ARTICLE IN BRIEF
No caption available.
Neurogeneticists weigh in on a recent call for a moratorium on research involving edits to the human germline, which can be inherited by future generations.
At the end of the three-day International Summit on Human Gene Editing in Washington, DC, in December, the meeting's organizing committee issued a statement calling for a moratorium on biomedical research involving edits to the human germline — modifications to the human genome that can be inherited by offspring.
The statement, which is not binding, reflected the current uncertainty about where gene editing research might lead, focusing in broad terms on the promises and pitfalls and the potential implications of editing the human germline.
Neurogeneticists who spoke with Neurology Today agreed with the call for a moratorium but differed in their views on the potential utility or harms of human germline editing. Some echoed the organizing committee's view that such edits could have unforeseen adverse consequences or may be abused by unethical actors; others questioned whether germline editing would serve any important clinical purpose in the future.
The meeting, co-hosted by the National Academy of Sciences, the Institute of Medicine, the Royal Society of London, and the Chinese Academy of Sciences, appears to have been prompted at least in part by the rapid ascent of CRISPR-Cas9 — a system that allows scientists to modify genes with unprecedented precision and ease — in biomedical research. Theoretically, the technology could be used to delete or modify harmful disease mutations or even, as some have suggested, enhance desirable traits such as physical strength or intelligence.
In April 2015, researchers at Sun-Yat Sen University in China reported in the journal Protein & Cell that they had used CRISPR-Cas9 to make multiple edits to non-viable human embryos. While the paper found significant problems with the technique, as many unintended edits occurred, many in the science community were aghast that the researchers would undertake such ethically dubious research at all, said Fuki Marie Hisama, MD, FAAN, medical director of the Genetic Medicine Clinic and a professor of medical genetics and neurology at the University of Washington in Seattle. (A ban on federally funded research that involves modifying the human germline is already in effect in the United States, but privately funded research remains legal.)
DR. FUKI MARIE HISAMA: “If you have someone who has a terrible disease and you try an experimental therapy — to which the patient has consented and which has been ethically approved by an institutional review board — on him or her and it doesn't work, that's one thing. But if you start editing the germline, those consequences are quite different. You're potentially affecting other human beings [in future generations] without their permission.”
The organizing committee of the summit wrote in its summary statement that “it would be irresponsible to proceed with any clinical use of germline editing unless and until the relevant safety and efficacy issues have been resolved, based on appropriate understanding and balancing of risks, potential benefits, and alternatives, and there is broad societal consensus about the appropriateness of the proposed application.”
RESPONSE TO THE STATEMENT
The four-point statement issued by the committee emphasized that basic and preclinical research on gene editing in human cells “is clearly needed and should proceed, subject to appropriate legal and ethical rules and oversight.
“If, in the process of research, early human embryos undergo gene editing, the modified cells should not be used to establish a pregnancy,” they added.
The proposed moratorium would not extend to clinical research and therapy involving gene editing in somatic cells — cells whose genomes are not heritable. “Because proposed clinical uses are intended to affect only the individual who receives them, they can be appropriately and rigorously evaluated within existing and evolving regulatory frameworks for gene therapy,” the committee noted.
In an editorial published in Science ahead of the meeting, however, George M. Church, PhD, a geneticist at Harvard Medical School, disputed the committee's position. He argued that “banning human germline editing could put a damper on the best medical research and instead drive the practice underground to black markets and uncontrolled medical tourism, which are fraught with much greater risk and misapplication.”
Germline editing is needed, he said, “because alternative methods for preventing the transmission of inherited diseases are problematic.” Prenatal genetic diagnosis during in vitro fertilization (IVF), for instance, “does not offer a solution for someone who has two copies of a deleterious, dominant version of a gene, nor for potential parents who both have two copies of a harmful, recessive version of a gene,” he wrote.
THE PROCESS OF CRISPR-CAS9 editing, shown here, is in use in many studies involving neurologic disorders. When used for genome editing, this system includes Cas9, CRISPR RNA (crRNA), trans-activating crRNA (tracrRNA), along with an optional section of DNA repair template that guides the cellular repair process, allowing insertion of a specific DNA sequence.
DR. KENNETH H. FISCHBECK said using CRISPR-Cas9 for somatic gene editing has many benefits for research on animal and cellular models of disease. But he said it is less clear how germline editing would fit into clinical research. People with known disease genes or mutations can already use IVF and pre-implantation diagnosis to eliminate the possibility of passing those genes on, he said, so “I can't see why you would want to correct the defect by editing embryos instead.”
But that situation is “exceedingly rare,” said Dr. Hisama. Aside from Dr. Church's hypothetical scenario, IVF and other available reproductive options offer a safe and effective way of ensuring that future generations do not inherit known disease genes without modifying the human germline, she said.
“The most important thing is that we use the technology in a safe and responsible way, and maintain the public trust,” said Dr. Hisama. “Having a moratorium on human germline editing is important for those two principles. If you have someone who has a terrible disease and you try an experimental therapy — to which the patient has consented and which has been ethically approved by an institutional review board — on him or her and it doesn't work, that's one thing. But if you start editing the germline, those consequences are quite different. You're potentially affecting other human beings [in future generations] without their permission.”
