Blog / Making the Cut / musings

Lately I've been thinking quite a bit about the definition of Precision Medicine. This was brought about by the CIAPM call for proposals and two associated workshops. The workshops have been stellar, with a feeling more of collaboration than competition. Over the two days, I got to thinking about what Precision Medicine seems to mean right now versus what it might mean in the future.

Wikipedia has an interesting contrast between Precision Medicine and Personalized Medicine. But both PMs are defined as not necessarily implying treatments that are customized for an individual (or even a subset of patients). Instead, they are focused on using large data sets (genomics, proteomics, other omics, health records, etc etc) to determine how some existing medicine should or should not be delivered to a patient.

Let's say you have a new drug that targets a particularly nasty form of cancer. PMs are currently focused on deciding how you're going to administer that drug - who will get it and who won't. That's very important, all the way from clinical trials into general use. Trials may read out falsely negative if people who have no hope of benefit are included in the trial, and since every drug has side effects it's best to pair a treatment with those for whom that risk:reward is favorable. But PMs are not about doing diagnostics on an individual patient and then custom-designing a new therapy for that patient.

This has all been weighing on my mind because of the two worlds in which I've worked. While I was in biopharma, we talked about Precision Medicine much like the above paragraph. "Precision" meant tens of thousands of people included, but excluding millions. Keith Yamamoto and Atul Butte (link probably obsolete soon, as Atul is now at UCSF) phrase this very nicely in terms of advancing human health by having the courage to tell people "No."

Now I work in a field in which people in my lab routinely design reagents capable of specifically targeting one gene and changing a single base. If even one person has a mutation that causes a disease, we could theoretically make a reagent to change that mutation within a week or so (in the lab!). We're not doing that in the clinic, but I think the writing is on the wall, and things might be different in a decade or so.

Widespread treatment-for-1 would be a major challenge, since it differs from normal medicine (and even Precision Medicine) in so many ways. How do we pay for such a thing? Will it be covered by insurance? What's the incentive for a drug company to make a therapy for only one customer? Or is the technology itself the product and the therapy just one small example? How should we regulate it? How do we know if an intervention is working? How do we know if it's safe? The N-of-1 trial might be the only thing possible, because there may be only one person with this particular mutation. 

As sequencing gets cheaper and faster, we'll quickly accumulate massive piles of data. That's currently a very centralized model, in which reams of data flow in to big centers and high-level rules for the application of treatment flow outwards. Turning the clock further forward, a decentralized future is also possible, in which hospital bedside sequencing informs programmable therapies that can be created in the very same hospital. Near-future Precision Medicine will save many lives, but a one-off-treatment system could fill in the corners to spell the end of orphan diseases. Science fiction at the moment, and much needs to happen to bring it about (not just biology, but engineering, regulation, and so on), but at least now we can see a path through the woods.

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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. 

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This post expands on a slide that I often present in seminars: what is the scale (in time and impact) of next generation genome editing? I'm not restricting this to CRISPR/Cas9, because the field is moving so fast that it's anyone's guess whether we'll soon see a next next-gen (Cas10?). But the accelerator has been pressed firmly to the floor, and there's no going back. To avoid overuse of speculative words like "might" and "could", I'll just speak as if I have a crystal ball. But futurism is often a fallacy and the genome editing field is only 2 years old and moving very quickly so consider what's below a sketch at best and random guessing at worst.

Edit: Here I'm focusing on just a few areas out of many. There are very exciting things on the horizon for editing of crops and livestock, synthetic biology in normally difficult systems, and much more. I'm leaving all of that aside for now as fodder for another post.

Short: In the next few years I think we'll see greater adoption of genome editing in many labs, both academic and industrial. This will mostly be what I call "RNAi v2.0" -- disruption of  genes in a very fast and easy mode (either via CRISPRcutting or CRISPRinhibition). This will extend to both human cells and model organisms, but the scope accessible for reverse genetics will be greatly expanded. Now that more and more genomes are sequenced, we'll finally have a way to figure out what biologies underly all of those great annotations in those organisms (reverse genetics) or screen for which genes are responsible for incredible phenotypes (forward genetics). How do salamanders regenerate limbs? How do some fungi turn insects into zombies? What are the roles of genes expressed during Plasmodium infection? Does ablating gene X slow tumor progression in this model system? Are all of these genes really necessary for epithelial differentiation in the gut? These kinds of questions will be broadly answerable in both academic and industrial research settings: fundamental discoveries that will accelerate and broaden our understanding of the world around us.

