The Science

While some applications of HGE are benign and hold great potential for preventing disease and alleviating human suffering, other applications could open the door to a human future more horrific than our worst nightmares.

Two very different applications of genetic engineering must be distinguished. One application changes the genes in cells in your body other than your egg and sperm cells. Such changes are not passed to any children you may have. Applications of this sort are currently in clinical trials and are generally considered socially acceptable. The technical term for this application is "somatic" genetic engineering (after the Greek "soma" for "body").

The other application of genetic engineering changes the genes in eggs, sperm, or very early embryos. This affects not only any children you might have, but also all succeeding generations. It opens the door to the reconfiguration of the human species. The technical term for this application is "germline" genetic engineering (because eggs and sperm are the "germinal" or "germline" cells).

Many advocates of germline engineering say it is needed to allow couples to avoid passing on genetic diseases such as cystic fibrosis or sickle cell anemia. This is simply not true. Far less consequential methods (such as pre-natal and pre-implantation screening) already exist to accomplish this same goal. Germline manipulation is necessary only if you wish to "enhance" your children with genes they wouldn't be able to get from you or your partner.

The History

The ability to directly manipulate plant and animal genes was developed during the late 1970's. Proposals to begin human gene manipulation were put forth in the early 1980's and aroused much controversy. A small number of researchers argued in favor of germline manipulation, but the majority of scientists and others opposed it. In 1983, a letter signed by 53 religious leaders declared that genetic engineering of the human germline "represents a fundamental threat to the preservation of the human species as we know it, and should be opposed with the same courage and conviction as we now oppose the threat of nuclear extinction."

In 1985, the US National Institutes of Health (NIH) approved somatic gene therapy trials, but said that it would not accept proposals for germline manipulation "at present." That ambiguous decision did little to discourage advocates of germline engineering, who knew that somatic experiments were the critical first step toward HGE experiments. Following the first approved clinical attempts at somatic gene therapy in 1990, advocates of germline engineering began writing advocacy pieces in medical, ethical, legal and other journals to build broader support.

By the mid- and late-1990s, the progress of the federally funded Human Genome Project in locating all 80,000-plus human genes fueled speculation about eventual applications, including germline engineering. In 1996, scientists cloned the first genetic duplicate of an adult mammal (the sheep "Dolly"). In 1999, researchers mastered the techniques for disassembling human embryos and keeping embryonic cells alive in laboratory cultures. These developments made it possible, for the first time, to imagine a procedure whereby the human germline could be engineered in a commercially practicable manner.

HGE advocates were further encouraged by the social, cultural and political conditions of the late 1990s -- a period characterized by technological enthusiasm, distrust of government regulation, the spread of consumerist/ competitive/ libertarian values, and the perceived weakened ability of national governments to enforce laws and treaties, as a result of globalization.

In March 1998, Gregory Stock, director of the Program on Medicine, Technology and Society at the University of California at Los Angeles (UCLA), organized a symposium on "Engineering the Human Germline." It was attended by nearly 1,000 people and received front-page coverage in The New York Times and The Washington Post. All the speakers were avid proponents of germline engineering.

Four months later, one of the symposium's key participants, HGE pioneer W. French Anderson, submitted a draft proposal to the NIH to begin somatic gene transfer experiments on human fetuses. He acknowledged that this procedure would have a "relatively high" potential for "inadvertent gene transfer to the germline." Anderson's proposal was widely acknowledged to be strategically crafted so that approval could be construed as acceptance of germline modification, at least in some circumstances. Anderson hopes to receive permission to begin clinical trials by 2003.

The New Ideology

Advocacy of germline engineering and techno-eugenics (i.e., technologically enabled human genetic manipulation and selection) is an integral element of a newly emerging socio-political ideology.

This ideology is gaining acceptance among scientific, high-tech, media and policy elites. A key foundational text is the book Remaking Eden: How Cloning and Beyond Will Change the Human Family, by Princeton University molecular biologist Lee Silver. Silver looks forward to a future in which the health, appearance, personality, cognitive ability, sensory capacity and the lifespan of our children all become artifacts of genetic manipulation. Silver acknowledges that financial constraints will limit their widespread adoption, so that over time society will segregate into the "GenRich" and the "Naturals."

