Programming Life with Rachel Haurwitz (Caribou Biosciences) and Trevor Martin (Mammoth Biosciences) | Disrupt SF (Day 2)
3:02AM Sep 7, 2018
Now CRISPR has taken biosciences by storm. And even now startups are starting to appear in this space. So to discuss this subject is Rachel Haurwitz from Caribou Biosciences and Trevor Martin from Mammoth Biosciences, and they're going to be joined by TechCrunch's very own Sarah Buhr to unpack this fascinating subject, where in the future we'll all be able to edit ourselves into the perfect being. Hello. Round of applause, please.
Alright, so we were just talking about, backstage about how cool this is that we all get to delve into the subject and you get to work with it every single day. And there's actually been an explosion of innovation in the space in the past couple of years, right? But there's a lot of confusion around it sounds very sci fi. So I want to delve into what is real in CRISPR?
Sure. So CRISPR is gene editing, which is basically the ability to go inside of a cell and precisely change DNA sequences. I like to think of it as kind of a word processor, the Microsoft Word of DNA, if you will, but it's nowhere near as good as as Microsoft Word, right? In a, in a word processor, you can do all kinds of sophisticated changes. We're not there yet. We're pretty good at deleting one gene at a time. And sometimes we can insert a new gene or possibly even change the spelling of one gene.
But it's still pretty simple. We're talking about really practically being able to make one edit at a time. I think, a few years from now, we'll be able to do a lot more. But it's definitely the early days of what's practically possible.
And to continue the software analogy, the way we think about CRISPR at Mammoth is really, as biology's search engine. So just like you go on to Google, and you can type in a search string, and it'll tell you what you want to know, and find things, we think of CRISPR as a search engine.
For Caribou, they're searching for things you want to edit. For us, we search for things that we want, then want to tell you whether it's present or absent. So we actually use CRISPR for diagnostics. But I think both of us really kind of use that core search functionality that's part of the CRISPR proteins.
Yeah. So here's what's really interesting though, is you were, both of your startups were co founded by Jennifer Doudna, who was the co inventor or co creator of, co discoverer, let's say co discoverer because that's more correct, of CRISPR technology. And she's actually quoted as saying that she thinks that CRISPR is going to change medicine in the next five to 10 years.
So I'm surprised to hear you say, you know, we're only at one gene at a time word processing. It sounds like it's very slow. Where does the, we're going to change medicine the next five to 10 years, come from?
Turns out, that's all it takes. So if you look at genetic diseases, they're probably 6000 different diseases that are caused by one single genetic mutation. And so the ability to change one gene could have a profound impact for all those different communities and patients. I'm not saying we're ready yet for all 6000, but certainly a laundry list of different groups and academia and industry are advancing programs to try to correct those genetic diseases.
Likewise, what we're doing at Caribou is actually using gene editing to reprogram the immune system to fight cancer. And so even being able to make a small number of changes gives us the opportunity to have a profound impact on a variety of different cancer patient populations.
So it turns out, you don't need to completely rewrite a genome to have a really profound impact on medicine. And I think she's right. I think five to 10 years from now, medicine and how we treat patients will look very different from how it does today.
And actually, at Caribou, you, you pivoted from doing animal research to human research. Is that because of the, why, why did you change to human research?
Yeah, we pivoted actually from a very broad model of really being experts at gene editing technology, and then partnering with other companies to help them use it. And so we've worked with plant groups and animal groups and research groups and industrial biotechnology and all kinds of applications. And along the way, really got good insights into where some of the technology challenges were, and so had the opportunity to really invest in solving some of those challenges.
And with these new technology solutions in hand, we have decided to focus our efforts on developing new therapies. We think that's the best place for us to make a bet using our capabilities.
Yeah, it's certainly more interesting. You want to say something Trevor?
Yeah, I mean, going back to your original point, which I think it's pretty interesting, that like changing healthcare in the next five to 10 years. I, I think that that's totally on the money, especially in terms of gene editing. And that's totally possible.
And the thing is the CRISPR field is developing over that time as well. So our company is based on a technology that was invented in Jennifer's lab that wasn't even around when Caribou was originally founded. So it's not just development on the commercialization side, there's also development on the basic research side.
