, and conditions like that. Stem cell technologies are integral to the development of this field, which we feel could change the nature of medicine in the coming decade." Courtesy of Roslin InstituteDolly with her first born, Bonnie PPL Therapeutics, the Scottish firm that worked with the Roslin Institute to produce Dolly, the first cloned sheep, estimates that the market for transplantable cellular therapies, such as for treating diabetes, and for solid organs derived from animals (e.g., pigs) using xenotransplantation can reach $12 billion. Therapeutic cloning also could be used to develop tools for drug testing, says Carl B. Feldbaum, president of BIO. Cloned normal human liver cells could be used to safely test toxic metabolites in drugs under development, he explained in testimony before a Senate commerce subcommittee in May. "This process could both safeguard and streamline the drug development process," he said, "bringing drugs to patients sooner and safely." Biopharmaceutical companies such as Geron Corp. in Menlo Park, Calif., plan to develop therapeutic and diagnostic products for drug discovery, regenerative medicine, and pharmaceutical protein production. Geron obtains frozen human embryos left over from in vitro fertilization clinics and breaks them open to harvest the ESCs for research. "We are learning how to turn undifferentiated human pluripotent stem cells into neurons, liver cells, and heart muscles," explained Thomas B. Okarma, president and CEO of Geron in testimony before a House judiciary subcommittee in June. Therapeutic cloning is essential, he maintains, because it is the only way to produce adequate replacement cells for clinical treatment. Advanced Cell Technology Inc. (ACT), a private biotech company in Worcester, Mass., last month confirmed press reports that it planned to use SCNT to fertilize human eggs obtained from paid donors and destroy the resulting embryos to derive stem cells for research, the first US public acknowledgement of the procedure. Robert P. Lanza, ACT's vice president of medical and scientific development, says the work is continuing but the company has not yet created human embryos. "All we are able to say is that when we have appropriate data we will present it through the appropriate channels, through a scientific peer reviewed publication." The House bill, if it were to become law, could force ACT officials to rethink at least where the company will continue its research, according to spokesman Tom Tureen. "I think it's unfortunate that a matter concerning the health of so many people was based on so little information and decided in just two hours," he says. ACT would have no choice but abide by any final decision. "We obey the law. Any research that was banned, we would not conduct in the United States. We would move to someplace where it was legal." In addition to Geron and ACT, only a handful of small US biotech companies employ SCNT using animal or nonembryonic human stem cells: Stemron in Rockville, Md., StemCells Inc. in Palo Alto, Calif., and VistaGen Inc. in Burlingame, Calif., among others. "The importance of the debate on cloning and stem cells is greater than the specific number of companies using these technologies," says Werner. If Congress bars or restricts SCNT, he says, "it would be the first time that a government has shut down a legitimate area of scientific inquiry," and it would set a dangerous precedent. Adds Rudolf Jaenisch, biology professor at the Massachusetts Institute of Technology and the Whitehead Institute in Cambridge, "It is premature to ban a technique that is still in the process of evolving." About the same time ACT announced its intention to investigate therapeutic human cloning, the Jones Institute for Reproductive Medicine of the Eastern Virginia Medical School in Norfolk, Va., published a research study declaring it already had created human embryos for research by using eggs and sperm obtained from paid, consenting anonymous donors.3 While pro-life advocates deplored the development, others saw ethical merit to the Jones approach. The Jones researchers "make a pretty good case that there may be some ethical advantages to doing it this way," says Sean Tipton, spokesman for the American Society of Reproductive Medicine, which published the Jones Institute report. "It's cleaner if you approach the donors from the beginning saying, 'we want to user your sperm or your egg in order to make embryos for research purposes,' than it is to deal with infertility patients," he says. The Federal Role Not surprisingly, the blockbuster announcements on cloning for profit further fueled the debate on Capitol Hill. No fewer than seven bills had been pending in the House and Senate to regulate human cloning, ranging from minimalist legislation by James Greenwood (R-Pa.) that would allow therapeutic cloning, to the more restrictive Weldon and Stupak bill that the House finally passed. "Proposals to criminalize laboratory techniques that otherwise might help us find cures for diseases such as cancer and Alzheimer's would cast a pall over the conduct of academic science," claimed Daniel Perry, executive director of the Alliance of Aging Research, in House testimony in June. Courtesy of Gerard BradleyGerard Bradley The Food and Drug Administration (FDA) since 1993 has claimed legal authority over "products" developed through human somatic cell therapy and gene therapy