Is Medicine Ready for Clinical CRISPR?

OXFORD UNIVERSITY PRESS, AUGUST 2016CRISPR-Cas9 genome editing has the potential to transform medicine in several important ways. First, the technique makes it possible to manipulate genes in a variety of mammals to create models of human health and disease. Previously, only mice could be engineered in this way, but genome editing has made it possible to precisely modify the genomes of almost any mammal. Because pig hearts or monkey brains are far more similar to their respective human organs than those of mice, this should have a major impact on our ability to understand the genetic basis of heart disease and various mental disorders. But such developments are likely to be controversial because of opposition by some people to experimentation on primates. Another way that genome editing affects medicine is by facilitating the study of physiological or pathological processes in human cells in culture. Using genome editing to precisely manipulate the genomes of human cells in vitro is making it possible to identify the genes involved in normal human physiology and in various types of human disease. I discuss these and other transformative applications of CRISPR-Cas9 genome editing in my new book Redesigning Life: How Genome Editing Will Transform the World. One particularly exciting development exists at the intersection of genome editing and stem cell technology. Pluripotent stem cells have the potential to develop into any cell type in the body. They can be isolated from human embryos as embryonic stem (ES) cells, or by activating specific genes in adult human cells to generate induced pluripotent stem (iPS) cells. Recently, scientists have coaxed ES and iPS cells to develop into organoids—structures resembling tissues from the eye, gut, kidney, pancreas, prostate, lung, stomach, breast, and even the brain. And genome editing is making it possible to manipulate such organoids so that they can provide insights into human embryo development or serve as disease models and drug-screening platforms. Su-Chun Zhang of the University of Wisconsin–Madison said in a statement released this summer that, “This marriage between human stem cells and genome editing technology will revolutionize the way we do science.” A team led by Pablo Ross at the University of California, Davis, recently used CRISPR-Cas9 to engineer pig embryos so that they could no longer grow a pancreas. Injecting human iPS cells into the embryos encouraged the growth of a rudimentary human pancreas. “Our hope is that this pig embryo will develop normally, but the pancreas will be made almost exclusively out of human cells and could be compatible with a patient for transplantation,” Ross recently told BBC News. Engineering stem cells to create human organs for transplant surgery is one potential direction for genome editing; another is to use the technology to correct genetic defects that underlie some human diseases. Recent studies have shown the potential of genome editing to repair the genetic defects in the genes for dystrophin and huntingtin, which cause Duchenne muscular dystrophy and Huntington’s disease, respectively. Citing successful animal studies, US regulators have green-lighted clinical trials that use genome editing to treat cancer and are considering trials of CRISPR-based treatments for a form of hereditary blindness. Some aspects of CRISPR’s incursion into the clinic are proving controversial. There is currently a debate taking place about the potential risks of this type of gene therapy. As Laurie Zoloth, a bioethicist at Northwestern University, recently told Nature: “Any first use in humans we have to be extraordinarily careful.” One particular concern is whether genome editing is accurate enough not to result in potentially adverse off-target effects in other parts of the genome than the targeted gene defect. Could introduced human cells, such as those iPS cells introduced into pigs, affect brain development or have other troubling, off-target effects in a recipient animal? Another bioethicist, Mildred Cho of Stanford University, believes that studies in animals can only take clinical research so far. “Often we have to take the leap of faith,” she told Nature. John Parrington is an associate professor in cellular and molecular pharmacology at the University of Oxford. Read an excerpt of Redesigning Life.