NEB Podcast #39 -
Interview with Neville Sanjana: Using chemically modified RNAs to guide CRISPR/Cas13 activity

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Interviewers: Lydia Morrison, Marketing Communications Writer & Podcast Host, New England Biolabs, Inc.
Interviewees: Neville Sanjana, Core Faculty Member, New York Genome Center; Kevin Holden, Head of Science, Synthego; G. Brett Robb, Scientific Director of RNA, New England Biolabs

Lydia Morrison:
Welcome to the Lessons from Lab & Life Podcast, brought to you by New England Biolabs. I'm your host, Lydia Morrison, and here's hoping this show offers you some new perspective. Today, I am joined by three authors of a recent Cell Chemical Biology publication, NEB Scientific Director of RNA, Brett Robb, and from Synthego, Head of Science, Kevin Holden.

Lydia Morrison:
Together, we'll interview Dr. Neville Sanjana, a core faculty member at the New York Genome Center, about their recent collaboration and publication detailing the use of chemically modified guide RNAs to enhance CRISPR-Cas13 knockdown in human cells. Hi, Brett, Kevin and Neville. Thanks so much for joining us today.

Neville Sanjana:
Glad to be here. Thank you.

Lydia Morrison:
I wanted to dive right in and ask you to tell us about your recent publication, Neville.

Neville Sanjana:
Yeah, so this work, which was really a collaboration with everybody who's here on this call today and some other folks in all of our groups and labs, explored chemically modified guide RNAs for use in an RNA targeting CRISPR enzyme called Cas13.

Lydia Morrison:
What are the advantages of using chemically modified guide RNAs as opposed to other methods of gene knock down? Are there drawbacks? Are there advantages? Why did you choose that?

Neville Sanjana:
I think the natural comparison for RNA targeting CRISPR enzymes or really any RNA targeting system is going to be RNA interference, which has been a huge discovery over the last 20, 30 years. And I think the most exciting thing about RNAi, RNA interference, is that it's already entering the clinic.

So you asked about drawbacks. So there are some drawbacks. RNAi, it's well known in the literature that it's prone to off target effects. And there's now advanced algorithms that can help you design different kinds of RNAi, like shRNA that are virally delivered, or siRNA that are chemically synthesized.

And you can use these algorithms to predict what is a better RNAi target. But this off target issues, they're kind of always a concern with these approaches. The other issues that RNAi doesn't use a CRISPR enzyme, but uses an endogenous nuclease, these proteins like Dicer and the RISC complex. And these proteins have a particular localization within the cell that they work in.

So they're found mostly in the cytoplasm. So for RNA targets in the nucleus like noncoding RNAs, which is something that my lab studies a lot of noncoding genome regulation and noncoding RNAs, they're really not possible to target using RNAi methods. Now there's a lot of RNAs that are not in the cytoplasm.

Those are much easier to target. So when we say that this is now entering the clinic, which is truly amazing for RNAi whatever 20 plus years from the initial discovery to be... There's now and the last two or three years, there are FDA approved therapies that use these RNAi reagents. I think the first one is Alnylam drug used to treat a very rare form of amyloidosis and there's many of these different hereditary mutations.

And so, I mean, it's rare. It's a debilitating progressive disease, fatal, and it's just caused by buildup over time of this amyloid in brain, heart, all sorts of organs. And this RNAi is great. It targets, regardless of the mutation you might have in this gene, TTR, the RNAi can target the gene and degrade it. And that transcript is available in the cytoplasm.

So it's an mRNA, a messenger RNA that can be degraded. So I think we're just seeing kind of the beginning of these RNAi therapeutics and I think there's a lot they can do. There's some things that they can't do. And I think in both categories actually, because it's not just like one thing and done.

I mean, we see even, this is a little bit of a tangent, but we see with Cas9, you see so many different, or with DNA targeting CRISPRs, you see so many different approaches for say sickle cell anemia now, right? That's a disease where there's many different gene editing approaches.

So I think it's the same thing with these kinds of drugs that we're seeing entering the clinic that use RNAi, that there actually might be many therapeutic opportunities that are RNAi based, that are Cas13 based. But Cas13 certainly has I think some very unique things that are possible like targeting in the nucleus.