In Silver's vision of the future:

The Environment

HGE enthusiasts typically anticipate a future in which genetic technology permeates, transforms and reconfigures all sectors of the natural world -- plants, animals, humans and ecosystems. Many look forward to what they call the "Singularity" -- that point in the next few decades when any distinction between the natural and the technological has been completely dissolved. Many couple their enthusiasm for genetic engineering with an explicit disparagement of environmentalist values. Nobel Laureate James Watson, for example, has complained that "ever since we achieved a breakthrough in the area of recombinant DNA in 1973, left-wing nuts and environmental kooks have been screaming that we will create some kind of Frankenstein bug or Andromeda strain that will destroy us all."

Gregory Stock has stated: "Even if half the world's species were lost, enormous diversity would still remain. When those in the distant future look back on this period of history, they will likely see it not as the era when the natural environment was impoverished, but as the age when a plethora of new forms -- some biological, some technological, some a combination of the two -- burst onto the scene. We best serve ourselves, as well as future generations, by focusing on the short-term consequences of our actions rather than our vague notions about the needs of the distant future."

It is difficult to see how a society that accepts the techno-eugenic re-engineering of the human species will maintain any sense of humility, reverence and respect regarding the rest of the natural world.

Promoting the 'Post-Human' Future

Supporters of human germline engineering and cloning have established institutes to spread their vision. In addition to Stock's program at UCLA, the Los Angeles-based Extropy Institute holds workshops on how to organize politically to advance the "post-human" agenda, including sessions on how to talk to the press and public about human genetic modification in ways that build support and diffuse opposition. In 1999, the Maryland-based Human Biodiversity Institute presented a seminar on the prospects for genetically modified humans at a Hudson Institute retreat attended by former British Prime Minister Margaret Thatcher.

Meanwhile, the biotech industry is actively developing the technologies that would make it possible to offer human germline engineering on a commercial basis. This work is almost completely unregulated. Geron Corporation of Menlo Park, California holds patents on human embryo manipulation and cloning techniques. Advanced Cell Technologies of Worcester, Massachusetts, announced in 1999 that it had created a human/bovine embryo by implanting the nucleus of a human cell into the egg of a cow. No laws exist that would have prevented this trans-species embryo from being implanted in a woman's uterus in an attempt to bring a baby to term. Such a child would have contained a small but significant proportion of cow genes.

Chromos Molecular Systems, Inc., in British Columbia, is developing artificial human chromosomes that would enable the engineering of multiple complex traits. People whose germlines were engineered with artificial chromosomes, and who wanted to pass complete sets of these to their children intact, would only be able to mate with others carrying the same artificial chromosomes. This condition, called "reproductive isolation," is the primary criteria that biologists use to classify a population as a separate species.

Where is the Opposition?

Given the enormity of what is at stake and the fact that advocates of the new techno-eugenics are hardly coy about their intentions, it is remarkable that organized opposition has been all but absent. Why is this?

One reason is that the most critical technologies have been developed only within the last three years or so -- there simply hasn't been time for people to fully understand their implications and respond. Further, the prospect of re-designing the human species is beyond anything that humanity has ever before had to confront. People have trouble taking this seriously -- it seems fantastical and beyond the limits of what anyone would actually do or that society would allow.

In addition, attitudes concerning human genetic engineering don't fit neatly along the familiar ideological axes of right/left or conservative/liberal. The additional axis of libertarian/communitarian attitudes is needed to fully categorize currently contending socio-politico commitments. The libertarian right and libertarian left tend to consider human genetic modification as a property right or as an individual right, respectively. By contrast, the communitarian right and communitarian left tend to be strongly opposed -- the former typically for reasons grounded in religious beliefs and the latter out of concern for human dignity, social equity and solidarity.

Finally, although people sense that the new genetic technologies are likely to introduce profound social and political challenges, they also associate these technologies with the promise of miracle cures. Before any sentiment in favor of banning certain uses of genetic technology can take root, people will have to understand that this would not foreclose means of preventing or curing genetic diseases.

What Is to be Done?

The core policies that humanity will need to adopt are straightforward: we will need global bans on altering the genes we pass to our children and on creating human clones. We'll also need effective, accountable systems for regulating those HGE technologies (such as somatic genetic manipulation) that have desirable applications but could be dangerously abused.

Many countries, including France, Germany and India, already have banned both germline engineering and cloning. The Council of Europe is working to have these banned in all 41 of its member countries. The United Nations and UNESCO have called for a global ban on human cloning and a World Health Organization study has called for a global ban on germline engineering.

