Gene therapy has the potential to be the most innovative and disruptive medical procedure in the modern world, but it is still in its earliest stages of development. Technology moves faster than any other industry on the planet, but when paired with science and medicine, the pace may be so fast that it becomes detrimental. Gene therapy is equal parts technology and medicine and there will be an eternal struggle between the two. From a technological standpoint, it’s full steam ahead for companies like CRISPR. For those focused on the medical side however, there is a long road ahead. It is important to remember that the success of gene therapy depends first on the development of the technology, but without testing and a safe implementation in the medical field, no lives will be saved. It is much different than Silicon Valley pushing Face ID or a new app because in both of those instances, the faster the technology is available to consumers the better, or so they have us believe. When Apple pushes new tech like Face ID, they know that they can usually work out the bugs with a software update, but things aren’t that simple when the technology involves pumping new genes into people’s bodies.
The science behind gene therapy is just as amazing as the technology behind deciding which specific genes need attention. In order for a patient to receive the treatment, the new genes must be introduced into the body via a number of possible procedures. The most common of which include specifically placed injections or IV treatments, depending on the disease the treatment is aimed to fight and where the problem is within the body. Once inside the body however, the procedure is essentially the same. The new or modified genes are brought to their desired locations using a vector. The most common vectors are bacteria, viruses, and plasmids. They are the most common because while they are completely different, they all share the essential characteristic of being able to multiply quickly once in a cell. Under normal circumstances, their hyperactivity is a bad thing because it is the very reason that diseases are able to spread so quickly. In gene therapy however, this trait makes them the perfect candidates to transport genes. The video below provides a visual demonstration of this process during a treatment of a retinal disease.
The use of vectors is relatively consistent across all forms of gene therapy, however, there are several different methods used to treat different diseases. On the most basic level, there are two forms of gene therapy, somatic and germline. Somatic treatments are targeted at cells that do not produce eggs or sperm, therefore the treatment will not be passed down to subsequent generations. Conversely, germline treatments target cells that do produce sperm or eggs, which means that any alterations made to cells in the patient’s body will be passed down. Germline treatments are arguably more dangerous because if something goes wrong during the procedure or if the new genes are incorrect, the faulty DNA will be passed down until it is corrected by another procedure.
Under the umbrella of somatic and germline treatments are three main forms of therapies that vary depending on the problem. The therapies include gene augmentation, gene inhibition, and targeted cell attacks. Gene augmentation is used when a cell has faulty DNA that needs to be corrected. In this case, the new genes are attached to a vector that will reproduce in the desired cells, and will replace the existing DNA in the hopes of delivering the correct directions. Gene inhibition does the opposite, as gene inhibition treatments are designed to stop cells from behaving a certain way instead of correcting an undesired behavior. This form of gene therapy is useful for treating cancer patients because the goal is to slow down the reproduction of cancerous cells. This is achieved by attaching genes to a vector that will tell the cancerous cells to stop reproducing. Doctors also have the ability to target a cluster of cells that they wish to eliminate altogether. This is achieved by either injecting vectors that will kills the cells directly, or by using vectors that will trigger an immune system response which will in turn kill the desired cells. This is slightly less effective because the vectors are used to trick the body into fighting a disease that it did not otherwise recognize. Regardless of the objective of the various forms of gene therapy, vectors are the most effective vehicles to deliver new genes to cells.
While the vectors are very useful for delivering the new genes to their desired targets, there are many risks involved with the procedure. Success of the treatment aside, there are risks associated with the injection alone. It is a high-risk procedure because while it can be extremely effective, it can just as easily catalyze a series of detrimental reactions within the body. If the new DNA is delivered to the wrong cells, it can disrupt necessary functionality completely unrelated to the disease it was aimed to fight. If the vectors used in the procedure trigger an unexpected immune system response, the treatment can be rejected altogether or in some cases even cause organs to fail.
Jesse Gelsinger’s story serves as a grim reminder of the unintended consequences of gene therapy. Jesse suffered from a rare metabolic disorder called ornithine transcarbamylase (OTC) deficiency, which made him an ideal candidate for a gene therapy experiment at the University of Pennsylvania. The vector that was used in the procedure was a weakened cold virus which was delivered via injections. The doctors at Penn had tested their vector on mice, baboons, monkeys, and one other human patient, so they were confident that Jesse had a real chance of improving. What the doctors did not predict, was the overwhelming inflammatory response that started a chain reaction in Jesse’s body. A mere 24 hours after the injection, there was 11 times the normal amount of ammonia in Jesse’s blood, he was hyperventilating, his ears had swollen shut, he had developed a blood clotting disorder called jaundice, his kidneys were starting to fail along with his lungs, and his brain had started to shut down. Shortly after the doctors thought they had things under control, Jesse died. His death marked the first documented casualty resulting from gene therapy and left the doctors in shock.
Jesse’s premature death exemplifies the uncertainty involved with gene therapy, and there will undoubtedly be others. The technology is so new that is impossible to predict the outcome of the treatments with any degree of certainty. On paper, Jesse’s treatment should have worked but all of the years of testing and analysis that took place before the procedure were flipped upside down when his body started to reject the treatment. The best doctors in the world cannot explain what caused Jesse’s body to react the way it did which speaks to the unpredictable nature of the technology. Gene therapy is an amazing advancement for both technology and medicine, but it is still wildly imperfect and will require many more brave patients like Jesse before it becomes a dependable procedure.