Kevin Holden:
Hey Neville, this is Kevin from Synthego here. And it was really great to work with you on this publication, this research. You talked a little bit about your motivation for, I guess, exploring the ability of the Cas13 nucleases to work effectively in cells compared to other types of gene knockdown.

Just thinking, you mentioned also working with SpCas9 and really a previous limitation of working with the Cas13 nucleases has been the ability to utilize them in primary cells, such as human T cells. What was really your motivation to want to do that work in that cell type and also your motivation for wanting to protect the guide RNAs?

Neville Sanjana:
That's a great question, yeah. So in our lab we also have a lot of interests in understanding immunotherapy and other kind of breakthrough technology of the last decade and understanding both in our earlier work, why does it fail?

In many cases, it doesn't succeed for the patient. What kinds of tumor mutations enable tumors to evade immunotherapies? And we're also very interested with very recent work in the lab, that hopefully I come back to tell you about next time, about how do we engineer better T cells? How do we supercharge T cells so we can avoid that?

We can make the failure rate drop down, or right now these kinds of like chimeric antigen receptor T cells, they're basically approved for very specific kinds of cancer, mostly liquid tumors, blood cancers. And there's a whole lot of cancer that isn't that, right? Solid tumors. We do a lot of work on melanoma, do some work on pancreatic cancer.

You don't really see CAR T therapies there. And so it'd be great if we could engineer CAR T therapies that are effective there. So our motivation would if working with primary cells like human T cells was so that we can do things like this, that we can engineer better CAR T, better TCRT, better kinds of these T cell immunotherapies.

And one thing that is, I think, foremost in the minds of synthetic biologists or genome engineers that are doing this kind of work, is that CAR Ts, even in cases where they work, you commonly have very severe side effects during treatment like these CRS or cytokine release syndrome.

And that might be that we're just pushing these T cells to be very aggressive, very active, and maybe that we need just a little bit more finesse in the approach. So one thing you might imagine doing is on the initial infusion of these, engineer T cells back into the patient. Imagine supercharging them for a week or two by targeting specific proteins' transcripts using Cas13 knockdown.

And then having that be on for a focus period of a week, two weeks and then go away. And so that's where I think Cas13 can be perhaps better than permanent genome modification where you say, knock out the immune checkpoint PD-1 or something like that in these T cells. I think this is just kind of our interest, and this is something that we've been trying to do since the work that we did with you guys.

But you could imagine flipping that around also, that you could temporarily modify tumor cells and go to the other side of that immune or that checkpoint synapse where they have all these things that they display, these immunoglobins on their cell surface that actually kind of push the T cells away. So you could imagine transiently knocking those down.

And that sounds kind of crazy. Oh, you're just going to deliver this to a tumor and transiently reshape the tumor micro environment. But we already have approved therapies that are kind of in a similar vein. Like for melanoma, we have oncolytic viruses that are approved, where you just locally inject at the side of the melanoma.

You inject the virus. And so you could imagine engineering a virus with Cas13 that, so this is maybe getting a little away from chemical modification, but you can imagine engineering virus Cas13 that does something similar. Remodels that tumor micro environment, makes it easier for your CAR T to come in.

So I think this was what we had in mind when we started working with you guys. This was the long term mission that we're making slow process toward.

Kevin Holden:
Yeah. And maybe just to recap, thought follow on... Specifically thinking about how you can get these systems to work in these cell types. Maybe you can talk a little bit about what motivated you to explore the modification space and the guide.

Neville Sanjana:
Yeah, the modifications were really simp... There was a pretty simple rationale for them, but I think it's something that probably everybody can understand now, now that much of the world has been exposed to modified RNA through the COVID vaccines that have just been truly amongst the most amazing science we've seen this last year.

So by chemically modifying the guide RNAs, what we do is we extend their usually short half lives I imagine. I mentioned already that even water is dangerous for these short RNAs. So we extend their usually very short half lives from... And can make Cas13 work. Instead of just working for hours, can now work for days or weeks.

But what we didn't know before we started working with all of you was how do we go about doing this? This hadn't been done with really any Cas13 before. And so the question was, do we just maximally modify every single base? Are there certain places, certain modifications or certain placement of the modifications that are better?

And that's really, I think the heart of the paper that we put together was saying, what modifications are good and where do we put them? And I think it was pretty worthwhile to do this study because I don't think we could have just looked at Cas9 and guessed it right off the bat that we just do the same things.