The base of any effective global movement to bring the new human genetic technologies under societal control will, as always, be strong activist civil society organizations. Among the most important of these are the environmental and Green organizations. In 1999, Friends of the Earth President Brent Blackwelder and Physicians for Social Responsibility Executive Director Robert Musil circulated a statement that declared:

In February 2000, nearly 250 concerned leaders, including environmentalists Bill McKibben, Amory Lovins, Terry Tempest Williams, Gary Snyder and Mark Dowie, signed an open letter warning that the prospect of human germline engineering "represents a point of decision -- one that ranks among the most consequential that humanity will ever make. We should acknowledge that human germline engineering is an unneeded technology that poses horrific risks, and adopt policies to ban it."

The next few years will be critical. Advocates of the techno-eugenic future are racing to create designer babies and human clones before people realize what is happening and what is at stake. They believe that once humanity is presented with such fait accompli, resistance will crumble and the new epoch will have been launched. It is imperative that those who value the beauty, vitality and wonder of the natural world begin organizing now to ensure that human beings do not become technological artifacts.

Richard Hayes is the Executive Director of  The Center for Genetics and Society

Gene Therapy Ordered Halted at University

By Sheryl Gay Stolberg
January 22, 2000

WASHINGTON, Jan. 21 -- The Food and Drug Administration temporarily shut down human gene therapy experiments at the University of Pennsylvania today after an inspection uncovered "numerous serious deficiencies" in ensuring patient safety during a clinical trial that cost an 18-year-old Arizona man his life.

The decision to place the entire program -- eight experiments, including five active clinical trials in diseases ranging from cystic fibrosis to breast cancer -- on "clinical hold" is highly unusual. The hold is indefinite, agency officials said, and will not be lifted until the agency is convinced that the university's Institute for Human Gene Therapy can follow federal rules designed to protect study volunteers from harm.

The agency notified the Penn scientists of the decision in a two-page letter today. In response, the university's president, Judith Rodin, pledged to appoint a committee of outside scientists to review the institute's work. In a statement, she said Penn "has cooperated fully with all aspects of the F.D.A.'s investigation and would continue to do so."

The agency's action comes two days after its investigators completed a detailed inspection of patient records and laboratory data from the experiment that killed the Tucson man, Jesse Gelsinger, on Sept. 17. Mr. Gelsinger died of multiple organ failure caused by a severe immune reaction to an infusion of corrective genes and is the first person to have died as a direct result of gene therapy.

Some of the findings, including evidence that Mr. Gelsinger was ineligible for the experiment and that the scientists had failed to report serious side effects in other patients that could have put a halt to the study, were made public last month during a meeting of the Recombinant D.N.A. Advisory Committee, the panel that oversees gene therapy research for the National Institutes of Health.

But the final inspection report, which cited 18 specific violations, also turned up new problems. It found, for instance, that the Pennsylvania scientists had enrolled all 18 patients without filling out eligibility forms. Instead, the Food and Drug Administration said, the scientists created the forms after Mr. Gelsinger died, leaving them unsigned and undated. By that time, the agency's inquiry had already begun.

"This is one of the many concerns that we have had about the conduct of the study," said Dr. Philip Noguchi, the agency official in charge of gene therapy research. 'It indicates to us that the sponsor was not following rules, was not following our regulations and in general was not reporting to F.D.A. in a timely fashion."

Dr. James Wilson, the director of the gene therapy institute, did not take telephone calls today. But in the past, he has strongly defended his work, including the decision to treat Mr. Gelsinger.

The death rocked the nine-year-old field of gene therapy, a field that has had few treatment successes, and today's announcement was another blow. Dr. Arthur Caplan, a bioethicist at the University of Pennsylvania, said the move could hurt gene therapy programs across the country.

"If there are violations and problems it can have a devastating impact across the board, for all gene therapy research, at every institution," Dr. Caplan said. He predicted a "loss of funding and a loss of enthusiasm."

Congress has already indicated its concern. Senator Bill Frist, Republican of Tennessee, has called a hearing for next week to examine whether there is sufficient oversight for patient safety in gene therapy experiments.

One of the speakers at next week's hearing will be Paul Gelsinger, Jesse Gelsinger's father. Until now, the elder Mr. Gelsinger has supported the scientists at Penn, even as the Food and Drug Administration released its highly critical preliminary results last month. But today Mr. Gelsinger indicated he had changed his mind and said he had hired a lawyer, although no suit has been filed.

