NEWS FEATURE: Science standing at edge of altering future generations

c. 1998 Religion News Service UNDATED _ Take a fetus. Fix a lethal gene in utero. Alter the inheritance of all that fetus’s descendants. The third step in this proposed sequence is the jaw-dropper. For the eight years medical researchers have pursued experimental human gene therapies _ with very modest results _ all their tinkering […]

c. 1998 Religion News Service

UNDATED _ Take a fetus. Fix a lethal gene in utero. Alter the inheritance of all that fetus’s descendants.

The third step in this proposed sequence is the jaw-dropper. For the eight years medical researchers have pursued experimental human gene therapies _ with very modest results _ all their tinkering was guaranteed to die with the individual who undertook the risk.


Now, Dr. W. French Anderson, a University of Southern California genetics pioneer, wants to cross this ethical and generational divide.

For two days in late September, Anderson hashed out the “pre-protocols” of experimental therapies he wants to try on fetuses with two kinds of catastrophic inherited diseases. In each case, his genetic interventions would most likely affect the chromosomes in the sperm and eggs of his research subjects, altering the DNA of their future children.

“He doesn’t expect us to bless or condemn these pre-protocols at this point,” said professor Eric T. Juengst, a bioethicist at Case Western Reserve University who serves on the federal advisory committee that is hearing Anderson out. “He’s committed to having the public understand this field as it evolves, and to win public support.”

At best, that support is several years away, Juengst said. “Both of the specific pre-protocols French floated were pretty thoroughly shredded by the RAC (Recombinant DNA Advisory Committee of the National Institutes of Health),” he said.

In one proposal, Anderson’s team hopes to cure ADA deficiency, a rare immune disease that can require children to live circumscribed lives in “bubbles.” In the other, the team would attempt to fix the genetic defect causing alpha thalassemia, a severe form of anemia, common in Asia, that kills the fetus before birth.

The technology _ inserting functioning genes into the rapidly dividing cells of second-trimester fetuses to replace defective DNA _ contains the possibility of unexpected, downstream consequences for both the developing fetus and its children. Researchers call this kind of experimentation germ line gene transfer.

“Germ line gene transfer raises the prospect of passing on genetic changes to unconsenting, unsuspecting future generations,” said professor Thomas H. Murray, director of the Case Western Reserve University Center for Biomedical Ethics. He and other scholars also worry that polishing Anderson’s technology will eventually allow doctors to engineer babies for attractive traits, not just cure disease.


Closer at hand is the risk that tampering with the human genome in utero might create a cascade of serious birth defects, scientists said.

“French clearly sees his allegiance to the children who would be born if not for fatal, prenatal disease,” Juengst said. “But people on the committee still think it’s likely to go wrong more than it’s likely to work. We can’t say what will happen to these newly integrated genes in mitosis, division, development and expression.

“One scientist, Dr. Jon Gordon (a neurobiologist at the Mount Sinai School of Medicine in New York City), raised the problem of insertional mutagenesis. That is how a new gene integrated in the wrong place interrupts an existing gene’s function. “If that gene has already done its work in the fetus and has shut off, that infant will never feel any effect of insertional mutagenesis. But its children would be seriously messed up.”

A much less exotic technology, in vitro fertilization (IVF), has already saddled many families with enduring birth defects, said Ronald M. Green, director of the Ethics Institute at Dartmouth College Medical School.

“In Europe and the United States, IVF has resulted in a great increase in the rate of higher-order multiple births, with their associated toll of birth defects and prematurity,” he said. Some describe the sharp increase in the number of infants struggling in neonatal intensive care units due to these fertility treatments as a new epidemic.

Murray seconded Green’s concern: “I think we have big enough problems with the consequences of IVF right now.” He said many people also look at the approaching germ line scenarios and accuse scientists of “playing God,” tampering with the “wisdom of evolution,” or violating the “integrity of the genome.”


Maxwell J. Mehlman, director of the CWRU Law-Medicine Center, isn’t one. “To me, we play God all the time trying to avoid illness,” he said. “If God didn’t want us to intervene, he wouldn’t give us the tools.”

Murray, Mehlman and Juengst organized a recent workshop of scientists, lawyers and scholars to explore the options society might exercise as germ line experimentation presses forward.

“The problem is this: In germ line gene transfer, we seem to have a public policy dominated by procrastination,” Murray said.

A decade ago, researchers assumed they would work out the kinks in somatic cell gene therapy _ the experimental approach of gene corrections that die with recipients _ before venturing into germ line work.

The problem is that somatic cell therapies for such inherited diseases as ADA deficiency and cystic fibrosis have worked only partially or not at all. That led Anderson to propose in utero attempts, when fetal chromosomes are more apt to respond to his interventions.

Anderson argues that fixing a mutation that causes a catastrophic disease and passing that correction to new generations would be a benefit, not a risk. But even that assessment is uncertain. Scientists have determined that inheriting one gene for sickle cell anemia protects an infant against malaria, but inheriting two _ from both mother and father _ gives the child the disease. Likewise, a single mutation for cystic fibrosis may protect a child against cholera, but inheriting two defects results in disease.


“As one of the basic philosophical questions, we’ll have to take a stand about whether a germ line gene transfer to eliminate a disease is a risk or a benefit,” Juengst said, referring to the federal advisory panel.

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A key worry of many scholars, including Juengst and Murray, is the unregulated context in which reproductive technologies now emerge in the United States.

“With more than 300 infertility programs, the United States is now the world’s leading provider of infertility services,” Green observed. When Congress eliminated federal funding for human embryo research in 1995, it also eliminated federal reviews and controls, putting infertility research in the unregulated hands of entrepreneurs.

The ironic result is that in an arena the public cares about deeply _ the creation of human life _ the anti-abortion and conservative forces in Congress have hamstrung the ability of the federal government to exercise oversight, or even protect the health and safety of women and children undergoing these

procedures, Green said.

“We’ve witnessed the growth of a proprietary infertility industry that appears to be driven more by profit than science,” Murray said. “The funding of infertility research is not disciplined by the sort of intense peer scrutiny to which applications to the National Institutes of Health are subjected.”

In other words, Juengst said, an individual researcher, hoping to help a desperate couple, might decide on his or her own to pursue germ line gene transfer.


Already, the American Society for Reproductive Medicine awarded its prize paper last year to a research team that inserted the nucleus of an older woman’s ovum into a younger woman’s egg cell from which the nucleus had been removed. In such cases, the younger woman’s mitochondrial DNA _ stored in cytoplasm outside the nucleus _ would be passed along to the older woman’s infant. An infant created this way would pass the donor woman’s mitochondrial DNA to all his or her progeny _ a kind of germ line gene transfer.

The Anderson pre-protocols and the mitochondrial genome mixing have opened the back door to germ line gene transfer. “So now we are faced with it,” Murray said. “What should our policy approach to these interventions look like?”

DEA END LONG

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