David Vetter's The Bubble Boy

Imagine living your entire life inside a sterile, plastic bubble and having to hug your loved ones through a padded, NASA space suit. This was reality—not science fiction—for David Vetter, also known as “The Bubble Boy,” who grew up in Texas in the 1970’s. While his story has been publicized and parodied in different ways, most famously in a Seinfeld episode, it is a tragic one (1).

David Vetter, who was diagnosed with a genetic disease called SCIDS, or Severe Combined Immunodeficiency Syndrome. He lacked a functional immune system that would otherwise defend his body against diseases (2). Even the common cold, which for most people would be a minor annoyance, could spell death for him. It is a dreaded condition that steals away the most basic and fundamental needs and comforts of a human being. Indeed, his permanent quarantine – in which he was deprived of physical contact with his family – started when he was a mere twenty

seconds old. His physical hardships were amplified by psychological ones, including persistent anxiety and paranoia, understandable given that everyday germs were a death sentence. He was stripped of all the opportunities that anyone should enjoy, and his utmost wish for his eleventh birthday – his second to last – was to be allowed outside to see the stars for twenty minutes. If David Vetter had been born a few decades later, perhaps he could have led a radically different life. Rather than crawling in the little space provided beneath the plastic, he could have run around freely with no gas masks or spacesuits. After David’s death, continual efforts have been made to cure this dangerous disorder. Scientists realized that to fully eliminate SCIDS, the defective gene itself must be directly corrected. But how can one manually edit one sliver of the genome, one of the most intricate, fragile, and sophisticated molecules?

What scientists in David’s day had not realized was the usability of something that had been editing, modifying, and shaping DNA since the beginning of life on earth. These master exploiters, known more commonly as viruses, have spent billions of years developing ways to override the cell’s basic defenses. Viruses have evolved the ability to change and insert their genes into ours (3). Though viruses are typically deleterious to human health, scientists speculated that they could also be engineered to save the lives of those suffering from incurable genetic diseases. Since viruses already know how to incorporate viral genes into our genetic codes, scientists hypothesized that they could also carry the therapeutic genes into the affected individuals’ bodies, and this very method was utilized to cure people of X-SCID, the very disease that David Vetter suffered from.

A landmark clinical trial in the early twenty-first century showed that retroviral vectors could successfully cure X- SCID, or X-linked severe combined immunodeficiency (4). In the trial, ten children with this monogenic disorder were treated with retroviral vectors containing the gene for the correct receptor that is lacking in X-SCID patients. Nine of the ten showed remarkable improvement in their immune systems over the next two years; however, two eventually developed leukemia, because the delivered gene was inserted near a gene that regulates the cell cycle, leading to the proliferation of white blood cells (4). Despite this setback, the study was a successful validation of the viability of gene therapy concept and marked a triumphant moment in the field of gene therapy, clearly demonstrating the effectiveness of viral vectors.

The emergence of viral vectors as tools for gene therapy opens a slew of new possibilities for the future. However, despite the limitless applications, the use of viral vectors is not yet a full-fledged technology and must continue to develop. In fact, some of the early human trials resulted in more tragedy than promise. For instance, Jesse Gelsinger suffered from a rare genetic disease in the liver that he was able to survive by following a limited-protein diet. This disorder, also known as orinthine trascarbamlase deficiency, while usually fatal at birth, failed to claim Jesse’s life, primarily because he developed this disease after birth due to a mutation. In 1999, at the age of eighteen, he took part in a clinical trial of adenoviral vectors that were injected directly into his liver. Unlike seventeen other participants, Gelsinger suffered from what scientists hypothesize was a high inflammatory reaction. His altruistic motives were met with an immune shock and multiple organ failures (5). His tragic and untimely death ultimately became a severe setback for the field of gene therapy.

As the story of Gelsinger woefully reminds us, scientific hurdles still remain before viral vectors may be effectively utilized.

But progress is being made every day. Scientists are starting to learn how to overcome the challenges that were previously present, such as the patient’s counterproductive immune response to viral vectors and the limited size of the genes that a viral vector can contain. The development of viral vectors is once again, a decade and a half later Gelsinger’s case, an exponentially growing field. Auspiciously, viral vectors have even started to demonstrate effectiveness against genetic disorders beyond X-SCIDS. For example, Choroideremia – a genetic disorder that causes progressive vision loss – had no effective treatment options for sufferers. However, in a recent clinical trial earlier this year, six patients with this dreaded condition were treated with viral vectors and for the first time in medical history, showed significant improvement in vision, demonstrating the potency of this new tool of gene therapy

(6).

Viral vectors are a revolutionary tool against genetic disorders that have thus far been difficult, or even impossible, to treat. Their immense potential is clearly demonstrated in the successes we hear from different clinical trials, and one can only look forward to a time when genetic disorder diagnoses need not be met with despair. Perhaps the next milestone could be against cystic fibrosis or even AIDS. With each small scientific victory, the next David Vetter stands a better chance of running around freely in the fields outside of the plastic bubble.