I mean, first of all, the guide RNAs, this is perhaps a bit technical discussion, but the guide RNAs for Cas13 are a bit different than for Cas9. They have a quite a different structure. And so I think it's really great that we did this very systematic study and I'm very grateful for Synthego for entertaining a whole bunch of requests during that process.

Brett Robb:
Great. Hey Neville, it's Brett from NEB here. I had a question. Many CRISPR based approaches routinely use mRNA or plasmids or viruses as you were just mentioning to introduce the nuclease to the editing reagents. I was wondering if you could just sort of talk us through, what do you see as the advantages of using the protein?

Neville Sanjana:
That's a great question. And this is something that we very explicitly tested in the paper. During the revision, I think this got buried a little bit maybe in the supplement, but we did do some work where we actually looked at the timing of the delivery of Cas13 protein versus alongside the chemically modified guide RNAs.

And something that we saw in many different forms of delivery, I think we looked at protein mRNA and having plasmid or integrated trans gene. We saw that if the Cas13 protein is not available when you put in those chemically modified guides, things are just a lot less efficient. They still work. You still see knockdown, but it's a lot less efficient.

And I think this is, we have this experiment with mRNA with the Cas13 delivered as mRNA. And there, you can see that if you co-deliver, you really don't get efficient knockdown. But if you deliver the mRNA in advance such that the protein is already made and waiting around in the cell, then when you put in those chemically modified guides, things work really well.

And so I think the really nice thing that we were able to take away from that is that, hey, we can actually do this ex vivo, we can make these RNPs, these ribonucleoprotein complexes, where we get this really nice Cas13 protein that came from your group. And so thank you guys for making this protein.

And then complex it just in a test tube, basically, just in like a salt buffer and then deliver it with electroporation or nucleofection directly into these primary cell types. So that was super exciting, I think, work that we were able to do and totally motivated by this idea that chemically modified guide RNAs, if they're just waiting around, there is going to be some... You're going to lose some effects, some impact if the protein is not there.

Kevin Holden:
Yeah, Neville, I had a kind of a following question from that. So you mentioned utilizing techniques like nucleofection to introduce the protein and the modified guides into the cells in vitro, essentially. Do you foresee any challenges or potential applications vis a vis with the modifications, perhaps for any types of in vivo targeting approaches?

Neville Sanjana:
Oh yeah. That's a fantastic question. I think always with genome editing, genome engineering, transcriptome engineering, the million dollar question, the much harder question, at least where we are in the field right now is always delivery, right?

And this is something that we, I would say the study, we really didn't focus on this too much. I think it's something we've got to think about carefully in the future. I think here, there's many different things you can imagine doing, right? You can imagine modifying.

Just sticking with the RNP idea, the ribonucleoprotein. You can imagine actually having a modified form of Cas13 that maybe has some peptide, some other things attached to it that could enhance delivery to specific tissues. You could imagine just... We talked about RNAi therapeutics earlier. Those are delivered with lipid nanoparticles. Same way the COVID vaccine is delivered also, lipid nanoparticles.

And so that's another avenue for delivery. I mean, this is just really brand new stuff and I just don't think there's been a lot that's happened here yet. There's so much to do, but there's already been, even though we're kind of early with Cas13, I think there's already some pretty exciting work. There's some pretty creative work right now in this area.

So there's work from Phil Santangelo's group at Georgia Tech, where they showed that I think it was mRNA of Cas13, they can deliver it by inhalation. So they were doing this for targeting, well, organisms that only live as RNA. So they were targeting flu and SARS‑CoV‑2 two, which has an RNA genome. It doesn't exist as DNA.

And they basically just aerosolized this mRNA, which perhaps had been modified in some way. And they showed that it was effective at preventing symptomatic disease with COVID-19. And so, I mean, that's just really creative. That's thinking about, okay, where's the place we need to deliver to? The lungs are the primary side of infection.

So let's make the mice breathe this thing in. And that, I mean, if you think about it even for humans, that would be really... People are afraid of getting needles or things like that. That's a pretty easy way to deliver a drug and so very creative, but again, early days. I think there's a lot of work ahead for delivery.

Brett Robb:
Terrific. So, I mean, throughout the conversation, you've really been talking a lot about how these could be applied, but I guess I'd wanted to ask a question or let you talk a little bit more about what other impacts on future therapeutics and/or diagnostics do you see this work is having? I mean, we talked obviously through conditioning cells, targeted therapies to tumors, et cetera.

