On Monday a story in the British newspaper The Independent had this breathless lede: “Scientists in the UK will be allowed to genetically modify human embryos for the first time in history, after they received a licence to go ahead with groundbreaking research into the early stages of human life.” Few in the scientific community would find this earth-shattering.
For one thing, the proposed research, to be performed at London’s Francis Crick Institute, is intended only to understand how the various genetic events that occur during the first week after fertilization affect the growth and behavior of embryos. (Many embryos fail and are lost during that period.) The work will not be permitted to extend to implanting the altered embryos into women, so no pregnancies will result. Second, it represents only a baby step toward the ultimate goal — eliminating terrible lethal genetic diseases from families through germ-line gene therapy, which is discussed below.
And finally, this is not a first. Chinese researchers last May published the results of similar experiments — a partially successful proof-of-principle attempt to perform “gene editing” on embryos in order to correct the genetic defect that causes a blood disorder called beta thalassemia. They used gene-editing system called CRISPR-Cas9, the same technique that will be employed by the British researchers. It should be noted that the Chinese group edited embryos that were non-viable and going to be discarded in any case, and the British scientists will use embryos from an in-vitro-fertilization facility that were also to be discarded.
Human-gene therapy has been one of the most ambitious goals of biotechnology since the advent of molecular techniques for genetic modification in the 1970s.
Human-gene therapy has been one of the most ambitious goals of biotechnology since the advent of molecular techniques for genetic modification in the 1970s. There are two distinct approaches, which present different kinds of benefits, risks, and controversies. Somatic-cell human-gene therapy (SHGT) alters a patient’s genes, either by the editing of existing genes or the insertion of new ones, to correct conditions present at birth or acquired later in life. Somatic cells are any cells in the body except eggs or sperm, so modifications in them are not heritable — that is, passed on to offspring and subsequent generations.
Since a four-year-old with a genetic defect called “severe combined immunodeficiency,” or “bubble-boy disease,” was first successfully treated at the National Institutes of Health in 1990, SHGT has achieved several other successes, including the correction of rare genetic abnormalities that cause recurring pancreatitis and blindness from choroideremia, a disease involving degeneration of the retina.
#share#Up to now, gene therapy has been of a type that affects only the patient being treated but does not modify sperm, eggs, or embryos in a way that would constitute germ-line gene therapy. That is, it does not create a heritable change that will affect future generations. However, the published report by the Chinese researchers last May was a step in that direction.
The Chinese experiment precipitated consternation in part of the scientific community, with some researchers and bioethicists calling for a ban on attempts to treat even imminently lethal diseases with gene-editing techniques that would modify germ cells. The move toward prohibition gained ground at a conference held in Washington, D.C., in December under the auspices of national academies of science and medicine of China, the United Kingdom, and the United States. The attendees called for what amounts to a moratorium on the gene editing of embryos that would be implanted and lead to a pregnancy, concluding that it would be “irresponsible to proceed” until the risks were better understood and until there was a “broad societal consensus” about such clinical research. However, those recommendations were by no means authoritative, and they raise the question whether societal consensus is appropriate for policy decisions that require difficult, complex scientific assessments of risks and benefits.
It is certainly unethical to modify normal embryos prior to implantation, but nobody is proposing to do that. Diseases that are genetically dominant, in which an abnormal gene from either parent causes the disease — examples include Huntington’s disease, familial hypercholesterolemia, polycystic kidney disease, and neurofibromatosis type 1 (the last three are relatively common) — are easily approachable without modifying embryos. One can simply perform pre-implantation genetic diagnosis to identify a normal embryo (the parents’ eggs and sperm would produce both affected and unaffected embryos) and then implant it in the uterus.
There is no need, therefore, to risk manipulating normal embryos. In fact, to perform germ-line gene therapy, it may not even be necessary to manipulate abnormal embryos, because other approaches are available, including generating normal sperm from abnormal ones via tissue culture and gene editing, or culturing abnormal germ-line stem cells outside the body and correcting them with gene editing.
There is an urgent need for germ-line gene therapy — for example, to correct debilitating and ultimately lethal sickle-cell anemia, the most common inherited blood disorder in the United States, which affects more than 100,000 patients. The abnormal erythrocyte “sickle cells” (so called because of their shape) obstruct small blood vessels, causing frequent infections, pain in the limbs, and damage to various organs, including the lungs, kidneys, spleen, and brain.
In genetics terms, sickle-cell anemia is an autosomal recessive disease, which means that an affected individual has inherited a defective hemoglobin gene from both parents, so every one of his or her sets of chromosomes carries a defective gene. (That results in a single aberrant amino acid being inserted into the hemoglobin protein.) It is noteworthy that every offspring of two patients with sickle-cell disease will be afflicted with the disease. Repair of this sort of molecular defect has been performed successfully in monkeys, with new, highly precise gene-editing techniques.
Progress in this field is extraordinarily rapid. Two articles published in December demonstrated an even higher degree of precision and specificity of gene editing than was previously possible, and that anomalous cuts in DNA made by CRISPR-Cas9 can now be reduced to fewer than one per 3 trillion base pairs of DNA. (The human genome is 3 billion base pairs in length.)
Such constant improvements serve as a reminder that technologies are seldom successful right out of the gate; as they’re applied and refined, they improve, sometimes with astonishing rapidity. When I was a medical student during the 1970s, bone-marrow transplantation was being performed in only a few institutions and as a last resort, and the success rate was abysmal. But the discovery of potent immunosuppressants and other technical advances improved the success rate markedly, and bone-marrow transplants are now routine in many institutions. Some leukemias that were once a death sentence now have cure rates around 90 percent. There are many similar stories in medicine, including open-heart surgery, which was remarkably primitive in its earliest incarnation but is now common and usually uneventful.
Interventions that involve germ-line gene therapy should be used sparingly and with scrutiny, to be sure, but if we don’t take the first small step — learning how to modify embryos precisely and reproducibly and implanting them — we’ll never reach the goal of ridding families of hideous genetic diseases.