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Researchers developed an electrocatalytic method for the detection of single-base mutations and lesions in duplexes. They used gold electrodes modified with preassembled DNA duplexes to measure the electrical signal of methylene blue, a redox-active DNA intercalator, coupled to an iron compound. Mismatched or damaged DNA reduces this signal. The method even detects mutations in perfect duplexes, and it can be adapted to a chip format.
Congratulations, it's
asymmetrical
(posted October 16, 2000)
Making therapeutic use of stem cells may rely on first gaining a better understanding of how they behave. New evidence shows that the cells that surround stem cells influence the way they divide. Researchers found that support cells control the population of stem cells by causing them to divide asymmetrically into one daughter stem cell and one differentiated daughter cell.
Still no bottom
line
(posted October 16, 2000)
Over 650 patients with a history of colorectal adenomas were randomly assigned to one of three daily interventions: 2 g of elemental calcium, fiber in the form of 3.5 g ispaghula husk, or placebo. Colonoscopy three years later on the 550 patients who remained in the trial found a significant difference in adenoma regrowth in just one group - but in the wrong direction. Ispaghula husk appeared to encourage regrowth, particularly in patients whose pretrial dietary calcium intake was above the median.
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The family of Jesse Gelsinger, the teenager who died in a gene therapy experiment a year ago, filed suit on September 18 against gene therapy researchers at the University of Pennsylvania. What impact has the lawsuit had on the day-to-day conduct of gene therapy research?
Not much, judging from interviews at Cold Spring Harbor Laboratory (CSHL)'s gene therapy meeting, which was held September 25-29, 2000. Eric Kremer, an American doing research at Genethon in Evry, France, said everyone had expected young Gelsinger's family to file suit, and he was only surprised that it took so long. In Jay Lozier's lab at the National Human Genome Research Institute in Bethesda, someone downloaded the complaint from the Web and passed it around, but there wasn't a lot of gossip about it. A group of young French scientists hadn't even heard about the lawsuit. Fintan Steele, the editor of the American Society of Gene Therapy's official journal, Molecular Therapy, said institutions might be scared, but that the suit has not had much effect on bench researchers. Katherine High, of Children's Hospital of Philadelphia (which is also a part of the University of Pennsylvania) agreed that the impact on daily conduct in her lab, where the scientists are doing basic research and are distant from clinical investigations, is minimal. "You're preoccupied with your experiments," she pointed out.
The lawsuit itself may be having little immediate effect on gene therapy researchers' state of mind, but the death of Jesse Gelsinger and its aftermath have made a lasting impact on research with human subjects and perhaps - this is much less clear - on the future of gene therapy itself. Lozier said, "It's not a chilling effect, but it makes me want to have even more focused questions and more evidence before going to clinical trials." He suggested that the impact might be greater on company researchers than on academic scientists. Steele has detected worry that corporate money will dry up. "I don't think there's anyone who hasn't been seriously concerned," said Gary Nabel of the Vaccine Research Center at the National Institute of Allergy and Infectious Diseases. "There's a reluctance to move forward to clinical trials." Some young investigators no longer see gene therapy's growth curve as exponential, he said.
Those worries may not be misplaced. Policy matters are not commonly part of the program at CSHL's rigorously scientific meetings, but the organizers of this one decided there must be a session on the ins and outs of clinical trials. Among the panelists was Kathryn Zoon, director of the Center for Biologics Evaluation and Research (CBER) at the Food and Drug Administration. She told startled gene therapists that Investigational New Drug applications for gene therapy had plummeted more than 50 percent in the past year. (An IND is a request to the FDA to permit researchers to try out an investigational drug or biological product on people, the mandatory first step on the long road to getting government approval to sell it.) INDs, she said, fell from 55 in fiscal year 1999 to 26 so far this fiscal year, which ends October 1. Furthermore, the drop was most precipitous for commercial applications. From 21 in 1999, they have fallen to just 8 this year.