Medium: Within five years true gene editing (surgically replacing one sequence with a defined replacement) will have matured and be as easy in human cells and model organisms as plasmid mutation currently is bacteria. We're already starting to see some hints of this on the horizon, so maybe this should even be in the "short" bin. But I think a lot of current work is focused on very low hanging fruit (important though it is), and there's still no clear path towards quickly and robustly engineering silent or deleterious variants, for example mutants with a fitness disadvantage. So this one goes into "medium term". Surgical introduction of mutation would be huge for any number of basic biologies, since it would enable one to readily ask reductionist and mechanistic questions in the context of a living cell or organism without confounding factors. On the translational front, in the medium term gene editing will totally change the way preclinical research is carried out. Custom-designed safety models (e.g. humanized rats), highly engineered cell lines to meld target and phenotypic screening, synthetic biology for enhanced drug production, and so on. People have been wanting to do these things for a long while and they might take a little longer to achieve in industry only because the focus will include robustness of the systems rather than purely speed, but they're coming. More relevant to the general public, in the medium term we'll start to see the widespread clinical emergence of ex vivo therapies that take advantage of gene editing, especially in the hematopoietic system. Clinical research and trials are already ongoing here (e.g. Sangamo's work with ZFN knockout of CCR5 for HIV), but now I'm talking about FDA approval and widespread use of an edited product as a therapeutic. The trial data has so far been very impressive on many fronts, but time will tell and the finish line is always further away than you think. 

Long:  Since the likelihood of anyone accurately predicting at this timescale is quite low, rather than make any specific predictions I'll instead wax philosophic. Here we're starting to talk about disruptive science fiction entering our lives in a real way. Things like in vivo editing in adult or postmitotic tissues. Sci-fi may actually be an apt comparison and offers a few positive examples of successful prognostication: Edward Bellamy predicted credit cards in 1888 and Arthur C. Clarke described communications satellites in 1945. And in a way, media of all kinds has been preparing us for genome editing for decades. I was recently asked how I explain what genome editing is and why it's practically beneficial. But the thing is, I actually don't need to do much explaining. I've talked about genome editing with taxi drivers, hair dressers, graphic designers, high school students, and Hollywood actresses. Everyone gets it right away. You don't need to know a thing about Cas9 or mechanisms of DNA break repair to understand genome editing. Most people very quickly understand what genome editing is and they see how much good it could do. But everyone also sees how much harm might come if we're reckless and how much care should be taken. So in the long term, our relationship with genetic diseases will fundamentally change. I'm not necessarily talking about germline editing, since one might have the same outcome with the ability to replace affected tissues with edited tissues. There is the opportunity for real and permanent cures for terrible diseases in which people currently just make do. That's powerful stuff. But it's a long road, and there's a lot left to be done. 

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There's been quite a lot of buzz around our recent Perspective piece in Science (Baltimore et al. with alphabetical author list, open access for now), stemming from an IGI-organized bioethics workshop in Napa. Ed Lanphier et al were clearly thinking along the same lines, and wrote a similar article for Nature. The crux of the matter stems from CRISPR/Cas9's ease of use. Germ line genome engineering has suddenly become surprisingly easy in a variety of organisms, and the same may be true for the human germ line (there are rumors that some have already tried).

This is a very important time for science, and much rests on clear communication and open discourse. Since germ line edits would be heritable, we are literally talking about the ability to change human evolution faster than natural selection. Many have drawn parallels between the 1975 conference on recombinant DNA technologies in Asilomar, including ourselves (several attendees of the original Asilomar meeting were at the Napa workshop). Some worry about the futility of trying to put the genome engineering genie back in the bottle.

To be clear, our position is not a call to outright ban engineering of the germ line. Instead, we ask for a halt to experiments along these lines until a much larger meeting whose attendees represent a broad cross-section of scientific, clinical, ethical, and regulatory expertise. Whether or not individual researchers have performed human germ line editing, we must stop and ask ourselves hard questions before embarking on this path in earnest. Is it acceptable to cure genetic disease? What about the introduction of naturally occurring advantageous alleles (e.g. PCSK9 mutation)? If we proceed, what safety standards should be put in place? It would be wise to hash things out before acting, rather than repenting at leisure.

In addition to a larger meeting, broad communication about the science is absolutely critical. America is at a strange point: the majority of people believe that science is a good thing, but simultaneously disagree with scientists on several scientific issues. For the last few weeks I've been experiencing the edges of this phenomenon, when journalist after journalist asks me about designer babies. We must do an excellent job of providing high quality information to non-scientists about the genome engineering revolution in which we find ourselves. The goal is not to pedantically "educate" the public. I've found that everyone, from taxi drivers to accountants to personal trainers to librarians, quickly and easily grasps what human genome engineering is all about. Science fiction has been priming us for this moment for decades. The real question, which must be put to everyone, is how should we proceed now that it's real?

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As announced at our Grand Opening, we've launched into a big collaboration with AstraZeneca to use CRISPR for basic research aimed at impacting human health. Just as important, we've also just started a very exciting partnership with Agilent, providing access to technologies we've previously only dreamed about. So what are these collaborations all about? What do we hope to do? Why are we working with companies at all? 