activities by defining a cloned human embryo as a biological product and drug.4 Numerous legal experts and congressmen say FDA's claim of statutory authority over human cloning will not stand up in court. But the agency has been responding, in part, to widely publicized statements by Severino Antinori, an Italian infertility specialist, Panos Zavos, an American physician, and Brigitte Boisselier, a leader of a group called the Raelians, which endorses the use of eugenics to create a world without crime. These three people claim to have both the ability and intention of cloning a human being in the near future. "Whatever Bush decides doesn't matter," says Glenn McGee, professor of bioethics at the University of Pennsylvania. "The research will continue." If public support for this research is not available, the research will move from universities and institutes to the private sector, where biotech companies stand to make a windfall, he says. Adds BIO's Werner, "Private sector research has led the way so far, and we would expect it to continue." But if the federal government pumps money into this area, "that will really accelerate the pace of discovery and ultimately bring products to patients faster and sooner." Ted Agres (tagres@usa.net) is a freelance writer based in Washington, D.C. References 1. T. Agres, "On the brink," The Scientist, 15[11]:1, May 28, 2001. 2. T. Agres, "New stem cell legislation introduced," The Scientist, 15[14]:15, July 9, 2001. 3. S. Lanzendorf et al, "Use of human gametes obtained from anonymous donors for the production of human embryonic stem cell lines," Fertility and Sterility, 76:132-37, July 2001. 4. H.I. Miller, "FDA clones misguided regulatory policy," The Scientist, 15[14]:39, July 9, 2001. Ethicists, Company Clash on Cloning As lawmakers in the nation's capital try to craft a national consensus on the morality of human cloning and stem cell research, two University of Pennsylvania bioethicists express dismay over their experiences at a US company that aims to use the research for commercial drug development and therapeutics. Courtesy of University of PennsylvaniaArthur Caplan Ethicists Glenn McGee and Arthur Caplan resigned from advisory boards of Advanced Cell Technology Inc. (ACT), a Worcester, Mass., biotechnology company that intends to clone human embryos to derive stem cells for research. The resignations not only focused scrutiny on ethical issues; the actions also raised questions about how the controversial research can be regulated in the private sector. "There has been no systematic effort by the company to keep its ethics advisory board informed or to bring us into any of the various important decisions that would properly have input from any ethics scholar," wrote McGee, a professor of bioethics at Penn, when he resigned last fall. For small biotech companies, "it's all too easy for the ethics advisory board to become a kind of rubber stamp," McGee now says. McGee's resignation followed that of colleague Caplan, who quit ACT's scientific advisory board last summer. "I started to see my name flying around as being one of their advisers and I was not happy about the fact that they hadn't used us," he says. The company's cloning of an Asian gaur, an endangered ox-like animal, without consulting the science board, particularly disturbed Caplan, director of Penn's Center for Bioethics. The creature died two days after birth. Robert P. Lanza, ACT's vice president of medical and scientific development, says he blames Caplan's frustrations on the company's hectic start-up. "We were trying to get the company organized and were trying to put together a scientific advisory board.... We hadn't even assembled the entire scientific board before he left. So it wasn't simply because we didn't want [the board's] advice. We certainly would have wanted their advice." Ronald M. Green, chairman of the ACT ethics board, says McGee's resignation puzzled him because the corporation had never withheld information. McGee's resignation "had little or nothing to do with the research" they were overseeing, adds Green, director of Dartmouth College's Institute for the Study of Applied and Professional Ethics. The ethical clash at ACT mirrors the atmosphere in Congress, where the fashioning of regulations for human embryonic cloning, somatic cell nuclear transfer (SCNT), and stem-cell research has eluded lawmakers since 1996 when Scottish scientists created Dolly, the first sheep clone. Proponents and opponents of embryonic stem cell (ESC) research debate when human life begins, whether destroying embryos amounts to murder, and whether the moral good of deriving medical breakthroughs outweighs the ethical injunctions. "It is critical that in our enthusiasm to prevent reproductive cloning, we not ban vital research, turning wholly legitimate biomedical researchers into outlaws and thus squelching the hope of relief for millions of suffering individuals," Carl B. Feldbaum, president of the Biotechnology Industry Organization (BIO), a Washington trade group that represents 950 biotech companies, testified in May. Some ethicists warn that human reproductive cloning is so alluring that any human cloning, such as therapeutic cloning to develop drugs, diagnostics, and tissues for regenerative medicine, should be avoided lest researchers start down a slippery slope that will inevitably lead to reproductive cloning. "Anyone