That’s unlikely, but the significance of Bennett’s trailblazing work is not. Hundreds of patients have received gene therapy for ocular diseases since the LCA trial. Bennett hopes that her model will help to develop therapies for other blindness disorders, named after notable ophthalmologists such as Karl Stargardt, Friedrich Best, and Charles Usher. Bennett and Maguire continue their research at the new Center for Advanced Retinal and Ocular Therapeutics, or CAROT for short.
Luxturna was not the first gene therapy to make it through the roller-coaster ride to approval. The first drug was actually Glybera, which was approved in Europe for an ultra-rare disorder called lipoprotein lipase deficiency, resulting in patients essentially having heavy cream in their bloodstream. Manufactured by UniQure, the therapy earned the inglorious mantle of “world’s most expensive drug.” The European market could not support a $1.5 million price and it was subsequently withdrawn, having been administered to just one patient in Berlin.
But drugs like Strimvelis for severe combined immune deficiency (SCID) and Zolgensma for spinal muscular atrophy (SMA), coupled to success in developing CAR-T immunotherapies (Kymriah and Yescarta), signal a new era for gene and cell therapy. There were more than nine hundred registered gene therapies with the FDA at the beginning of 2020. UC Berkeley’s David Schaffer put it nicely: “After twenty years, gene therapy is an overnight success.”11
In late 2017, I invited Shakir Cannon, an African American patient advocate, to write a personal essay for the inaugural issue of a new science journal dedicated to all things CRISPR.II I had heard Cannon speak at the first CRISPRcon meeting at Berkeley about his struggles with sickle-cell disease (SCD) and his hopes that CRISPR might one day prove an effective therapy, if not a cure. His personal motto was, “Any day without pain is a good day.” He accepted my invitation, signing his email “Thankful.” After a few weeks, I reached out for an update. My emails went unanswered.
Then I heard the awful news. Shakir had died suddenly on December 5, 2017, of pneumonia, just thirty-four years of age. Shakir was one of 100,000 Americans and an estimated 20 million affected worldwide, primarily in Africa and parts of Asia. Together with other mutations in the beta-globin gene resulting in beta thalassemia, these are some of the most common genetic diseases on the planet. Each year 300,000 SCD babies are born.
SCD is a recessive disorder caused by the inheritance of a faulty gene from each parent. Hemoglobin, the protein that carries oxygen in our body, is made up of a quartet of peptide chains—a pair of alpha chains and a pair of beta chains. A tiny mutation, the switch of a T for an A in the beta-globin gene, produces a misformed protein that clumps together. This results in the red blood cells, normally a beautiful flexible biconcave shape, deforming to form rigid sickle-shaped cells that are prone to aggregate and block normal blood flow. Across Africa, SCD has various names—Ahututuo, Chwecheechwe, Nuidudui, Nwiiwii. Roughly translated, they mean “beaten up,” “body biting,” or “body chewing.” About 30 percent of adults with SCD experience debilitating pain every day, in some cases requiring heavy doses of prescription painkillers. “It’s like having your hand slammed in a car door, but instead of it lasting for a few seconds, it lasts for weeks,” said one patient.
Shakir’s short life is a case in point. At age three, Shakir had a stroke, which he overcame with years of physical therapy. Once a month he skipped school to have a blood transfusion. Every night, he received a subcutaneous injection of a drug called Desferal. A portacath was implanted in his chest to help the injections (classmates joked it was his third nipple). He received growth hormone injections because of his short stature. While attending a basketball game with a friend, Shakir experienced a pain crisis so severe he could barely breathe or talk. His parents rushed him to the emergency room at Albany Medical Center, where he stayed for a week.12 Despite this, Shakir cofounded the Minority Coalition for Precision Medicine and accepted an invitation from the Obama administration to present at the White House.13
While the average SCD patient lifespan in the United States is about forty, in Africa most sickle-cell children don’t reach double digits. So why is this deadly disease so prevalent? Sickle-cell carriers (one mutant, one normal beta-globin gene) are inherently resistant to malaria, which kills 500,000 people in Africa each year. This “heterozygous advantage” provides a life-saving selective advantage like a built-in vaccine for SCD carriers and ensures that the sickle-cell gene continues to thrive in areas of the world prone to malaria.
“Blood is by far the most common cell in the body, so it’s not surprising that critters want to feed on blood,” says Merlin Crossley, a geneticist at the University of New South Wales in Sydney. There are about 100 trillion mosquitoes spread across most inhabited areas of the planet. Only a few species spread disease however, and of those, it is only the female mosquitoes that enjoy sucking human blood. In so doing, Crossley’s critters, chiefly Anopheles gambiae, transmit parasites such as Plasmodium falciparum, which causes malaria.
Recent analysis suggests that the SCD mutation first arose in a newborn in West Africa some 7,300 years ago, during the African humid period.14 That infant unknowingly possessed a stealthy superpower: (s)he would be resistant to malaria, greatly increasing the chances of reaching reproductive age—and a 50:50 chance of passing the same trait onto his or her children. Over the subsequent 250 or so generations to the present day, that single mutation has spread around the globe, especially in Africa, the Mediterranean and Asia, areas devastated by malaria.III Today it is estimated that 5 percent of the world population carries the sickle-cell trait or another mutation in the beta-globin gene.
We know more about SCD than almost any of the other 6,000 or more documented genetic disorders. The disease was first described by Chicago physician James Herrick in 1910.15 Herrick reported “freakish” cells in a blood sample from “an intelligent negro of 20”—actually Walter Noel, a dental student from Grenada. Subsequent case reports with multiple affected siblings pointed to a genetic basis. The editors of the Journal of the American Medical Association made a striking pronouncement in 1947:
The most significant feature of sickle cell anemia is not its characteristic bizarre deformation of erythrocytes but the fact that it is apparently the only known disease that is completely confined to a single race… [SCD] is independent of either geography or customs and habits. Its occurrence depends entirely on the presence of Negro blood, even though in extremely small amounts.16
Two years later, Nobel laureate Linus Pauling discovered that extracted red blood cell proteins from SCD patients ran differently in a gel than healthy controls, predicting (correctly) that the hemoglobin molecule in SCD patients (HbS) carried two additional positive charges. Pauling proposed that SCD was “a disease of the hemoglobin molecule”—the first molecular disease. His prediction was confirmed when a South African physician scientist, Anthony Allison, showed that sickle-cell carriers were resistant to the malaria parasite.17
Vernon IngramIV was a German national who immigrated to the United Kingdom as a teenager one year before World War II. In 1957, Ingram was able to zoom into the amino-acid sequence of the globin chains to pinpoint the molecular aberration in SCD predicted by Pauling—a single amino-acid alteration (glutamic acid to valine) in the beta globin chain. Ingram made his breakthrough at the Cavendish Laboratory in Cambridge, where Crick and Watson had assembled the double helix four years earlier, although Ingram’s lab was a converted bicycle shed.18 A decade later, Makio Murayama showed how the appearance of that rogue valine residue creates a hydrophobic surface that enables the sickle chains to clump together forming stiff polymers.