"Everybody was wrong," Mr. Gelsinger said sadly in a telephone conversation from Tucson. "Even me."

He declined to elaborate, referring questions to the lawyer, Alan Milstein, who said he was not surprised by the agency's move. "It seems appropriate in light of what happened to Jesse," Mr. Milstein said.

In interviews today, leaders in the gene therapy field also appeared to be backing away from their support of Dr. Wilson.

"All I can say is we are surprised at this," Dr. Savio Woo, president of the American Society for Gene Therapy, said in a telephone interview.

"But that being said, we support the F.D.A.'s action as being appropriate. If there are all these numerous violations then any situation would need to be put on hold until they can clean up their act."

Among the agency's findings were serious flaws in the way Penn scientists explained the benefits and the risks of the experiment to patients, a process known as informed consent. For 9 of the 18 patients, the agency said, "the consent process was not well documented."

Investigators could not always determine who had conducted the informed consent discussions and who had answered the questions; in one case, for example, a patient and a witness signed the informed consent document on March 17, 1997, but the investigator signed it on June 5, a week before the gene therapy was administered.

While those failures may sound like minor details of recordkeeping, Dr. W. French Anderson, a gene therapy scientist at the University of Southern California, said the agency took them seriously, especially when a pattern emerged.

Dr. Noguchi said today that the investigation was continuing. The next step, he said, is for Dr. Wilson to respond to the inspection.

One reason Mr. Gelsinger's death has generated so much controversy is that he was not particularly sick before he died. He suffered from a relatively mild form of ornithine transcarbamylase deficiency, an inherited disorder in which the liver is unable to process ammonia, a toxic breakdown product of protein. The disorder was kept in check through diet and drugs.

The experiment in which Mr. Gelsinger participated was designed to test a treatment for babies with a fatal form of the disease. It involved an infusion of trillions of particles of the ornithine transcarbamylase gene, tucked inside a weakened cold virus.

Dr. Wilson has consistently maintained that the Penn scientists had no evidence that would have led them to predict Mr. Gelsinger's death, and Dr. Noguchi, of the F.D.A., would not say whether the agency thought the death could have been prevented. "I'm not going to speculate on what these things really mean," he said.

Trials Are Halted on a Gene Therapy

By Sheryl Gay Stolberg
New York Times
October 4, 2002

WASHINGTON, Oct. 3 — Officials in the United States and France said today that they had suspended four gene therapy experiments because the treatment, which cured a 3-year-old boy of a fatal immune deficiency, may have given him an illness similar to leukemia.

Scientists conducting the research said it was not clear whether the boy, who was treated as an infant in France, was made sick by the therapy. But officials at the Food and Drug Administration said they suspected that the experiment, which until now had been hailed as the only unequivocal gene therapy success, was responsible.

"It is not absolutely a definitive thing, but the preliminary data that we have leads us to suspect that it surely isn't a coincidence," said Dr. Philip Noguchi, the agency official who oversees gene therapy research. "It's a sobering experience, but we are doing what should be done."

The experiments — one in France, three in the United States — were suspended in early September. But the news was not made public until today, authorities said, to give the researchers time to notify the families of 14 children enrolled in the trials.

The move is yet another major setback for the fledgling field of gene therapy, which involves using viruses to introduce healthy genes into cells. The field is still reeling from the death of Jesse Gelsinger, 18, who lost his life three years ago while undergoing gene therapy at the University of Pennsylvania.

Scientists have long theorized that retroviruses, which were used in the suspended experiments, could trigger cancer. The risk was that the virus, which integrates itself into the patient's DNA, would lodge in or near a cancer-causing gene.

But researchers said they had never seen this before, either in animals or humans, even though hundreds of people have received retroviruses in gene therapy experiments for a number of diseases. Experts said it was too soon to tell whether other children treated for immune deficiency were at risk.

"This has been a spectacularly successful endeavor up to this point," said Dr. Savio Woo, former president of the American Society of Gene Therapy. "This is a new enemy that we have discovered. We know that there is a theoretical possibility, but it has never been seen before."

The suspended trials sought to cure severe combined immune deficiency, a disorder that leaves infants without working immune systems. Abbreviated as SCID, but commonly called "bubble boy disease," it is extremely rare and is fatal in the first year of life if left untreated.