Neville Sanjana:
That's a very good question, a very open ended question. So I think the diagnostics front is a little bit easier to address, right? Because we've already seen, I mean, less so with Cas13d, which is what our three groups here worked on together, but more with some of the other Cas13 orthologs like Cas13a and B.

And I know that your group, Brett at NEB, you guys have been very involved with labs all over the place with the Cas13 diagnostics making Cas13a and b enzymes. And so I think that's very cool because you can... People have now shown you can freeze dry it, you can deliver this stuff in the field and it can work basically anywhere.

It can be quickly reprogrammed. So if you have to update for Omicron variant or something like that, and you have to change out the guide RNA, it's really simple. So I think Cas13 is undeniably with techniques like Sherlock from say from Feng Zhang's lab already had very impressive impact on the field of diagnostics.

So I think about diagnostics. I'll just put my spin on it because... So a lot of what my lab does are these high throughput functional genomic screens, right? We do this, like using Cas9 to target every gene in the genome, understand what genes are important for cancer drug resistance or immunotherapy resistance.

And again, thinking about what are the unique properties of Cas13? I mean, this is a little bit different than what we've been talking about with the protein and chemically modified guides, but I think we're very excited to use Cas13 also to screen non-coding RNAs. Again, these nuclear localized RNAs, and you might say, well, why is that relevant to diagnostics?

We don't know a whole lot about some of these classes of RNA, like these long noncoding RNAs, or circular RNAs, or enhancer RNAs, or a million other RNAs that are in the nucleus. And I think because we can, as your group did, you guys stuck this NLS tag, this nuclear localization sequence, on Cas13, we can just direct it wherever we want.

In the bacteria, there's no nucleus, right? So we can just sculpt the protein to go wherever we want it to go. It doesn't require other proteins. It just needs Cas13 to kind of do its thing. And so for me, I think that's a very exciting thing that we can potentially discover, say, diagnostic, prognostic markers in that non-coding RNA space that might be useful for different indications, different types of cancer, things like this.

So hopefully that that showcases one thing that's actually happening and then one perhaps more future oriented thing.

Brett Robb:
Great, that's terrific. So what's next for you sort of, or immediately next, if you could talk about that? Do you have any sort of studies planned using the approach from the paper? What's new and exciting you guys are working on?

Neville Sanjana:
Absolutely, yeah. So I think going back to one of the unsolved challenges for us is really delivery. And so we want to try and move this. I think the paper was really amazing because we went from kind of simple cell lines to primary human donor drive T cell. So I think we covered a lot of ground in one study, but obviously we want to try and take this stuff in vivo.

And so we're thinking right now about how to use Cas13 in vivo mostly in mouse models. What's the delivery look like? How do we efficiently package this? Very basic things like do you deliver... Is protein delivery the right way to go? Or is it much easier to do what a lot of people in the field are doing, which is deliver Cas13 as mRNA and encapsulate that along with these chemically modified guide RNAs?

And so we actually have some new graduate students that just joined the lab in the last year who started making some of these lipid nano particles. We know very little about it, but it's been really fun learning about delivery because I think you can either kind of stay with what you know, which for us is CRISPR screens and some transcriptome engineering and things using existing enzymes, or you can try and push yourself, I think a little bit outside of your comfort zone.

And so we're doing that. We'll see how successful it may or may not be. But I think doing this in complex tissues, understanding can we deliver to particular regions of the brain, the spinal cord? We're very interested in developing single cell technologies to interface with this. And so can we look at how Cas13 affects different... If we target the same transcript in different cell types within the spinal cord, do we see differences in ventral versus dorsal regions, motor versus sensory regions?

And again, always thinking about both the science aspect, but also kind of a translational aspect. So for us, a lot of the focus is moving in vivo now with these tools, but it wouldn't have been possible, I think, without doing this kind of really initial work with you guys.

Lydia Morrison:
I actually wanted to back up and ask a follow up question about the temporal control of the guide RNAs themselves. So I was just curious, what is the level of attenuation that you can achieve? You sort of talked about hours versus days or hours versus weeks. How specifically would you be able to sort of fine tune that in terms of the actual delivery and longevity of the treatment?

