What is gene therapy?

 

 In medicine these days, the word “gene” shows up in all sorts of different contexts and conjugations. There’s genetics, of course, and there’s genomics. Then there’s meta-genomics — and don’t forget genetic engineering, gene-finding, and molecular genotyping! It’s easy to mix up the various distinct branches within the realm of DNA science, but if there’s one subcategory worth keeping straight in your head for the coming years, it’s gene therapy. What is gene therapy? Gene therapy is the use of genetic material as medicine.
To get at just what that means, and why it could be so powerful, we have to start with a quick refresher on how genes actually do things. Genes sit in the cell’s highly protected genome, the library of blueprints that lets every living thing run and rebuild itself properly. To put their code into practice, most genes must be “translated” into a protein — the DNA code specifies the order of amino acids to be added to a chain, which then folds up into a shape determined by that sequence. It’s through this folded three-dimensional structure that the protein performs its function within the cell.

This mice had its genetic deafness partially reversed.

So, if you want to change something happening in a cell, you can achieve this by changing the DNA that codes for the protein shape that does the something. And if there’s a problem of dosage, like having only one copy of a gene instead of two, we could perhaps increase the protein output by inserting a second copy of our own. In either case, we’re changing the genes available to the cell’s regular protein-making machinery, in order to change how the cells behave.
In principle, it’s easy — but is it easy to actually do? Of course not.
First, it’s very difficult to actually get new or edited genes inside the cells they need to correct. Cells have specifically evolved to try to stop that from happening — and indeed, scientists have had to hijack viruses, evolution’s specialized, semi-living DNA syringes, for this purpose. They’re still imperfect, however; every individual cell in your body has its own personal copy of your genome, complete and (mostly) identical to the others; if your problem is genetically inherited, that means every cell in your body also has that same defect, and there’s no way we’ll be able to change every cell in your body. Even if we successfully edit millions of copies of your genome, we’ve still left billions of others untreated.
So, the earliest and still most important applications for gene therapy involve test tubes — remove a sample of a patient’s bone marrow and change a gene of interest, then inject the fixed cells back into the host. This tends to work only if the fixed cells have better fitness or longer lifetimes than the natural type, so they can out-compete the disease cells and dominate the population.

It’s only now becoming possible to edit genes within the body of a living patient. In vivo gene therapy is currently best suited to problems that only affect a specific cell type, offering a limited number and physical distribution of targets. The genetic problem we set out to address will still be in the rest of the untreated cells, but if it’s not used by them to function then it’s not a medical issue. Examples of modern target cell types include certain types of liver cells, and the cochlear hair cells of the mammalian ear.
In both cases, repeated virus-treatment can “infect” a high-enough proportion of a specific population of cells with our therapeutic gene to have the effect we’re looking for. Some gene therapy techniques simply insert the medical gene into the host cell’s nucleus where the genome lives, there to sit and make protein alongside the natural blueprints. However, that only works long-term in cells that don’t divide over time, such as neurons. If the cells are dividing, as most cells do, our gene has to be actually spliced into the host cell’s genome or else get left behind every time the cell reproduces.
The primary technology for achieving this sort of splicing is called CRISPR technology; it stands for clustered regularly interspaced short palindromic repeats, not that it matters. What’s important is that by inserting our gene along with the CRISPR system of proteins and RNAs, the gene can be spliced into the genome wherever desired, and the original version spliced out. From that point on, the cells will divide and replicate the inserted gene as though it had been there all along.
It’s important to remember that by fixing a genetic problem, we haven’t changed anything about the heritability of the disease. Fixing someone’s deafness by editing the DNA in their cochlear hair cells, for instance, won’t make them any less likely to pass on the disease to their offspring — though with gene therapy’s available to help address the problem, that might not be the biggest downside in the world.