Olivier Danos, also at Genethon, thinks the drop-off is transient. "The reason is investors," he said. "It means delays, but not necessarily abandonment." Nabel is not so sure it's a temporary phenomenon. "My impression is that a considerable damper has developed on the field," he declared. Danos, who is also this year's president of the European Society for Gene Therapy, forecast that a short-term reduction in human testing will help ensure that the overall quality of clinical trials will be much better, even if it takes more time. Nabel agreed, with a caveat. Fewer clinical trials are not necessarily bad if the quality is higher, he said. "But the fewer things you try, the fewer succeed."
Margaret Liu, a physician-researcher who is now a private vaccine and gene therapy consultant, argues that the reduction in testing is not related to the Gelsinger case. She left Chiron last fall when the company shut down several projects, one of them hers. Chiron decided that the potential payoffs from gene therapy are too long-term, she said. Nabel agreed that companies are not fleeing so much because of the risks, but because they think commercialization of gene therapy will be slow in coming.
Gene therapy researchers have argued all along that the Gelsinger case was an aberration, not at all typical of clinical gene therapy research. "There's nothing special about gene therapy," Danos said. "It could have happened anywhere." Now the U.S. government backs them up. The FDA has done random inspections of 69 assorted clinical trials it is monitoring, some gene therapy and some not. Zoon reported that the agency sees no more deviation from good practice in gene therapy trials than in the others. Gene therapy is high-profile, so it has become the poster child for many of the issues that pervade clinical research, she declared.
Her colleague Jay Siegel, also of CBER, agreed. Not only have sponsors of gene therapy trials modified their procedures, he said, but the Gelsinger case sparked a discussion that is leading to changes in the conduct of clinical trials of all kinds. One significant change may be that investigators will no longer be permitted to conduct Phase I trials themselves, he said. The agency is also exploring ways to help academic institutions cover the costs of clinical trials.
"Everybody recognizes the need for more oversight," Nabel declared. "But there will be costs associated with that, both money and time." High emphasized the need to train clinical investigators in gene therapy, which are in short supply. She reported that the American Society for Gene Therapy is designing a course in clinical gene therapy research, which will be offered for the first time next spring at the annual meeting in Seattle. She also emphasized the need for a standardized set of reporting requirements for adverse events. "We need to report these things to docs who understand clinical trials, as opposed to somebody who's just checking off boxes," she said. Zoon said the FDA was establishing an IND adverse event database.
In addition to more oversight in general, gene therapists can also expect much more attention to safety. Since Jesse Gelsinger's death, the use of adenovirus vectors for delivering therapeutic genes has, of course, been examined more rigorously. Nabel urged that adenoviruses not be discarded, especially for DNA vaccines. "The public health implications for millions of people are pretty spectacular," he pointed out.
Several papers at the meeting focused on developing HIV lentivirus vectors because they are so talented at integrating into the genome. But their potential risks will be a barrier to testing them on people. "Lentivirus vectors are very powerful, but there's still a big gap between the lab and clinical studies," Danos warned. "More emphasis on toxicology is needed." The FDA's Siegel said it was too early at this point for the agency to offer guidance on the use of lentiviruses. The NIH's Recombinant DNA Advisory Committee is expected to consider HIV vectors in the next few months.
Danos, for one, is determined to view the events of the past year as an opportunity rather than a problem. "It raised awareness in a positive way. Everybody has a more mature view of gene therapy now, the media and the public as well as scientists themselves," he said. Basic scientists now connect what they are doing in the lab with safety and toxicity issues that will arise at later stages. "It's an opportunity to start talking about these things and find solutions."
He thinks the controversy will have another salutary effect: it will discourage scientists who saw gene therapy as a way to get famous quickly. He contends, "the time when you wanted to be the first in your village to do gene therapy is over."
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In the first actual case of a controversial possibility, a Colorado couple has transfused cord blood from a six-week-old baby specifically conceived as a tissue match for his older sister, who has Fanconi anemia. The pioneer of this kind of endeavor lost his federal funding three years ago for violating a ban that forbids exactly such embryonic selection as government-funded research.
