When it comes to science, Hollywood has taught us to envisage the lone scientist working late at night, hunched over a microscope. Suddenly, a test tube starts fizzing and he's got his breakthrough formula made.
Scientists lovingly call this the Breakthrough Myth.
The unsexy reality is that it usually takes the work of multiple teams of researchers, in different labs around the world, over several decades, for new treatments to be developed and introduced safely into medicine.
For example, the first bone marrow transplant was performed in 1957. But it was 30 years before immunity-suppressing drugs emerged and the survival rate of bone marrow transplant recipients began to exceed 1%.
Chemotherapy was another slow-to-emerge treatment that has improved with age.
The science behind chemotherapy began during post-World War I autopsies. People who had been poisoned with mustard gas subsequently had far too few white blood cells.
Even though the gas was a harmful toxin, this prompted researchers to wonder if mustard gas could be used to reduce the excessive numbers of white blood cells in leukaemia patients.
A toxin as a treatment.
The very first chemotherapies emerged three decades later in 1948 and were used to treat children with leukaemia.
By the 1980s the cure rate was 60-70%, and by the 1990s it was 85-90%. That's 75 years from the initial concept to reliable treatment.
Gene therapy—first dreamed up 60 years ago—is turning out to be no different.
How Gene Therapy Works
Your DNA resides in the nucleus of every single cell in your body. This means that every cell comprises 46 chromosomes, containing 20,500 genes, which code for around 100,000 different proteins.
(If that's a string of alien words to you, check out How Does DNA Work? before reading on.)
The only exception to this rule are gametes (egg and sperm cells), which each contain half the number of chromosomes (23 per cell). When they come together, the offspring then possesses half of its mother's chromosomes and half of its father's chromosomes.
Inherited diseases occur when a gene (or genes) mutate and this faulty bit of code is passed on via the egg or sperm.
Mutated genes may no longer code for their original protein, which can sometimes be a good thing, but can also leave the body vulnerable to disease because there are many different proteins critical to healthy biological function.
This was the case for four-year-old Ashi DeSilva who, in 1990, was the first human being ever to receive gene therapy.
Ashi had adenosine deaminase (ADA) deficiency. Babies born with this rare immunodeficiency disease don't have the genetic recipe to produce the protein enzyme ADA. Her body was unable to perform a key biochemical reaction that otherwise provides protection via an immune response from most bacteria, viruses and fungi.
"Ashi had her first infection at just two days old," explains Ricki Lewis in her detective-style book, The Forever Fix: Gene Therapy and The Boy Who Saved It.. "By the time she was walking, she was constantly hacking and dripping with coughs and colds."
Most infants with ADA deficiency don't survive past their second birthday. Ashi was lucky. After her diagnosis she was put on enzyme replacement therapy—a treatment developed in the 1980s in which ADA was taken from cows and linked with polyethylene glycol, or antifreeze, for infusion into the bloodstream.
Although expensive at $250,000 per year and only partially effective, at least the enzyme therapy helped keep Ashi alive into her preschool years.
When her white blood cell count started falling again, a gene therapy trial—the very first of its kind in humans—looked like her only hope.
Here's how doctors carried out that gene therapy on Ashi DeSilva:
Step 1. Insert target genes into the viral vector.
Doctors took ADA-producing genes from a healthy volunteer and inserted them into an engineered retrovirus.
Viruses are pretty basic biological machines with just a shell and a squiggle of DNA inside. Scientists still can't agree if they're living or non-living, since they meet so few of the criteria for life.
Nonetheless, viruses hijack the machinery of living cells to reproduce and spread themselves (the "virus" part) and some of them even insert their own DNA in among your DNA (the "retro" part) so they become a part of you forever.
In gene therapy, the virus is relieved of its own DNA, so it simply acts as a transport vector for healthy gene payload.
Besides being able to cure horrible diseases, this is the coolest part of gene therapy because we're hijacking the hijacker.
Step 2. Replicate the patient's white blood cells.
At the same time, doctors took a sample of white blood cells from Ashi and placed them in a culture to replicate themselves and create more. Lots more.
Now, I don't know what you think white blood cells look like, but apparently I think they look like testicles.
Step 3. Mix the cell culture with the retrovirus.
The next stage is to combine the virus with the patient's cell culture. In Ashi's example, the retrovirus attacked the white blood cells because that's what viruses do best. They injected the healthy ADA-genes into the blood cells en masse.
When the gene insertion is done outside the body like this, it's called ex vivo ("ex" = outside, "vivo" = life).
Step 4. Return the modified white blood cells to the patient.
Finally, a pint or so of murky fluid containing around 10 million of Ashi's genetically modified white blood cells was returned to her bloodstream. The infusion took just 28 minutes.
Below is an actual drawing made by a nine-year-old girl who was treated with the same gene therapy shortly after Ashi, also for ADA deficiency. I love that of all the details contained within this landmark moment, the girl noted that she watched the movie Willow during the gene therapy infusion.
Above: Image courtesy of the National Museum of American History
How's Ashi DeSilva Now?
Today, Ashi is alive and well. She's a 30-something married woman with a Masters in Public Policy.