In the most severe form, the disease affects boys who have faulty X-chromosomes. The only treatment is bone marrow transplant. But the transplants fail in as many as 40 percent of all children who lack a perfect donor match, so scientists looked to gene therapy as an alternative.

In April 2000, Dr. Alain Fischer and his colleagues at the Necker children's hospital in Paris announced that they had used gene therapy to successfully insert corrective genes into the bone marrow stem cells of three babies with X-linked SCID. Coming on the heels of Mr. Gelsinger's death, Dr. Fischer's study was hailed as long-sought proof that gene therapy could work.

Dr. Fischer went on to treat six more babies and a teenager, who survived because he had a partial immune deficiency. "Up until now, all these patients, more than three and a half years after treatment, are doing well," he said. All had "close to normal immune functions," he said.

But last spring, Dr. Fischer said, one of the boys showed elevated levels of a particular type of white blood cell, known as a T-lymphocyte, though he had no symptoms. Subsequently, though, the boy developed chickenpox. By August, Dr. Fischer said, he had a "significant increase" in the white cell counts, as well as an enlarged spleen, anemia and a drop in platelets.

When scientists examined the child's cells, Dr. Fischer said, they could see that the genetic material of the retrovirus had inserted into a particular gene on the 11th chromosome that controls the proliferation of cells. But he said he was not yet convinced the gene therapy was entirely to blame.

Other factors, including the chickenpox infection and a family history of cancer, could also be at work, Dr. Fischer said. But Dr. W. French Anderson, a professor at the University of Southern California who was among the first scientists to use gene therapy to treat SCID, said the gene therapy was likely responsible.

"We knew it would happen sooner or later," he said. But even if it turns out that gene therapy causes the disease, Dr. Anderson and other experts said gene therapy might still be used to treat SCID because the illness was so devastating.

The child does not have leukemia per se, Dr. Fischer said. There is no name for his proliferation of cells because scientists have never seen it before, so Dr. Fischer is calling it "lymphoproliferation."

The boy is being treated with chemotherapy and is responding, Dr. Fischer said. But the abnormal cells have not disappeared, he said.

Dr. Fischer said he notified French authorities, as well as the F.D.A. and his colleagues in the field, right after Labor Day, as soon as he knew the problem was serious.

The food and drug agency immediately put what it calls "a clinical hold" on three trials in the United States, two at Children's Hospital in Los Angeles and one at the National Institutes of Health in Bethesda, Md. The N.I.H. study, and one of the Los Angeles studies, have yet to enroll any patients, he said.

The other Los Angeles study is being run by Dr. Donald Kohn, president-elect of the American Society of Gene Therapy. The four children Dr. Kohn and his collaborators have treated all have a form of SCID that is not the X-linked type. But Dr. Kohn said the F.D.A. was correct in suspending his research. "The clinical hold, I think, is the only ethical and responsible course of action until we have more answers," he said.

The F.D.A. will convene a meeting of outside experts next week to discuss the trials, Dr. Noguchi said. He added that other SCID trials had been going on in England and Germany. The German studies have been suspended, but the British research is continuing, he said.

At Cincinnati Children's Hospital Medical Center, researchers said they were collaborating with Dr. Fischer to try to determine what, if anything, went wrong in the study.

But Dr. Christof von Kalle, who is leading the effort, said it could take months, if not years, for a definitive determination.

Today's announcement came as a panel of independent experts released a study of the safety of clinical trials that was prompted by Mr. Gelsinger's death. The panel, at the Institute of Medicine, called for major reforms, including a federal law that would require all research organizations to develop patient protection programs.

Dr. Daniel Federman, a professor of medicine at Harvard Medical School who was chairman of the panel, said the panel was especially concerned about financial conflicts of interest in research. He spoke of a "hodgepodge of protections" that was so haphazard it was impossible to catalog how many Americans were enrolled in research experiments, and how many had been harmed by them.

"At the present time, a lot of people are trying to do a good job, and almost certainly are," Dr. Federman said. "What we are trying to do is raise the level of the system as a whole."

Mr. Gelsinger's father, Paul, who has become an advocate for patient protection and reviewed the study in advance of its publication, applauded the work.

"I have always felt like what happened to Jesse blew the lid off the can of worms of medical research," Mr. Gelsinger said. "The system needs to be looked at, it needs to be unraveled. This study goes a long way toward doing that."

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