THE PROMISE AND PERILS
The benefits of CRISPR-Cas9 for somatic gene editing are manifold. By adding or modifying specific genes or mutations of interest in animal and cellular models of disease, for example, researchers can better study the disease and test new treatments, said Kenneth H. Fischbeck, MD, FAAN, NIH distinguished investigator in the neurogenetics branch at the National Institute of Neurological Disorders and Stroke.
Researchers are also beginning to experiment with silencing or inhibiting known disease genes in animal models. For example, several groups have used gene editing techniques to inhibit the mutant huntingtin gene in mouse models of Huntington's disease. [See the Neurology Today article, “Gene Editing Techniques Show Promise in Silencing or Inhibiting the Mutant Huntington's Disease Gene”: http://bit.ly/HD-gene-editing.]
Less clear is how germline editing would fit into clinical practice. People with known disease genes or mutations can already use IVF and pre-implantation diagnosis to eliminate the possibility of passing those genes on, Dr. Fischbeck noted, so “I can't see why you would want to correct the defect by editing embryos instead.”
Brent Fogel, MD, PhD, director of the Neurogenetics Clinic at the University of California, Los Angeles David Geffen School of Medicine, said, “It is difficult to envision a scenario where the technology would be used clinically in an embryo. In vitro fertilization is simpler and more efficient to prevent passing on pathogenic mutations.”
More importantly, the technique isn't perfect. Grave errors are possible. “The technology is aimed at going into the specific site we want to modify, snipping out the bad sequence, let's say, and replacing it with a normal sequence. The problem is that it's not 100 percent specific,” said Louis Ptacek, MD, a professor of neurology, the John C. Coleman distinguished professor of neurodegenerative diseases, and an investigator in the Howard Hughes Medical Institute at the University of California, San Francisco. “When we do it in mice, we sometimes accidentally affect other sites, which could lead to introduction of a new mutation that could have deleterious consequences.”
“Off-target effects would be a key concern, as there is potential to inactivate a critical gene or create an unintended modification that leads to cancer, for example,” Dr. Fogel said.
That is particularly troubling when it comes to germline editing. “If you make a mistake with somatic [gene] editing, you have harmed that individual. But if you edit the germline, it could spread into the world, and you may not know the effect for a long time,” said Teepu Siddique, MD, FAAN, the Les Turner ALS Foundation/Herbert C. Wenske professor of neurology and clinical science at Northwestern University's Feinberg School of Medicine and a neurologist at Northwestern Memorial Hospital in Chicago. “It could, for example, release endogenous viruses that are [present] in the human and animal genomes. We have to move with great caution and deliberation.”
And other questions remain. “Even if you know the gene and can edit it, is it too late to do it in somebody who is already fully developed? Delivering the right gene to the right cell or the right organ at the right time in the right amount may still be a problem in terms of developing a successful treatment,” said Dr. Hisama. That's something that can be investigated even with a moratorium on human germline editing, she noted.
ETHICAL CONSIDERATIONS
Even if the technology can be developed and refined to the point where it is entirely safe and specific for use in humans, the notion of editing the human germline to create a healthier, “better” human being still raises a number of ethical questions.
DR. LOUIS PTACEK: “The [gene editing] technology is aimed at going into the specific site we want to modify, snipping out the bad sequence, let's say, and replacing it with a normal sequence. The problem is that it's not 100 percent specific. When we do it in mice, we sometimes accidentally affect other sites, which could lead to introduction of a new mutation that could have deleterious consequences.”
DR. TEEPU SIDDIQUE: “If you make a mistake with somatic [gene] editing, you have harmed that individual. But if you edit the germline, it could spread into the world, and you may not know the effect for a long time. It could, for example, release endogenous viruses that are [present] in the human and animal genomes. We have to move with great caution and deliberation.”
For some, it invokes the specter of eugenics. Most people would agree that wiping out a mutation that causes a childhood-onset neurodegenerative disease is worthwhile, said Dr. Ptacek, but the idea of genetic modifications aimed at making an individual “bigger, stronger, faster, smarter,” or editing out certain traits perceived as “undesirable,” raises ethical red flags. “It's a very complicated question, and I think the moratorium is appropriate [while] we discuss the issues at great length,” he said.
In light of these ethical concerns, the call for a moratorium on germline editing “was an important first step,” but the discussion should go even further, said Dr. Siddique. “This is not a wide enough forum,” he said, since germline editing potentially “affects all of humanity.
DR. BRENT FOGEL: “It is difficult to envision a scenario where the technology would be used clinically in an embryo. In vitro fertilization is simpler and more efficient to prevent passing on pathogenic mutations.”
“Science must go forth, but we must have ethical constraints that will not allow abuse of this [technology].” For example, he said, “you could eliminate entire populations, or make them sick or ill. You could introduce degenerative diseases, [make people] vulnerable to infection, god knows what.”
Others felt those concerns were still very far off. “We know what mutations cause people to be worse, but we don't have a clear idea of how we would make people ‘better,’” said Dr. Fischbeck. For example, “there are a lot of genes linked to developmental disability. But I think ‘better’ intelligence may just be a lack of variants that cause impairment.
“I don't think we could enhance human performance with this technique any time soon, even if we wanted to,” he said. “But it is a really powerful tool for understanding disease mechanisms and thereby developing better diagnosis and ultimately treatment for hereditary neurologic diseases.”