Neville Sanjana:
Oh, that's a fantastic question. I think there's actually many ways that you can potentially attenuate. So I think the obvious one with the people who are on this call or podcast right here would be with different chemical modifications. Certainly in the paper, if you just look at the data that we have, you can see that there are different levels in the kind of the cell surface proteins that we target, which we can easily read out with FACS based assays, flow cytometry based assays.

You can see that there are different levels due to different modifications. I think that's a very straightforward conclusion you can take. It's a takeaway you can grab from the paper and then apply in your work. I think there's actually other ways that we haven't really explored so well right now. So a lot of our previous work that led to this current paper was really about what makes for efficient guide RNAs?

What makes for the best guide RNA, for the best knockdown? That's what we were focused on. How do you get 100% target knockdown? But through doing that and some more recent studies we've done in the lab, we've also been able to learn from kind of large data sets, what if I don't have a guide RNA that's perfectly matching maybe the target?

But what if I strategically introduce maybe one or two bases where I have a mismatch, can I tighter the effects of the Cas13 knockdown? So we normally think like, oh no, I mean, that's terrible. We want to avoid... We want the guide RNA to be perfectly matched. We want it to perfectly match just the target, avoid any other transcript in the transcriptome.

That's kind of what we're thinking, high on target activity, zero off target activity. But there actually might be places where it's advantageous to design maybe certain kinds of variant guide RNAs that can tighter the effect of Cas13. And so that's something we have some initial work going on in the lab.

We have nothing that we've published yet, but I think that actually could be very useful because we've certainly in some cases we achieve very effective knockdown and maybe you want to dial it down. And I think compared to, say, Cas9 knock out, this is a nice advantage of Cas13. Not to say you couldn't do this with Cas9.

There's techniques like CRISPR inhibition that allow you to do this. But this is not a zero sum game. There's going to be different approaches that are going to have different pros and cons. And at this really early stage in the genome engineering revolution, whatever you want to call it, I think we need to have as many approaches, as many arrows in our quiver as possible.

Kevin Holden:
Yeah, I just wanted to add onto of that. This is something we've thought about at Synthego actually quite a bit, which is actually developing temporal control of editing through guide RNA chemistry. And so we actually did put out a paper in Nature Communications last year for a process we call CRISPR off where essentially we engineer photo-cleavable linkers into SpCas9 guide RNAs, and then we can use light to control when the editing can actually be turned off.

And then we presented a poster earlier this year at Keystone showing that we can also do the opposite, which is turn on the guide RNA as well. So yeah, this is all controlled through light. So obviously in vitro in cells, it's very easy to shine light onto the cells and get this CRISPR on off activity and in exact temporal control on a guide RNA.

It would be interesting to see if this is possible to do in vivo. Maybe you could shine a light on somebody, I don't know, but... And of course Neville, if you're interested, we'd be interested in potentially collaborating around this on Cas13 as well. So just let us know.

Neville Sanjana:
Absolutely. I think I actually did see this paper. I've got to take a closer look and yeah, I mean, that's very cool. I think there's probably a whole class of chemical modifications, elements that we could add to the guide RNA, maybe even sequence elements that extend half lives. All of this I think is probably... I mean, it sounds like Synthego has already started exploring this, but I think there's probably so much room to do things.

I wonder if we could also have, chemically in the same way you have the photo-cleavable stuff, I wonder if there's chemical cages you might have too. Yeah, that's super exciting. That's awesome. I have to check that out a little bit more and we'll think about that.

Lydia Morrison:
I was curious if you've discovered any silver linings within the sort of pandemic era. We've all been living in this brave new world for the last 18 months or more. And I think a lot of people have found the time to reflect or to reconnect, or maybe just to slow down a little bit. I'm sure life at the New York Genome Center is super fast paced. And I was just curious, have you found any sort of silver linings for yourself personally or professionally in the pandemic?

Neville Sanjana:
Definitely. I think it's hard to... I'm laughing just because I think this pandemic is just, like everybody, it's just gone on so long and it's just so unexpectedly crazy and absolutely tragic to see whatever the current totals are. 800,000 people in the United States have lost their life. I don't know the numbers worldwide, but it's, I'm sure, much higher than that.

So I mean, I think the number one thing that comes out of this pandemic is a great tragedy, which is yeah, very tragic. But I think the most positive thing that's come out for me really is to see kind of what the scientific community is capable of. Obviously, the collaboration we're talking about right here, we had great technology tools that facilitated... None of us met in person while putting together this study, right?

