I met two-year-old Jameson Golliday on a patch of lawn in Bloomington, Illinios. He had blue eyes, dark hair, and wore a striped shirt, shorts, and Crocs. He followed his mother, Jennifer, 31, as she pushed a wheelbarrow around the yard, picking up sticks. The neighbors were burning lawn debris and fly ash was swirling in the sky, big fluffy flakes, falling lightly all around us. Jameson’s brother, Shawn, 5, was wearing a Star Wars t-shirt and tossed a plastic sword to his grandfather. There was the bat-bat of plastic, and things quickly turned Galactic.
Jamie and his mother retreated to a quiet spot in the yard. She lets him run free in the backyard, but he can’t play with other children or touch high-contact surfaces such as playground equipment.
“It’s super sad,” Jennifer told me. “He sees kids off in the distance and points at them. I know he wants to interact.”
Jamie was born with X-SCID, or "bubble boy disease," which means he has no immune system. At birth he had no mature T-cells, the rugged soldiers of the immune system that sense and fight infections, due to mutations in the IL-2 gene on his X-chromosome, which rendered the gene non-functional.
David Vetter was the most famous bubble boy. In the 1970s and 1980s he lived in a bubble, using only items sterilized with 140-degree ethylene oxide gas. Doctors tried a bone marrow transplant from his sister to introduce working T-cells into his system. But the Epstein-Barr virus was sleeping in the marrow, and it triggered the growth of many tumors. Vetter died at age 12.
When Jamie was born he had a small cough, but unlike most colds, it didn’t go away, not for a year. His mom noticed a bump on his hip one day, which turned out to be a cluster of B-cells unsuccessfully trying to fight an infection. This clustering looked like cancer, and caused doctors to diagnose Jamie with diffuse B-cell lymphoma, which is very uncommon in infants. Later tests revealed Jamie’s illness for what it was—X-SCID.
In April 2012, not long after Jamie’s diagnosis, Jennifer and Jamie, then 1, took a medical jet to Cincinnati Children’s Hospital, so that Jamie could participate in a trial for gene therapy—a treatment that wasn’t available in David Vetter’s time. Jennifer improvised a ‘bubble stroller’ out of a rain tarp and a baby stroller, to transport him back and forth between the hospital and the Ronald McDonald House where they stayed in Cincinnati. Inside, he wore a surgical mask.
Doctors drew some of Jamie’s bone marrow, and dosed it with a virus carrying the IL-2 gene. The virus serves as a tiny pilot, carrying the payload of the IL-2 gene into his cells, installing it in his genome. That gene builds a protein called a cytokine, which sends a signal telling T-cells to mature. Weeks after Jamie received his shiny new IL-2 gene, a blood test showed 13 mature T-cells per microliter, where before he’d had none.
Jamie’s cold soon vanished. “It was our first victory,” Jennifer said.
The ash continued to fall. Jamie quietly colored with chalk on the driveway. Shawn’s grandfather was on the defense in the light saber fight, and the Galactic battle shifted to the front yard. Shawn had become oppositional since he had to leave school when a classmate became sick. He couldn’t risk bringing a cold home to his brother. But Shawn will soon be back in school. With Jamie’s T-cell count on the rise, he could cautiously explore his grandfather’s yard, loose of masks and bubble strollers,
Jamie still wasn’t allowed to interact with people outside his family. But still he romped up to me, and thrust his tiny arm skyward.
“What’s he doing?” I asked his mom.
“I think he wants to hold your hand,” she said.
The First Tools
In 1982, Richard C. Mulligan was at MIT when he deleted an element in a gamma retrovirus called psi, which was used by the virus to package itself to travel to new places. He gutted the virus of its contents, and in its place he installed a human gene. He had developed the first tool for genetic engineering: a virus with a one-way ticket to the human genome that could not move to a new address. It would sit tight and publish copies of the gene he installed, and its first task would be to treat X-SCID patients.
But problems soon arose. Mulligan had no way to tell the virus where to install. It might integrate near a cell cycle gene and boost the signal for cell division, leading to uncontrolled cell growth. By the year 2000, twenty X-SCID patients had been treated with the tool, but five of those patients developed leukemia-like conditions. One of those patients died.