And we're excited to leverage that and commercialize it very quickly. So we were founded a year and a half ago to leverage this technology that came out more recently through that kind of core research that was going on. And we're going to different field diagnostics. So it's very different pipelines.
And I think that's kind of, part of, what sets these timelines is you have to make sure that you have something that's safe and very well working, and really something that's effective and usable in the healthcare setting. Because healthcare is not like other fields where you can necessarily, you know, break things as much. You really want to make sure that something safe and effective.
Some might ask if, if you switch to human research, maybe because you found a way around the current and patent battle situation, if that might be part of it.
Sure. So if the IP landscape definitely makes things more interesting in CRISPR land. And part of what we've done at Caribou is actually invent a new version of guiding technology. How we actually get the CRISPR system to the right place in the genome. And it gives us a pretty strong IP portfolio. And that's absolutely part of the calculus for us.
Yeah, so tell us a little bit about that. So that's not just the so CRISPR Cas9 is the enzyme that you use. And then there's a whole new technology. That, on top of that you've also developed.
Right, so how CRISPR actually works is based on cutting the DNA at the place that you want to edit it. And it turns out most cells hate to have their DNA broken. And they actually die unless they can fix it. But how they fix it creates some changes in the sequence, and that's actually where the edits come from. So again, some differences between Microsoft Word and and how CRISPR Cas9 works.
But Cas9 on its own can't cut DNA. It actually needs a piece of RNA to drag it to the right place in the genome. And so what we've done is actually develop a new guide that's some DNA nucleotides and some RNA nucleotides. And that really improves the specificity of the system, it increases the chances that Cas9 goes to the place that we wanted, rather than accidentally going somewhere else in the genome.
And so we think that's really important to Trevor's point, as you think about safety. And as you think about efficacy, really trying to tune the specificity of these systems is is really important.
Yeah. Trevor, where, where do you come in on what Caribou is doing?
So we're in a different field. So we're really focused on using CRISPR for diagnostics and that has its own sets of challenges and opportunities.
For example, there's an entirely different regulatory path for diagnostics versus gene editing. And there's also totally different applications. Obviously, we're right now here at mammoth, we're really focused on building the diagnostics platform. So there's obvious applications and things like health care. So detecting like infectious disease at detecting RNA or DNA biomarkers for cancer risk or cancer presence.
But even outside of healthcare, there's lots of exciting applications around like environmental DNA and RNA in aggregate, things like agriculture.
Taking brown brown spots out of mushrooms, apparently, you can CRISPR brown spots out of mushrooms. So we're, we're cutting genes out of our food.
Yeah, so that's more on the gene editing side. So on our side, we'd be more detecting, like, maybe what species of mushroom is this? And is this the species that you actually wanted to get at the grocery store as an example, or what's kind of is the soil microbiome of this farm? Is that something that is going to help these plants grow?
We're we're not determining what those biomarkers are. We're working with partners who are experts in those verticals, so experts in farming experts and infectious disease experts in cancer and they have these biomarkers that they spend a lot of time, a lot of research figuring out and we offer them and affordable and very effective way of actually detecting this biomarkers in a commercial setting.
There doesn't seem to be a lot of regulation around the food sector for CRISPR, but they're definitely as around the human sector. And there's been some concern that China might beat us because there's not enough they're not there's not as much regulation there. They're able to do human experience embryo experiments, and they seem to be possibly getting ahead of us. What do you both of you think about that?
Yeah, I mean
I think. That they're going to think that they're.
So CRISPR is a worldwide phenomenon, whether it's China or someone in Europe, for someone anywhere in the world. I think that it's such an exciting technology. And importantly, it's a democratizing technology, the barriers to entry are very low.
So I think whether we're talking about China or somewhere else, I think that there's opportunities for people all over the world to leverage this technology and the lots of different regulatory frameworks. So on our end, we're thinking about diagnostics.
And we're, you know, very eager to make sure that we're creating a product that's working with those regulatory bodies across the world to actually come to market. But I think in general, it's not just a kind of this country or that country. I think in general, there's kind of a global CRISPR ecosystem that you have to think about when you're in this field, because the technology is very accessible and democratize.
