Factual · Powerful · Original · Iconoclastic
Just weeks ago gene therapy celebrated one of its greatest successes, the almost-miraculous cure of a two-year-old Dutch child afflicted with "bubble boy syndrome." His severe combined immunodeficiency (SCID) forced him to spend what was destined to be a short life hermetically sealed in plastic. But by removing stem cells from his marrow, genetically modifying them, and re-injecting them, researchers gave him a shiny new fully functional immune system.
Now such SCID treatments in the U.S. have ground to a halt. Why? Similar therapy, which had cured a 3-year-old French boy, appears to have given him a leukemia-like illness.
Rhys Evans lived in a bubble until cured by gene therapy.
Gene therapy has always been controversial, mostly because it got off to a promising start and then floundered for almost a decade. But it’s now the "comeback kid" of biotech, and is involved in over 600 clinical trials in 20 different countries. Gene therapy has shown promise not just against SCID but many hereditary disorders. Five percent of children worldwide are born with congenital or hereditary problems and nearly 40 percent of adults are thought to have some genetic predisposition to common illnesses ranging from minor ailments to killers like cancer and sickle cell anemia.
Originally, the purpose of gene therapy was precisely what the "bubble boy" doctors did: treat a disease caused by a single defective gene by substituting a good one for a bad one. Then scientists made a discovery that changed all that. They found that adding genes that caused the right proteins to be produced could potentially alleviate any number of disorders.
Gene therapy is being applied to problems ranging from Parkinson’s to heart disease to AIDS, although about two-thirds of the clinical trials are for cancer. A rodent study at Jefferson Medical College in Philadelphia was spectacularly successful in actually preventing the animals from developing stomach cancer after they were heavily dosed with a powerful carcinogen. Further, the genes were delivered orally. Can anyone say: "cancer prevention pill"?
Looking further, the researchers found that among 26 different cancer cell lines – including tumors of the lung, head and neck, esophagus, stomach, cervix, pancreas and kidney – the new genes inhibited tumor cell growth in more than half of the experiments.
The tragic case of the French toddler must be seen as a lesson, not the end of the road. And part of that lesson is that using viruses to insert and spread the corrective genes appears to have major limitations.
All of the early gene therapy experiments took advantage of the infectious power of viruses, which by nature burrow into the nucleus of living creatures and set up house.
Viruses comprise a small piece of DNA or RNA stuffed inside a protein envelope. Researchers render the virus theoretically harmless by deleting some or all of its genes. They then splice the therapeutic gene into the remaining genetic material and mix it with human cells. The altered virus, called a carrier or vector, can then deliver the therapeutic gene into the nucleus. Even the aforementioned rat pills contained viruses.
But in the French child’s case a retrovirus was used, and it’s long been suspected that in exceptional cases these could cause cancer if they lodged in or near a cancer-causing gene. The one gene therapy-related death, that of Jesse Gelsinger in 1999, was an apparent reaction to proteins on a mere cold virus.
Add to this that many genes are far too large to be inserted with a tiny virus. But scientists are working hard to come up with alternatives.
Researchers at Friedrich Schiller University in Jena, Germany are using infrared lasers to cut temporary holes in mammal cells and insert DNA. The genetic material was encoded so that it would glow green. This allowed the Germans to see that only the cells they aimed for were hit, that they were undamaged, and that they went on to grow and divide naturally.
Using bacteria would be another way to avoid viruses and to insert genes far larger than a virus could handle. Virginia Waters of the University of California-San Diego in La Jolla has found that bacteria can "have sex" with mammalian cells. That may strike some puritans as perverse, but it’s really just good, clean science.
The bacteria Waters used had been genetically engineered to contain pieces of DNA called plasmids. These readily transfer between two bacteria and are a vital tool in creating transgenic crops. But mammalian cells aren’t known to accept bacterial DNA. Was this a matter of mean-spirited discrimination, a hate crime waiting to happen, or perhaps just something that rarely occurred and had never been observed?
To find out, Waters inserted a gene into one of the plasmids that would show up under a special light. She then laid the bacteria on top of a layer of mammalian cells, perhaps played some romantic music and turned the lights down low, and after eight hours used the light to determine that the desired hanky-panky had indeed occurred. This "bacterial conjugation," as she described it, could conceivably deliver even the largest genes to a variety of sites in humans.
Just as it would have been wrong to blast the space program as unethical because brave astronauts were killed and hurt, so too with gene therapy. Yet this isn’t about beating the Russkies to a cold rock, but rather treating and curing an as-yet unknown but vast array of crippling and killing diseases. Let’s take a deep breath, try to figure out what went wrong, and plow ahead.
We owe it to the bubble boys, and to ourselves.