truly serious about preventing human reproductive cloning must seek to stop the process from the beginning," Leon Kass, professor of social thought at the University of Chicago, said before a House judiciary subcommittee in June. For many scientists, the ethical debate remains theoretical; human embryo researchers must rely on private funding because the law bans federal support. The Bush administration has yet to offer an opinion. Ethicist McGee says the whole controversy has made him rather testy. "I'm having to be the spoiler here, because I'm in favor of stem cell research," he complains. "My concern is just about the nature of oversight. I think we have got to find a way to work with companies responsibly. But the right way is probably not ethics advisory boards." --Ted Agres Scientists Clone Solutions to Stem Cell Debate Scientists quietly advance their understanding of human cloning and embryonic stem cell (ESC) research even as the public debates the ethics of the procedures. Over the past few months, researchers who have used stem cells to produce neurons and insulin-secreting cells in mice have demonstrated the potential of cloning for therapy development and disease research; others have raised questions about the constancy of cloned embryonic cells. Courtesy of University of HawaiiRyuzo Yanagimachi Work by Rudolf Jaenisch at the Whitehead Institute for Biomedical Research in Cambridge, Mass., and Ryuzo Yanagimachi at the University of Hawaii have demonstrated that ESCs in culture are extremely genetically unstable.1 This instability--in cells cloned through somatic cell nuclear transfer (SCNT)--helps explain why most animal clones die before birth and survivors often have respiratory and circulatory problems and growth abnormalities. While reproductive cloning is inefficient and dangerous, the researchers emphasize that therapeutic cloning does not appear to be similarly negatively affected by genetic instabilities. Jaenisch and Yanagimachi cloned mice from the nuclei of ESCs and monitored activity of imprinted genes--developmental genes controlled by special tags that do not affect the DNA base sequence of the genes themselves. They found donor ESCs lost tags that would instruct an imprinted gene to be turned on or off during development. Despite this instability, many embryos survived to adulthood. The researchers examined imprinted genes in the placenta, kidney, heart, and liver in about 40 cloned mice and found to their surprise that in none of the mice did all work correctly. The differences in genetic expression appeared to be random, with wide variations between different ESC lines, between individual colonies of cells or subclones, and even between individual cells within each colony. These differences in gene activation may or may not trigger abnormalities later in development, and it may only be the cumulative action of many abnormally expressed genes that produces the excessive growth typical in clones, the researchers reported. While some opponents of human embryo research latched onto the findings as supporting their position, members of the research team emphasized that the genetic instability of cultured ESCs does not interfere with their in vitro differentiation into different tissue types, a hallmark of therapeutic cloning. "We see a good future in ESC research, and we shouldn't abandon this potential," says Yanagimachi. Nevertheless, "we should be more cautious for future therapeutic purposes." Photo: Sam OgdenRudolf Jaenisch In therapeutic or research cloning, nuclear material from a donor somatic cell is transferred into an enucleated egg cell and ESCs are harvested from the resulting blastocyst. If the ESCs can be coaxed to differentiate into functioning tissues, the new cells might be reintroduced into the donor to regenerate diseased tissue and even organs. New research suggests progress in this area. In one study,2 researchers at Rockefeller University and the Sloan-Kettering Institute, the basic research unit of Memorial Sloan-Kettering Cancer Center, in New York derived 35 ESC lines using a cell from a mouse tail in SCNT. After about four days, they harvested the cells from the mouse blastocyst and chemically induced them to differentiate into dopamine-secreting neurons. The next step is to introduce the neurons back into mice with a Parkinson's-like condition to see if damaged nerve tissue can be regenerated without triggering an immune system rejection. Two of the scientists, Teruhiko Wakayama and Anthony Perry, plan to continue this research at Advanced Cell Technology Inc. (ACT) of Worcester, Mass., a biotech company. In a separate approach showing potential, researchers at PPL Therapeutics Inc. in Blacksburg, Va., took adult skin cells from cattle and reprogrammed them into multipotent stem cells without first producing an embryo. They then transformed these stem cells into heart cell tissue. If the non-embryonic approach proves applicable to humans, the approach could sidestep some ethical and legal objections to human SCNT research. --Ted Agres References 1. D. Humpherys et al, "Epigenetic instability in ES cells and cloned mice," Science, 293:95-97, July 6, 2001. 2. T. Wakayama et al, "Differentiation of embryonic stem cells lines generated from adult somatic cells by nuclear transfer," Science, 292:740-43, April 27, 2001.

Cloning Capsized?

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