Rewiring the Genome: The Future of Medicine Gets Personal

Fifteen years ago, the promise of gene therapy was dealt a stunning blow by the widely reported death of eighteen-year-old Jesse Gelsinger during a clinical trial. Researchers were attempting to cure Gelsinger and other patients suffering from a rare condition called ornithine transcarbamylase deficiency, which leaves people unable to process nitrogen in their blood—making protein-rich foods potentially deadly. To treat Gelsinger, scientists injected him with a virus engineered to include a functional version of the gene that was faulty in OTCD patients. But within 48 hours, Gelsinger’s condition dived dramatically; his body swelled, his skin and eyes yellowed, showing signs of liver damage, and his fever spiked dangerously high. Four days after injection, doctors found Gelsinger had no hope of recovery, and his family decided to take him off of life support.

The virus used as a courier was an adenovirus—best known for causing the common cold, but also very good at delivering genes into cells. Researchers think that Gelsinger might have been exposed to the specific kind of adenovirus before treatment, so his body would have carried antibodies that triggered an intense immune system reaction when the viral vector reached his liver.

The tragedy of Gelsinger’s death, coupled with concerning developments in other studies and the pop of the dotcom bubble, could have ended gene therapy altogether. But in the last several years, the practice has started to make a comeback. Gene therapy has performed well in trials for cancer, hemophilia B, and blindness treatments. In 2012, the first gene therapy treatment was approved in the West when the European Medicines Agency authorized the commercial use of Glybera for lipoprotein lipase deficiency, a disease that causes high levels of blood fats.

Instead of an adenovirus, Glybera uses an adeno-associated virus. Adeno-associated viruses often show up with adenoviruses in cultures of sick people, but they don’t trigger an immune response.

Gene therapy is currently unavailable in the U.S. outside of a clinical trial, but that may soon change. Some companies are feeling hopeful. UniQure, the maker of Glybera,  is currently building a 55,000-square-foot plant in Massachusetts. George Church, founder of the Personal Genome Project, expects that in one to three years we’ll be seeing a commercial gene therapy in the U.S.

In addition to the numerous developments in adeno-associated vectors, gene therapy has also expanded in new directions: Cimeric Antigen Receptor (CAR) cells are engineered versions of T-cells, a critical part of our immune system that kill bacterially infected cells as well as tumorous ones. CAR cells include extra genes that direct them toward tumors. When they are injected into a cancer patient, they multiply and attack. Clinical trials with CAR cells have shown promising results, and if this trend continues, it could be the forefront of a revolutionary treatment in cancer.

Another promising front is the work of Dr. Paula Amato and her colleagues, who are seeking to prevent mitochondrial diseases—which affect the energy-generating parts of cells—through what is called a spindle transfer. In a spindle transfer, the DNA from the nucleus of a mother’s egg is removed and put into an donor egg where nuclear DNA has been removed, but healthy mitochondrial DNA left behind. The child that develops from this hybrid egg is genetically related to his or her mother but won’t carry any genetic mutations in his or her mitochondrial DNA. Dr. Amato’s team has tested this hypothesis in human cells and is awaiting FDA approval on a clinical trial.

Dr. Amato’s brand of gene therapy is called germ-line therapy, meaning that the modification will be heritable. Germ-line therapy is controversial because there’s no way to test the long-term implications on humans without doing exactly that—testing humans—and seeing how things play out down the generational lines. It also plays into fears of eugenics and “designer babies.” But science still has a ways to go before it catches up with dystopian science fiction; the ability to modify nuclear DNA does not yet exist, so parents can’t tweak a baby’s eye color or brainpower just yet.

Genome editing represents yet another frontier. This involves modifying existing genes (usually with enzymes) instead of adding new ones. Genome editing is currently having success in clinical trials to treat HIV, offering hope that infectious diseases might also be tackled with gene therapy.

So there’s quite a lot that gene therapy could do, but both the scientific and ethical limits are still up in the air. Is germ-line therapy is worth the risk? What constitutes “disease” and what necessitates treatment?

The FDA recently convened an advisory committee to determine if germ-line therapy studies like Dr. Amato’s are safe enough to proceed. That decision will be one in a long line of parameters set around a fast-growing field with new, widespread implications for public health.

Want to hear more? George Church and Paula Amato joined Sheldon Krimsky, Nita A. Farahany, and Jamie A. Grifo at Designer Genes: Fashioning our Biological Future, a program in the Big Ideas Series at the 2014 World Science Festival.