Victoria Gray (right), shown with researcher Haydar Frangoul, was the first patient to be treated with the -editing tool CRISPR for sickle cell disease.

protects blood cells from malaria parasites.) People with beta-thalassemia make little or no functioning because of mutations that affect the same subunit of the as in sickle cell. About 60,000 babies are born each year globally with symptoms of the disease, largely of Mediterranean, Middle Eastern, and South Asian ancestry. Blood transfusions are standard treatment for both diseases, relieving the severe anemia they can cause, and drugs can somewhat reduce the debilitating “crises” that often hospitalize sickle cell patients. In the two new treatments, investigators have tinkered with to counter the mal- functioning hemoglobin. They remove a pa- Downloaded from tient’s blood stem cells and, in the lab, disable a genetic switch called BCL11A that shuts off the gene for a fetal form of hemoglobin early in life. The patient then receives chemo- therapy to wipe out their diseased cells, and IN DEPTH the altered stem cells are infused. With the http://science.sciencemag.org/ fetal gene now active, the fetal protein re- stores missing hemoglobin in thalassemia. In sickle cell disease it replaces some of the BIOMEDICINE flawed adult hemoglobin, and also blocks any that remains from forming sticky polymers. “It’s enough to dilute the effect,” says Tweaking genes with CRISPR Samarth Kulkarni, CEO of CRISPR Thera- peutics, which partnered with Vertex Phar- maceuticals on using the genome editor.

The companies engineered CRISPR’s DNA- or viruses fixes blood disorders on December 10, 2020 cutting enzyme and “guide RNA” to home in People with sickle cell disease or beta-thalassemia could on and break the BCL11A gene. A team led be freed of debilitating symptoms for a lifetime by gene therapy researcher David Williams of Boston Children’s Hospital achieved the same goal with a harmless virus that pasted into By Jocelyn Kaiser the same safety issues as those transplants, the genomes of harvested blood stem cells a and may also be extraordinarily expensive, stretch of DNA encoding RNA that silences t is a double milestone: new evidence that but there is hope those risks can be elimi- the off switch. cures are possible for many people born nated and the costs pared down. “This is an Patients treated in both trials have begun with sickle cell disease and another seri- amazing time, and it’s exciting because it’s to make sufficiently high levels of fetal hemo- ous blood disorder, beta-thalassemia, and happening all at once,” says hematologist globin and no longer have sickle cell crises or, a first for the genome editor CRISPR. Alexis Thompson of Northwestern Univer- except in one case, a need for transfusions. In Two strategies for directly fixing mal- sity, who with a company called Bluebird Bio one NEJM paper, the Boston Children’s team Ifunctioning blood cells have dramatically continues to test yet another genetic strategy described the success of its virus gene ther- improved the health of a handful of people that first demonstrated a sickle cell fix several apy in six sickle cell patients treated for at with these genetic diseases, teams reported years ago. least 6 months. They include a teenager who online on 5 December in studies in The New People born with sickle cell disease have can now swim without pain, and a young England Journal of Medicine (NEJM) and at mutations in their two copies of a gene for man who once needed transfusions but has the American Society of Hematology (ASH) hemoglobin, the oxygen-carrying protein in gone without them for nearly 2.5 years, says meeting. One relies on CRISPR, marking the red blood cells. The altered stiffen Erica Esrick of Boston Children’s. “He feels first inherited disease clearly helped by the the normally flexible cells into a sickle perfectly normal.” powerful tool created just 8 years ago. And shape. The cells can clog blood vessels, trig- The first sickle cell patient to receive both treatments are among a wave of genetic gering severe pain and raising the risk of or- CRISPR, 17 months ago, a Mississippi mother strategies poised to expand who can get du- gan damage and strokes. Sickle cell disease of four named Victoria Gray, has called the re- rable relief from the blood disorders. The is among the most common inherited dis- sults “wonderful.” “We have ameliorated the only current cure, a bone marrow transplant, eases, affecting 100,000 Black people in the symptoms,” says Haydar Frangoul, a hemato- is risky, and matched donors are often scarce. United States alone. (The sickling mutations logist at the Sarah Cannon Research Insti-

The novel genetic treatments have many of became widespread in Africa, as one copy tute who treated Gray as part of the CRISPR CENTENNIAL TRISTAR AT HOSPITAL CHILDREN’S INSTITUTE/THE RESEARCH CANNON STULTS/SARAH AMANDA PHOTO:

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trial. A beta-thalassemia patient treated with BIODIVERSITY the genome editor 22 months ago is also doing well, the companies report in NEJM. Frangoul described positive results for 10 pa- Spare a thought for the teeming tients with these diseases at the ASH meeting. The CRISPR results “are really very im- pressive,” says Boston Children’s stem cell ecosystem beneath your feet biologist Stuart Orkin, whose lab discovered the BCL11A switch that led to both trials. (He Global review of soil biodiversity calls for protecting is not involved with either.) often overlooked subterranean life The results are comparable to those of the Bluebird strategy, which relies on adding a gene for an adult hemoglobin that has been By Elizabeth Pennisi “The organisms below ground are argu- tweaked so it reduces polymerization of the ably just as important, if not more impor- sickling form. Among 32 sickle cell disease each down and scoop up some tant, than what’s above ground,” says Noah patients who received the treatment within soil. Cupped in your hands may be Fierer, a soil ecologist at the University of the past 3 years, 19 who previously experi- 5000 different kinds of creatures— Colorado, Boulder, who did not contribute enced severe pain crises have had none for and as many individual cells as to the report. It details how life in the soil 6 months or more, Thompson reported at the there are humans on the globe. That boosts crop growth and purifies soil and ASH meeting. The Bluebird treatment was random handful might hold micro- water. Together with plant root systems, Downloaded from approved in Europe in 2019 for certain beta- Rscopic fungi, decomposing plant matter, a soil organisms store more carbon, poten- thalassemia patients, and the firm expects to whisker-size nematode munching on the tially for longer, than the aboveground seek U.S. approval for both diseases in the fungi, and a predatory, pinhead-size mite parts of trees do. “Depending on how we next few years. Bluebird Chief Scientific Of- about to pounce on the nematode. One handle soil, it could become a help or a ficer Philip Gregory says the long-term data bacterium may fend off another with a po- burden to face the crisis of biodiversity or

for the firm’s methods is an advantage over tent antibiotic. It’s a whole world of often climate change,” says Francisco Pugnaire, http://science.sciencemag.org/ other approaches. “We’ve set a very high bar.” overlooked biodiversity. a soil and plant ecologist at the Spanish Others who treat these diseases say it’s too Last week, on the eve of World Soil Day, National Research Council’s Experimental early to crown a specific genetic treatment the Food and Agriculture Organization of Station of Arid Zones. the winner. For example, reversing the fetal the United Nations released its first ever Yet with each pass of the bulldozer or hemoglobin off switch, as the new CRISPR global assessment of the biodiversity in this tractor, each forest fire, each oil spill, even and RNA-based gene therapy strategies do, underground world. Some 300 experts have the constant traffic of hikers along a popu- allows blood cells to make natural levels of pooled their knowledge and data to describe lar trail, more and more soil organisms are the protein, unlike Bluebird’s approach. And the diversity of these organisms, the roles being killed off. By compiling research on although a virus-carrying gene can land in they play in both natural and agricultural these subterranean ecosystems and how

the wrong place and trigger cancer, CRISPR environments, and the threats they face. they affect visible ones, the report’s au- on December 10, 2020 could in theory similarly make harmful off- thors hope to convince scientists, policy- target edits. “We need long-term follow-up” makers, and the general public to take for all the strategies, says the National Insti- steps to slow this loss. tutes of Health’s (NIH’s) John Tisdale, a co- “You just can’t have a Mars-like soil and leader of the Bluebird study. expect to maintain the food supply and These genetic treatments, as currently forests,” warns Diana Wall, an ecologist at practiced, seem unlikely to help the many Colorado State University who contributed patients worldwide who don’t have access to to the report. Current conservation efforts sophisticated health care. Bluebird expects to are not helping much, she adds. For exam- charge $1.8 million for its beta-thalassemia ple, soil biodiversity hot spots aren’t neces- product in Europe—a sum it bases on a pa- sarily in the same place as the biodiversity tient’s gains in life span and quality of life— hot spots that conservationists focus on. and the other genetic treatments are likely to “We are managing [conservation] by what be similarly expensive. we see above ground, which doesn’t nec- Bluebird and other groups are exploring essarily match what’s below ground.” In whether antibodies, instead of harsh chemo- contrast, Fierer says, “If you preserve therapy, can wipe out a patient’s mutant cells. the soil, you will likely preserve the In a bolder effort to reduce costs and increase whole ecosystem.” safety, NIH and the Bill & Melinda Gates Soil is a mix of organic material, miner- Foundation last year announced a plan to als, gases, and other components that pro- each put at least $100 million into developing vide the substrate for plants to grow. About technologies that would modify blood stem 40% of all animals find food, shelter, or ref- cells directly in a patient’s blood marrow. “It’s uge in soil during part of their life cycle. a big hairy goal, but it’s an engineering chal- Scientists have mostly focused on the lenge,” says gene therapy researcher Donald largest and smallest soil creatures. For Kohn of the University of California, Los An- centuries, natural historians have ob- geles, who leads another sickle cell treatment A complex dance among microbes, plants, and served the moles, earthworms, ants, and j PHOTO: © MATTEO SALA © MATTEO PHOTO: trial. “We’ll get there.” arthropods and other animals sustains soil ecosystems. termites that chew, wiggle, and dig their

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