After the therapy, Ashi had no side effects, and continued to improve over 11 gene infusions during the next two years. Her blood showed more corrected T-cells and more ADA production. Thanks to the genetic modification, she began making her own antibodies to protect against infections, and her treated cells were even outliving the ADA-deficient ones.
The results prompted researchers to treat newborn babies with ADA deficiency in the same way. They could even take blood straight out of the umbilical cord and enable infants to produce their own ADA from the start of their lives.
When Gene Therapy Goes Wrong
Ashi's case was a resounding success for gene therapy. Despite the experimental complication that she was being treated with the cow enzyme at the same time, gene therapy was looking extremely promising.
So it was a shock to the research community when, later that decade, a gene therapy trial resulted in the sudden death of 18-year old Jesse Gelsinger.
Jesse suffered from a rare metabolic disorder called ornithine transcarbamylase (OTC) deficiency, which meant he couldn't digest protein. Babies born with the disease suffer from the excessive build-up of ammonia and die soon after birth. Jesse had only a partial deficiency, so that he was able to make some OTC himself, and could manage his partial deficiency with medication and a strict no-protein diet.
When a teenage Jesse enrolled in a gene therapy clinical trial in 1999, he was hoping to help babies born with the fatal form of his disease, who could be cured with a new gene therapy vector. Researchers would inject Jesse with a virus carrying corrected genes destined for his liver cells, in order to test the safety of the procedure.
But the trial was doomed. As a direct result of the viral infusion, Jesse suffered from a massive immune response, with fever and blood clots and inflammation throughout his body. Multiple organ failure ensued. Four days later, he died.
Jesse's doctors were shocked. The trial was investigated at length by the FDA. What had gone wrong? Why had nobody seen this coming? Why had gene therapy worked on countless other patients but killed a fit 18-year-old in four days flat? Jesse's family understandably wanted answers.
The FDA investigation concluded multiple factors in the death of Jesse Gelsinger.
As a result of his OTC deficiency, Jesse had high ammonia levels which triggered safety protocol. This should have excluded him from the trial, but he was entered nonetheless.
What's more, prior to that fateful day, two other gene therapy patients had suffered serious side effects, and three monkeys had died from a clotting disorder and severe liver inflammation after being injected, all of which went unreported.
Besides these ethical and procedural failures, what had gone wrong with Jesse's specific gene therapy?
Unexpectedly, it came down to the particular viral vector being used to introduce the new genes into the body.
As the eighteenth and final patient in the Phase I experiment, Jesse received the highest dose of the virus: 3.8x1013 (380,000,000,000,000) virus particles via the groin artery and advanced to the liver vessel. This was orders of magnitude greater than was required for treatment.
What's more, the type of vector he received was an adenovirus (as opposed to a retrovirus) which are known for stimulating an immune response, even when inactive.
The severe inflammation caused by adenoviruses is particularly dangerous for OTC patients, and especially in the liver, which is exactly where Jesse was treated. Still, out of 4,000 gene therapy patients, Jesse is the only one whose death was caused by the viral vector.
Combining the effects of the vector type, the excessive dose, and the complications of having OTC, the tragedy was a perfect storm of events.
Nonetheless, Jesse's case drew attention to numerous oversights and inadequate regulations which have since led to stricter controls over clinical trials.
Gene Therapy Today
After the catastrophe that killed Jesse Gelsinger in 1999, gene therapy trials have continued to forge ahead, but with tighter protocols in place to protect volunteers.
Two-thirds of them take place in the US, followed by the UK and Germany. Even in 2018, nearly 30 years after the initial trial involving Ashi DeSilva, gene therapy is still an experimental technique requiring greater refinement and proof of safety in its many forms.
Above: Number of worldwide gene therapy trials per year Source: Journal of Market Access & Health Policy
Most gene therapies are now aimed at targeting cancer because of its widespread incidence and money-making potential.
The second most popular target for gene therapy is monogenic disease, or any disease caused by a single-gene mutation, eg cystic fibrosis.
Therapies for cardiovascular disease, infectious disease and inflammatory disease come after those.
Two different vector systems are used in gene therapy today: viral and non-viral. Retrovirus and adenovirus are still among the top used in viral vectors.
Non-viral vectors include chemical and physical systems like cationic liposomes, particle bombardment, electroporation and ultrasound. These are less efficient but their availability and cost-effectiveness make them extremely useful.
In fact, the largest challenge faced in gene therapy is how to deliver the new genes into the patient's cells.
Different cells are responsible for different jobs, and only a subset may be involved in disease (for example Ashi's white blood cells, or Jesse's liver cells) so gene therapy need only target the affected cells.
However, when a virus is introduced, the body responds as a whole with an immune response, which can be life-threatening. There are other vector problems too, including dose-related toxicity, pre-existing neutralising antibodies, and insufficient gene expression.
Researchers are working to re-engineer next generation viruses to ensure the safety and efficacy of gene therapy.
For all its challenges and setbacks, gene therapy is considered a very promising treatment for numerous disabling and otherwise incurable diseases. Investment is growing and regulators are creating specific rapid access paths, providing hope for doctors and patients.
While Jesse Gelsinger lost his life to gene therapy, thousands—even millions—may one day owe their lives to it.