Many of you have likely heard of the phrase "gene therapy" before, and if surveyed for its definition, the majority of you would likely respond with something along the lines of "fixing mutations in an individual's DNA to treat disease". Completely excluding fringe scientists who want to clone humans, the field of gene therapy has been quite a rollercoaster the past 15 years. There have been remarkable achievements and alarming failures. Many of the scientific challenges associated with gene therapy approaches are aggrandized further with media sensationalism and hype about its potential to treat disease (and perhaps even "cure" disease, despite my usual refusal to use that word in discussions of science).
The University of Pennsylvania is the paramount institution in the world for gene therapy research, and though I am not a student of that scientific trade (I am a developmental biologist), I have plenty of friends and colleagues in the gene therapy community that I stay somewhat informed of the research going on. The aforementioned successes are oft mentioned at conferences and recruiting sessions, while the quite literally deadly failures are swept under the rug, left only to murmurs among students and faculty, though that is a topic for another article.
For those of you in the scientific community, you are quite aware that there are far more failures than successes in science, and even failures and successes can be distributed along a spectrum of importance. But for a small few members of the research community, a combination of acumen, creativity, and yes, even luck, can produce truly spectacular results that transcend the field of science and have impact for years, even decades into the future. This latest achievement that I was first introduced to at our CAMB symposium back in October 2010 could be one of these moments.
First, a quick background on gene therapy technique. Traditionally, gene therapy involves injecting wild type (or normal for those not familiar with scientific terminology) genes into patients possessing mutated copies. The concept behind gene therapy is that if these normal gene copies can integrate into our DNA, they can encode normal proteins and effectively treat disease. This has proven to be successful (see my "remarkable achievements" link above) in dogs and humans. The main problem with this approach is that gene integration is predominantly random, which can pose two main problems: 1) too many copies of the gene get integrated (the adage "too much of a good thing" most certainly applies to biology); and 2) because of random integration, the injected genes can integrate into other coding DNA and disrupt otherwise normal genes – most notably tumor suppressor genes, which can lead to incidents of cancer. The use of viruses as vectors for these genes is a major problem as well, but scientists are getting better at using non-virulent vectors.
Back to the CAMB symposium: A brilliant graduate student (and now Doctor after successfully defending his thesis) named Hojun Li stepped up to the podium to give a talk on his research project, which involved using proteins called zinc finger nucleases (ZFNs) to edit the genome in vivo. Instead of injecting wild type copies of genes basically blindly, if one could molecularly specify the site of integration, the problem of random integration could be avoided. Using engineered ZFNs and flanking the to-be-injected gene with homologous sequences to the endogenous DNA sequence, one should be able to direct gene therapy (via homologous recombination) and treat disease.
Even to a scientist this seems technically quite difficult, as the efficiency of this technique even when optimized is likely to be low. This is where Hojun's scientific acumen shined. Haemophilia is a disease that inhibits the ability of blood to clot following a punctured blood vessel. Haemophilia B is caused by a mutation in the F9 gene, which encodes for the Factor IX protein, causing levels to be at less than 1% of normal. Importantly, a level of Factor IX only at 5% of normal renders a very mild form of the disease, essentially thought of as normal. If Hojun's concept would work, even with low efficiency, then it had a possibility to be effective at treating Hemophilia B.
The fruit of multiple years of hard work and elegant experiments displayed prominently from projector to screen that October 2010 afternoon. Even being at a place like Penn, not many research presentations thrill me due to lack of interest in the research field or students/professors overstating the importance of their data. But Hojun's work was simply amazing, and had faculty and students buzzing the rest of the symposium and beyond. I won't get into the specific science here for the sake of keeping my audience of non-scientists around (you are welcome to read the journal article yourself from the link at the end of this diary, and you can definitely engage me in the comments), but nevertheless the result was astounding. Hojun, along with the help and collaboration with his lab mates and thesis adviser, was successful in treating mice afflicted with Haemophilia B, even despite the low efficiency of genome editing that he correctly predicted.
For his and his lab's success, Hojun's results were just published in Nature, one of the top three scientific journals in the world. Thankfully, I was fortunate enough to learn about his research many months ago an was quite pleased to see it highlighted by Scientific American magazine today. As always with science, there is much more work to do, even after producing amazing results. The low efficiency of successful genome editing needs to be improved, because many diseases require much more than a 5% level of normal protein to be treated. But the fact that Hojun was able to direct site-specific genome editing in vivo and treat disease in a mouse model of Haemophilia B offers much promise to the research community that gene therapy without the problems of the past is possible. It's a grand first step that could move the field of gene therapy far ahead. It is these rare but momentous successes that remind us of the power of scientific research.
Hojun's journal article, "In vivo genome editing restores haemostasis in a mouse model of haemophilia", can be read at Nature online (access required)