The ban is still in effect. Although the U.S. government acted last August specifically to allow research on existing human pluripotent stem cells, the 1996 ban on human embryo research has been upheld every year.
The couple in question, Jack and Lisa Nash, first approached medical geneticist Mark Hughes to conduct prenatal genetic diagnosis (PGD) followed by in vitro fertilization (IVF). Later, Hughes was the subject of congressional hearings because employees in his lab, at a private hospital near the National Institutes of Health, claimed he was using NIH funding for research that was subject to the ban. After his funding was revoked, he referred the Nashes to the Reproductive Genetics Institute in Chicago, one of about a dozen U.S. clinics that do PGD.
There was no prohibition on such testing in private clinics, and the procedure itself was perfectly legal. However, it is possible only in private clinics, not as part of federally funded research.
"We've had a whole bunch of these [cases]," Hughes told BioMedNet. "This was the first time we've gone all the way through to transplantation."
Hughes, who now works at Wayne State University in Michigan, calls the Nash case "a miracle, and everything that medicine should be trying to do." But other critics echo an ethicist at the University of Minnesota where the baby was born, who told the Minneapolis Star Tribune that "we have crossed the line" toward choosing babies to be what their parents want.
The Nashes reportedly went through PGD and IVF five times before bringing to term an infant who could serve as a cord-blood donor to restore their daughter's hematopoietic system. She recently began to show signs of leukemia.
The Nashes' son was born on August 29, and on September 19 they revealed at a press conference their intentions to transfuse his cord blood into their six-year-old daughter. The transfusion took place a week later.
The episode resonates with the earlier case of Anissa Ayala, who had leukemia. Her father had a vasectomy reversed, intending to have a younger child who could donate blood to Anissa. The Ayalas got lucky: without prenatal diagnosis, their daughter Marissa was a compatible blood donor. Anissa, 17 years older than her donor-sister, was reported six years ago to be married, leukemia free, and working as a bank clerk. In 1993, the story was made into a television movie.
Hughes would draw a distinction between the Nash case and the Ayala case. Leukemia is not a genetic disease like Fanconi anemia, he said, and 16 years have not passed during which the Nashes showed no intention of having another child.
When families first began to approach him with this kind of request, Hughes said, he was "quite concerned about this" kind of moral question. Drawing especially on the counsel of ethicists Ronald Green of Dartmouth University and John Fletcher of the University of Virginia, he says, "what we came down to was that the motive of the family is most critical. If the Nashes were interested in having a healthy baby and avoiding transmitting a genetic disease, and at the same time wanted to help their daughter, that's fine. If they were viewing the baby as a commodity whose only raison d'être is as a source of transplant material, you can't do that."
It's impossible to create a national program based on this kind of judgment, he added. "But if you're a physician speaking to a patient, you know [their motives] - unless they lie to you."
More than a decade after Hughes pioneered prenatal genetic diagnosis, he says, there are very few labs capable of the technology. His own clinic collaborates with 26 IVF clinics worldwide. Hughes predicts that it such procedures will always be done on a referral basis to a few specialty centers. Thus the doctors who know the couple well, and who must judge their motives, will almost always be distant from the scientists who perform the embryo testing. "There's no right and wrong," he went on. "You have to be careful with this technology."
Another observer who has thought long about such issues is research associate Erik Parens of the Hastings Center for Bioethics, a think tank in Garrison, New York. Parens too feels we have crossed a moral line. "There is a difference between testing against [genetic disease] and testing for [a trait]," he told BioMedNet.
"We stand in awe of the ability for doctors to allow people to have a healthy baby and to throw into the pot the ability to cure a second child," he added. "But at the same time it makes you shudder, the prospect of being able to specify the desirable traits of our children.
"Why does it make me think that the market will be driving decisions about the traits parents want their children to have? Of course, the companies will be selling only probabilities. We will have to deal with the disappointments, when science is not able to live up to the promise."
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