We, but you do have one company country that's saying, sure, we're going to do whatever we want. You have another country that's saying hang on, we were talking about changing the entire human genome.
Yeah, I think there are two ways that the differences in regulation in China versus the US are playing out with respect to gene editing right now. One is for traditional therapies. See, look at the potential of gene editing in the cell therapy cancer world. There's a lot of activity both in the US and in China, but a lot more clinical trials are happening in China right now than in the US. Why?
Well, at least according to The Wall Street Journal, it's because in China, what it takes to actually start a human trial is very simple compared to the FDA mandated process here in the United States. And so it's definitely setting a very different tempo of what's happening. I think there are also some questions about transparency and clarity that are are concerning.
But there's also the question of human embryo editing that you brought up. And I'd say they're interesting differences, not just between China and the US, but even US and several different European countries for where it's legal to do research on human embryos where it's not and how that impacts even just the basic research.
So what do you think? I mean, what what do you think of that? Do you agree with the FDA that we need to have more regulation around this or do you think we need to relax it a little bit.
So Caribou policy is no human embryo editing full stop, as we look at our organization and where where we think we can do good in the world. There are a lot of other problems that we can solve. And we just aren't going.
Mainly looking at human diseases when we're already we've already grown up and exactly become who we are. Yeah, okay.
It's actually not the FDA who said, No, it's the NIH. It's the funding bodies here in the United States who are really first movers around driving, who does what research, whereas in other countries like the UK, for example, it is governmental agencies that are regulating what's legal and what's not. And that's leading to very different experiments happening in different places.
How has the legal battle affected development for both of your companies? Because you are, you know, you're both co founded by Jennifer Doudna, none hold certain patents versus what MIT is doing.
Sure. So I think Trevor's lucky that he's he's not part of that.
Right. You don't worry about not so much just search engine.
Yeah, it's a great question. I can you maybe preface a little bit in terms of we're talking about this a bit earlier as well. And I think actually the fact that there's multiple companies in the space can actually spur innovation and can spur
The kind of speed that these technologies come to market. So people always think of it as something that's, like blocking and something's preventing. But actually, I think there's real advantages in terms of like having multiple players in a market that really can help spur innovation. So.
Yeah, I completely agree with that, you know, caribou is the exclusive licensee of the University of California and University of Vienna on on that side of the fence. So we do have the pleasure of paying for some of the legal bills associated with this, but it doesn't impact the speed of innovation and probably has actually.
You don't have to go to MIT and say, Hey, we want to work on this particular area. You don't have to work with them on that.
What I would say is what we've seen with previous similar IP battles around other technologies like RNA or otherwise, as products start to advance towards commercial readiness, which obviously our field is not there yet people figure out what the licensing relationship is that's going to get them their products on the market and so
it's it's a it's a business resolution at the end of the day, but we're still early in that field.
CRISPR is not the first field to go through an IP battle. So, you know, right. Obviously it's in the news. But I think that there's a clear path that's been followed for it.
As you get further down. There may be companies that need to work with both of you. There may be.
Could be absolutely, yeah.
Okay. That's good to know. And how do you, so, Jennifer Doudna is a very busy woman, she co founder, both your companies along with several other startups. She's on the board of many companies. apparently she's starting her own lab. I just read about she's starting her own lab with an UCSF affiliate today. So how involved is she in each of your companies? How much do you see her?
Yeah, so Jennifer is a co founder and chair of our scientific advisory board and I think that's the role that is really impactful for us as a startup. Um, you know, as great as it would be to have Jennifer in the lab doing experiments. I think that would not be lovely.
Leveraging her time in an effective way. And she's been completely available. And it's very enthusiastic about commercializing these technologies. And the reality situation is, you know, other people in the company are doing the experience every day. And she's helping set the scientific vision and the scientific agenda and the broader idea of where CRISPR is headed. And that's incredibly valuable to us as a startup. And that's not something that requires being in the wild with a pipe every day.
So I think that we're incredibly lucky to have her involved in the company. And she's really been a driving force and making sure we can commercialize this technology.
She's not day to day she's just sort of guiding everything.