I think this is all about two-way communication. From my time at Genentech, I know that industry certainly pays a lot of attention to what's going on in academia (below I'm mostly talking about academics trying to directly make an impact for human health). But there's also frustration, because some ideas are really great and then plow themselves right into the ground during execution. For example, a super-cool proof of concept that will has no chance of impacting patients because the [assay|intervention|etc] is unnecessarily jury-rigged or the [results|compounds|cells] weren't discussed with anyone who might spend the next 12+ years to turn the idea into a therapy. Derek Lowe has any number of posts about these kinds of papers, and has strong words to say about most academic small molecule screens. In these cases, industry wistfully sighs, "If only they had done X, Y, or Z, we would be so excited to work with them to make it go further!" But unfortunately, there's very little bandwidth for those kinds of long-term gambles in an industry lab (Genentech was an exception, thankfully for me). In this way, some academic work that aims to help people instead just nets the authors a cool paper and then dwindles away. This is incredibly frustrating for both sides, since everyone truly wants to make a positive impact on the world and 

That's exactly what we want to avoid, and we're going to do it with two-way communication and tight collaboration. What high-risk (e.g. academic) research needs to be done in the medium term to help better therapies get to patients faster? What are new and emerging areas where breakthrough science meets potential to impact health? What are the long-term moonshots that might actually get picked up and turned into a world-changing therapy if successful? Both academic and industry scientists have strong feelings about these questions, but all too often we exist in the monoculture of our immediate environment and fail to really communicate with one another.

The IGI's collaborations with Agilent and AstraZeneca represents our first steps in the road to reversing this trend. We'll be doing basic research together with groups from both companies, in a truly collaborative mode. We hope to both to give them insight into new and great scientific discoveries on the horizon, and also to get their insight into areas where basic research now can have a dramatic impact in the long term. I think that through collaborations with industry groups we can make a very positive impact in the fight against many diseases (stay tuned for more on the science!); it's going to be an exciting time!

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It's a brand new year, and lots to do! The IGI is having our official Grand Opening in February; we're teaching an open CRISPR Workshop in July with Dana Carroll organizing and lecturers include Jennifer Doudna, Jonathan Weissman, myself, and more (check our website for more details on how to apply after January 30th); and we're convening a bioethics retreat very soon. Not to mention all the goings-on in the lab, including three new postdocs starting before March. Exciting times!

I'll be in Big Sky, MT for the next week at the Keystone Genome Editing and Synthetic Biology meeting. I'm looking forward to hearing some great talks, catching up with friends I haven't seen in a while, and generally immersing myself in interesting science. I'm also looking for talented and motivated research scientists and postdocs. No CRISPR experience necessary, feel free to come up and say "Hi" if you're curious about the IGI.

I find conferences to be a great way to even further boost my excitement about projects in the lab -- by the end I'm worked up about all the new ideas, collaborations, and projects spurred by conversations with unexpected people. The boost might also relate to the copious amounts of coffee I inevitably end up drinking. Perhaps this time I'll try water during the coffee breaks.

Check the @igisci twitter feed and this blog for updates from the conference. Don't expect liveblogging, but I'll post general thoughts as they come.

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There's nothing like hands-on experience to figure out how something works. In that spirit, I worked with 3D Molecular Designs to get a deconstructable, 3D printed model of Cas9 doing its thing. The model is based on the Jinek lab's recent structure of Cas9 bound to PAM-containing DNA, with some artistic license to build in the full non-complementary strand and the upstream and downstream duplexes. I think the model tuned out extremely well and beautifully illustrates how Cas9 tightly binds DNA by using the sgRNA protospacer. It also very concretely highlights some interesting mysteries about the structure, such as the HNH active site pointing towards the wrong DNA strand. Just the few hours I've been playing with this model have led to some neat insights.

Edit: correctly linked to 3D Molecular Designs instead of MSOE (sister organizations).

Cas9 bound to sgRNA and DNA target	HnH domain removed (sgRNA in orange, DNA in blue)
The DNA and sgRNA can be removed from the model (PAM in green)	The DNA strands can even be separated at the actual Cas9 cleavage site

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It's definitely recommendation-letter-writing season here at the IGI (multiple postdocs applying for fellowships, graduate rotation students going for the NSF, a friend is applying for academic jobs, and two people who reported to me while I was in biotech are up for promotions). Pairing that with several new students and some other exciting developments (more on that later) has led me to unfortunate delays between blog posts.

Yesterday I had a very interesting conversation with Hopi Hoekstra, who was visiting Berkeley to speak for this year's Allan Wilson Memorial lecture. Her talk was fabulous, and during our one-on-one she made the great point that the Cas9 literature is moving so fast that it's hard for people in various model organisms to keep track of what's going on. What works best in mice? How about in flies? Nematodes? Planaria? Wheat? The list goes on and on.  It's sometimes hard for me to keep up, and this is my field! Imagine what it's like for someone in (for example) EvoDevo who doesn't care about the tech and just wants to know what will work to answer their question.

It's clearly too much for any one person to collate while still doing their day job. But Hopi had the great idea to start some kind of community-led effort. People working with each model organism would contribute to resources (or forums?) that would provide primers for labs wanting to get started (or do a better job) in their area of interest. And a general resource to touch on the latest-and-greatest that could help everyone. This would be some kind of organized but open format, where anyone could contribute but information was relatively easy to find. Great idea, right? But how to actually get it started... A wiki? A Google Group?

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