Our focus on the future present

It’s been a rather wild ride in the last month, which hasn’t left much time for blog posts. But I’m planning to  turn over a new leaf and start posting at least something short at the beginning of every week.

This week’s post addresses a question that I’ve been asked in many ways by many people: what about germline editing? After the IGI started the ball rolling with a small meeting in Napa, we penned a call for a temporary moratorium on germline editing and have been lobbying for a larger summit, which is now slated for October. I think it likely that restriction or proscription of germline editing will be the outcome.

At this time, the IGI Lab will not do research on human germline editing for several reasons, including:

1. The IGI Lab is focusing on diseases for which somatic (non-heritable) editing would be a transformative advance. The media loves to talk about designer babies, but we actually don’t know the first thing about the genetic basis behind complex traits like beauty or intelligence. But we do know a lot about genetic disease, particularly so-called monogenic disorders, in which a problem in a single gene causes the disease. Online Mendelian Inheritance in Man currently contains about 3,500 disorders that have a clinical phenotype for which the molecular basis is known. It’s clear that we should start with one of these, such as sickle cell disease, cystic fibrosis, muscular dystrophy, or Huntington’s disease. The thing is, curing most genetic diseases wouldn’t require germline editing. Almost any hematopoietic disease could be cured non-heritably by taking a patient’s bone marrow, performing gene correction, and then re-implanting the edited bone marrow. By now we’re very good at bone marrow transplants. And once delivery systems are ironed out, even non-hematopoietic diseases could be cured in adults with gene correction therapy. But eventually achieving the above will take a lot of work. At the IGI Lab, we’re focusing on that future transformation of genetic disease from something we treat with pallative care to something we cure.

2. Cas9 technology is currently too nascent for me to consider germline editing wise. Gene correction is still a relatively new field, with few clinical successes (or even attempts) to refer to.  And compared to other gene editing technologies, such as ZFNs or TALENs, Cas9 is the new kid on the block. There are just so many questions still outstanding about the technology, as evidenced by the huge surge of papers from all over the world that do nothing but figure out new things about Cas9: how does it find targets?, what do off-target sequences even look like?, what happens between cutting and the appearance of edits? At the IGI we spend a lot of time using Cas9 to do gene editing in somatic cells, and we’ve gotten very good at it (more on that when the papers come out). But sometimes we get surprised by the outcomes. That makes me nervous enough for somatic editing, and we obsessively characterize individual reagents for our clinical projects. But the Rumsfeldian Known Unknowns and Unknown Unknowns are too great in relation to a heritable change in someone’s genome. When moving to the clinic, one should prefer a boring tech over one that’s exciting and new but poorly understood, and if no boring tech exists then keep working. In the balance of impact vs risk, a person’s life rests in one pan.