Okay, that's interesting. You kind of got into some of the issues around CRISPR we talked about sounds like you have something new. That's kind of interesting, but there have been a few recent scientific papers who have suggested there are problems with CRISPR. You mentioned one of the problems is that the when you splice the DNA tends to damage the Janet around it. We talk about some of the problems that we're seeing right now. And maybe you mentioned one solution for some other solutions you've seen.
That's a great point. And I think it's so unique to the CRISPR world right now, because there are thousands of labs who are using this as a tool. And so we're seeing many, many different groups working with it, collecting data and publishing on it. And so the community is learning a tremendous amount really quickly, which actually think is fabulous for patients. The more we can understand how this technology works, more likely we are to actually deploy it safely and effectively in the clinic.
But it does mean that because it is such a high profile, high attention technology, sometimes when these papers come out, they catch the attention of major newspapers and the link between the science and the conclusion kind of gets lost in the weeds. And so, you know, some papers end up being summarized as CRISPR causes cancer which is a not true and be not not what the papers were trying to claim.
But I think they do all really point to the fact that if you're making changes to the DNA, they're all kinds of consequences, both intended and unintended. And so one of the things that I'm really excited about is the whole industry is coming together to try to figure out how do we rigorously measure this, there isn't a gold standard for how to measure what we call off target effects.
And so NIST, which is a national body for standards, is actually helping the genome editing community solve this problem, which I think is fabulous. It's it was I look at the different companies. It's really a pre competitive challenge. And if we can all talk the same language and measure things the same way. We have much more effective conversations with regulators, with patient advocacy, advocacy groups and others.
I understand that CRISPR as we know it right now is about 99.5. I've seen different figures but it's around 99.5% effective or accurate.
It depends. It's a range.
It's a range. So I mean, even if there's like a half a percent of a margin of error, and you're experimenting on humans, how does that does that weigh on you?
It's it's a great question. Most groups ours included, are starting with therapeutic programs where you're actually editing cells outside of the patient's body. And so you have a lot more control over the quality over what you can study about the cells before you put them back into the patient. And so we think that's a way to to de risk the technology.
There are other groups who are looking to deploy it directly in a particular organ but again, they're really relying on other technologies to help ensure that they're getting it just to the organ that they intend. But all of this really fits within the purview of the regulatory process of the FDA and and other places. You know, there's a long, long history of how you think about safety and how you measure that in all kinds of essays in cells and animals in the research labs long before anyone's ever comfortable with the idea of putting it into humans.
And I think that's a great point, the difference between in vivo and in vitro. So, for mammoth, we were doing in vitro diagnostic. So actually, we're not putting CRISPR into human cells, for example. And I think that there's a very different regulatory path for that. And as a society through things like the FDA, we've determined like this is the regulatory path for things, for example, that are in vitro verse in vivo.
And there's always going to be some balance between the benefit of what you're doing, whether that's diagnostics or gene editing. And the risk involves like that half a percent or whatever it ends up being. And that's why we have these rigorous regulatory processes to try and weigh those two things. And as a society, we've determined that these are the milestones you need to meet before we say this is something that should be widely distributed, whether that's diagnostics or therapy.
Last question what is something that both of you are excited about in CRISPR that's coming down the line what what you can you tell us is exciting to you?
Yeah. So at mammoth are incredibly excited to bring in vitro diagnostics with CRISPR into the market, there's a very different pathway to bringing out in compared to things like.
Maybe explain what in vitro diagnostic is.
Yeah. So that's, for example, like if you came into the hospital and you wanted to know, if you had some sort of infectious disease, for example, or like a, do you need an antibiotic? Because you have a bacterial versus viral infection, I could there be a tool that's accessible, affordable with high specificity and sensitivity that could give you that answer using CRISPR. So that's what we're really excited about bringing to market and that's something that wasn't possible even two years ago.
How about you?
Yeah I'm really jazzed that I think CRISPR is the tool to unlocking what people have thought of as genomic medicines, really, the ability to treat a disease at the genetic level, you know, we've had the human genome sequence for quite some time now, and I think it never really bore the fruit that people hoped it initially would.
And I think gene editing will really allow us as a community to turn the corner and really think about treating disease at a genetic level. It's a much more personalized approach to medicine and I think it holds a lot of potential.
Great. Thank you so much, both of you. And lovely. Thank you.