David A. Williams, chief of hematology at Boston Children’s Hospital, was one of Mulligan’s post-doc students at MIT. By the time leukemia developed in the X-SCID patients, he was working at Cincinnati Children’s with Christopher Baum, and the two scientists thought up an elegant solution.
Genes have switches called promoters and enhancers that control when a gene gets turned on, and how strongly it gets expressed. It turns out that gamma retrovirus has very potent forms of these switches, and if, per chance, the virus installs near a cell cycle gene, those switches turn up the volume on cell division.
Williams and Baum deleted those switches, and installed a weaker version of a promoter. The theory was that even if the virus did install next to a cancer-related gene, it might not cause cancer.
Jamie Golliday was one of four children treated with the new tool in the U.S.
“I heard about success with early trials in England, and I thought, if he has a bone marrow transplant, he might have to have chemo anyway,” Jennifer says. “I was willing to risk it.”
It has been two years since the new group of patients began treatment with the “safer” gamma retrovirus. None have yet developed leukemia. “It’s still early,” Williams cautions. In the previous trials, it took three years for the first signs of a cancer to show up.
Jennifer Golliday took walks, she picked up sticks, sidewalk chalk and light sabers… and she waited.
Gene Therapy 2.0
Bluebird Bio, Inc’s chief scientific officer Mitch Finer believes that gamma retrovirus is the past. His company is now using a virus called lentivirus to deliver and install genes.
Finer explained that Baum developed a test to show that lentivirus has a 30 to 100-fold reduction in causing cancer cells compared to gamma retrovirus. He also showed why: gamma retroviruses like to install near cell cycle genes, where they can switch on cell growth. That’s not surprising, since viruses naturally want cells to create millions of copies of them.
Baum found that lentiviruses, in particular a defanged HIV-1 virus, do not thrust cells into growth modes. Baum pinpointed where the lentivirus was installing, and it had no preference for cell cycle genes. So, Bluebird would hang its hat on lentivirus.
David Williams is preparing to supervise a trial with Bluebird using lentivirus to install a gene to replace a missing enzyme in patients with adrenoleukodystrophy at Boston Children’s Hospital. In 2009 researchers at San Raffaele-Telethon Institute for Gene Therapy in Milan, Italy performed a similar pilot study, and it and the virus stopped the disease in its tracks. Then last month, the institute reported success in using lentivirus to treat metachromatic leukodystrophy, another enzyme deficiency disorder.
But despite a number of promising trials, the Food and Drug Administration still has not approved a gene therapy drug for market in the U.S.
“What has been missing, oddly, is the ability of industry to come forth with large reproducible clinical trials,” Mulligan says. “Big companies were not interested, at least initially, in very rare diseases. This is honestly the reason things did not move faster.”
But Bluebird and several other researchers now have their eyes using gene therapy to target blood and immune system cancers, and even solid-state tumors. And cancer cures mean dollars.
With safe viruses that appear to be working, and the return of biotech investment after deaths halted research a decade ago, David Williams predicts the FDA will approve the first gene therapy drug in the U.S. within the next five years.
Back in Bloomington
The Resistance was confident about its position in the light saber fight against its grandfather. Shawn chucked his sword into a tree, and sat down on a swinging chair in the front yard.
Ms. Baird, Shawn’s former preschool teacher, stopped by on a walk.
“We didn’t even know she lived in the neighborhood,” his grandfather said.
Shawn loved his teacher, and after leaving school, he became obsessed with hand sanitizer. “He’s just so scared he’s going to bring something home, and his brother is going to get sick and it’s going to be his fault,” Jennifer said. Shawn was afraid his mom would go back to Cincinnati and he’d lose her again. But since his mom returned home, Shawn’s been calming down.
Jamie hid his eyes when Ms. Baird approached. Jennifer’s theory is that he associates unknown women with nurses and expects them to poke him with a needle. Though he’s free of the bubble, Jamie still has a port in his chest, which nurses use to inject mature antibodies into his system, every few weeks, until his immune system's T-cells become strong and numerous enough to signal Jamie’s B-cells to produce those antibodies.
Shawn will begin kindergarten this month.. He sat quietly on the bench, thinking about school.
“I’m excited,” he said.
Jamie might even attend preschool on regular schedule, according to his mom.
But on this day, there was no school. The sky looked big, the yard ran forever, and Jamie was scribbling chalk on the sidewalk, exploring a world outside the bubble.
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