Early in the 20th century, medical researchers began to realize that some diseases are caused by broken genes. In 1909, British physician Archibald Garrod reported that certain "inborn errors of metabolism" ran in families, in a pattern that matched Mendel's laws of genetics. Garrod's findings inspired the Nobel Prize-winning discovery of George Beadle and Edward Tatum, who, working at Stanford University in the 1940s, showed that each metabolic enzyme corresponded to a specific gene. Take away the gene, and the enzyme won’t get made. In the decades since Beadle and Tatum's work, we’ve discovered that mutations that break genes are responsible for thousands of human diseases.
If a disease is caused by a damaged gene, then there’s an obvious cure: Fix the gene. But repairing genes in patients has largely been out of our reach because editing the DNA of living humans is hard. Instead of fixing the underlying genetic cause, we treat these disease—when it is treatable—with drugs. Drugs can mitigate the consequences of genetic diseases, but they have to be administered over a patient’s entire life because the disease-causing mutation doesn’t go away. In some cases, the treatments are cheap and effective: Children with phenylketonuria can avoid nearly all of the symptoms by eating a diet low in the amino acid phenylalanine. More often the treatment options aren't good, and so despite the huge technical challenges, scientists have tried to find effective ways to edit DNA in live humans.
As the technological challenges of gene therapy diminish, we'll be faced with the question, should some DNA edits be off limits?
Progress has been very slow and sometimes thwarted by major setbacks—in 1999 18-year-old Jess Gelsinger suffered a fatal immune reaction after receiving a virus-based gene therapy. After decades of attempts, one gene therapy was finally approved in Europe in 2012, while the FDA has yet to approve any in the U.S.
But in the last few years, the prospects for gene therapy have suddenly started to look a whole lot better. In the same year that Europe approved its first gene therapy, a team of researchers at Umeå University in Sweden and the University of California-Berkeley figured out a new way to edit DNA by hacking the immune system of the bacteria Streptococcus pyogenes. Emmanuelle Charpentier, Jennifer A. Doudna, and their colleagues showed that the simple bacterial system called CRISPR/Cas9 could be easily controlled to make precise DNA edits. Their discovery was the latest in a string of new "programmable" DNA editing platforms, including modified bacterial proteins called TALENs reported in 2011, and so-called zinc-finger nucleases in 2003. With these DNA editing technologies, we can directly edit genes in living human cells with a precision that was previously impossible. And now with CRISPR/Cas9, programming these edits has become trivially easy. These new DNA editing systems are so efficient that they are revolutionizing research on genetic diseases in the lab.
Will they revolutionize gene therapy as well? Several studies published this month show what the elements of successful gene therapy could look like in the near future. Last week in Nature, a team of researchers at the Vita Salute San Raffaele University, working with Sangamo BioSciences in California, reported that they used zinc-finger nucleases to successfully correct a gene in the bone marrow cells of a patient suffering from a genetic disease called severe combined immunodeficiency. In the study, the researchers did not put the corrected cells back into the patient, but in a clinical trial, that would be a routine procedure.
In another recent study, researchers at the University of Tübingen in Germany corrected a gene in cells taken from patients with the neuron-damaging Parkinson's disease. The scientists didn't need to take the patients' brain cells—they took skin cells, which they first converted into stem cells, and then into neurons. After using zinc-finger nucleases to correct mutations in a gene called GBA1, the scientists found that the skin cell-derived neurons functioned normally. A process like this one could be used to create cells that are transplanted back into Parkinson's patient's brains.
These encouraging results aren't just limited to the lab. Promising results from the first clinical trial of a zinc-finger nuclease gene therapy, for treating AIDS, was published earlier this year. Next-generation gene therapies will first be aimed at diseases such as AIDS and leukemia, because those diseases involve cells that can be easily removed, edited, and then put back. But as newer editing systems like CRISPR/Cas9 develop, we'll be able to do more gene edits in other parts of the body. In March, researchers at MIT reported that they were able to correct a gene in the liver cells of mice, by injecting CRISPR/Cas9 components into the blood stream.
So we may finally have the tools to fix broken genes. But these tools aren’t limited to broken genes. As the technological challenges of gene therapy diminish, we'll be faced with the question, should some DNA edits be off limits? In an effort to understand human genetics, researchers are compiling catalogs of small genetic changes that, in some cases, can have a big impact. DNA edits that boost athletic performance wouldn’t be beyond the resources of major athletic teams. And what about cosmetic edits that change someone’s physical appearance, or, say, edits that parents might order for their children to prevent them from becoming gay? Some of these cliché science fiction scenarios may prove impossible, but some won’t. And the tools to realize them are already here.