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Genetic Linkage

Gene Therapy and the 10,000-Hour Rule

“Breakthroughs” in biomedicine are rarely that – they typically rest on a decade or more of experiments. Consider gene therapy.

I just unearthed an article from the December 1990 issue of Biology Digest, "Gene Therapy." I wrote it a mere two months after the very first gene therapy experiment, the much-publicized case of 4-year-old Ashi DeSilva, who had a form of severe combined immune deficiency (ADA deficiency). Although Ashi is alive and well, whether or not her good health stems from the infusions of her own doctored white blood cells so many years ago isn’t clear, because she had enzyme replacement therapy (PEG-ADA) at the same time, in case the experiment failed.

One person who has no doubt that Ashi’s gene therapy worked is the physician-scientist who gave it to her, William French Anderson. "It certainly saved Ashi. She had approximately 20% gene corrected T-cells in spite of the inhibitory effect of PEG-ADA," he wrote to me while I was writing my
upcoming book

Dr. Anderson meticulously edited my typed manuscript in pencil from prison, where he is serving a 14-year sentence. When he read the part about researchers questioning whether Ashi’s gene therapy had worked, he implored me to track down the other two researchers to obtain the results of her blood tests over the years. That was the only way to tell if the genetic correction had been maintained. I failed, and so whether the gene therapy from 1990 actually worked may be lost to history. However, UCLA’s Donald Kohn has recently perfected gene therapy for kids with Ashi’s disease. He’s been working on it since the early 1990s too.

Back in 1990, just after the first gene therapy experiment and as the human genome project was transitioning from dream to reality, the researchers I spoke to for my Biology Digest article were enthusiastic. One of Ashi’s doctors predicted gene therapy for cystic fibrosis (CF) within six years. That didn’t happen. FDA will announce the fate of a promising new treatment for CF from Vertex Pharmaceuticals in April 2012. But Kalydeco (ivacaftor) targets the errant protein in the disease, not the underlying faulty genetic instructions. It must be taken daily.

Predicted another ebullient gene therapy guru in 1990, “No one is shy about using the words ‘gene therapy’ anymore. It’s a certainty now that disease will be treated at the level of the genes. Many of the conceptual and public policy hurdles have now been cleared. The remaining questions are largely technical – what disease to pursue, and when.”

If only it had been that simple. Science rarely is. Gene therapy hit bumps in the road to the clinic, some minor, others catastrophic.

Ashi’s gene therapy came from her bloodstream, tapping into the ability of many cell types to know better where they should go than we do. Other routes proved more problematical. For some diseases, like CF, gene-corrected cells were shed too quickly to alleviate symptoms. For others, such as the muscular dystrophies, fixing enough cells in enough muscles was too difficult.

Then in 1999, the viruses carrying healing genes into the liver of 18-year-old Jesse Gelsinger detoured into his immune system cells, killing him in just days. As many gene therapy trials screeched to a halt, researchers in France gave gene therapy to two baby boys with an inherited immune deficiency called SCID-X1, using viruses that delivered their healing cargo, but also disrupted an oncogene. Two years later, when one of the boys developed leukemia and would ultimately die of it, and then others developed it too, the field of gene therapy, desperately trying to get back on its wobbly feet, slowed again.

Although clinical trials stopped, researchers kept right on finding new viruses and conducting animal experiments, so that within a few years, the successes began. And they were startling.

By 2007, the first young people given genes to correct their retinal disease (Leber congenital amaurosis type 2) left no doubt that gene therapy works: an 18-year-old could suddenly walk in the early evening without crashing into things; a young woman could see the green lights on the clock in a car; and most dramatic of all, 8-year-old Corey Haas screamed when looking up at the sky at the Philadelphia zoo just 4 days after his gene therapy – it was the first time he’d seen the sun, and the glare hurt and frightened him. Gene therapies for other diseases have followed at a slow but steady pace.

Corey’s newfound vision at the zoo opens my book. As I wait these last few weeks before publication, finding the 22-year-old Biology Digest article made me think of writer Malcolm Gladwell’s essay on the “10,000-hour rule” in his 2008 book "Outliers."

According to the rule, which Gladwell borrowed from Florida State University psychologist of K. Anders Ericsson, an expert on experts, people who seem to achieve great success overnight have actually put in at least 10,000 hours practicing. Familiar examples are the Beatles, Bill Gates, and Mozart, writes Gladwell.

The 10,000-hour rule – and then some -- applies to most if not all of the biomedical breakthroughs we hear about in the media, presented as if they happened overnight. They didn’t.

I’m so glad that gene therapy’s time has finally come!

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