We just sent things back and forth and we got science done. With the pandemic, there's been so much amazing translational science and it's been done so quickly. That's the other thing that's been just astounding. Just think of these amazing things like the waste water testing, right? Can tell you whether a variant is circulating in a population before the population knows.

Work we've done like functional genomics of the spike protein. We worked on the very first mutation in spike D614G, and we're able to understand why is it more infectious? Why did it replace the original variant? And of course there's the number one most amazing thing, which is the RNA vaccines, which saved our lives quite literally.

And so right now it's really, I think we're just so bogged down this just to see that we're still here. I think it's sad, but I do think as we get through this, as we get to the other end of it, which fingers crossed 2022, I think we're going to look back and see that this accelerated science climate that happened now actually is going to have some other very positive benefits.

If you look at, for instance, like BioNTech or something that made one of these COVID vaccines, they're now not talking about work toward a malaria vaccine. Current malaria vaccines are not very effective. Imagine if instead of a 30% effective malaria vaccine, you had 90% effective malaria vaccine like what we have with COVID.

What I hope is that some of the things we discover here are going to have great impacts for human health in other dimensions. But again, there's just so much here. Like, why are we so ill prepared for pandemics and things like... There's other, I think, implications beyond science that are going to be hopefully somebody will reflect on them.

But at least from my perspective where I sit, just really amazed at the scientific community, amazed at the people in my lab who contributed to some of the COVID science, but also just how science... This is kind of like textbook scientists coming together and doing something amazing. So it's good to see that and good to know kind of what humans are capable of.

Lydia Morrison:
Absolutely, it's nice to see science save the day and I think hopefully get the recognition that it deserves for really protecting the global community. And hopefully, I think you're absolutely right. It would be amazing to see an mRNA vaccine against diseases like malaria or some of the sort of third world diseases that don't get the attention that they necessarily should from the scientific community at large. So that would absolutely be, I think, a silver lining. I'm going to count that as a silver lining.

Neville Sanjana:
Yeah. I mean, the principle of mRNA really seems to be that you could target really anything and that's going to really change vaccine development. We need to see more data beyond on SARS-CoV-2 but this is potentially going to be really amazing for all sorts of infectious disease, maybe even cancer also.

Lydia Morrison:
Yeah, and I think the speed with which the RNA therapeutics can adjust for changes in variants or changes in, I guess, specific mutations of individuals with cancers or something like that, it should be really amazing to see what comes next.

Neville Sanjana:
Absolutely. Actually I've become so used to RNA vaccines that when they were talking about the Omicron variant, they said something, whatever, Pfizer, Moderna. They said they'll take them three months. I was like, three months to do a new variant? Go faster than that, come on. But you quickly become, first, the technology is magic, and then you become used to it within no time at all.

Lydia Morrison:
Right. It's like next day shipping.

Neville Sanjana:
Exactly, you're right.

Lydia Morrison:
Now I'm disappointed if I don't get it.

Brett Robb:
I would say I have one silver lining. I say I would just contribute to this group. I think it's some of those early days of the pandemic. They're now the early days when we were working together on this project. I think sort of looking forward to getting on Zoom calls with you guys or seeing data that you guys were generating.

That was just such a high point for me in some of those very early days when we were sort of stuck in home offices and dealing with all kinds of other stuff in personal and professional lives. Actually seeing science happen in real time in that period of time and in that environment was a big silver lining for me.

Neville Sanjana:
That's so good to hear. I think there's so many people actually that came to us in the first days of the pandemic because we had just released kind of the ability to predict effective Cas13 guides. And it was clear that a lot of people were making Cas13 guides to target SARS-CoV-2.

So I think that the work that we were doing at that time and earlier Cas13 work, I think it really disseminated out even though in our collaborative paper, there's really only just a small bit, kind of a proof of concept of how to target the universal leader sequence that's on all the subgenomic RNAs. But yeah, I think there's actually a lot of groups doing that based on how many emails we received for guide RNA predictions.

And I don't know, Synthego and Kevin probably know more about how many guides they've synthesized against SARS-CoV-2. But yeah, I think it was great that we launched the project when we did.

Kevin Holden:
Yeah, I'll just add on, Brett, to what you said. I'm sure NEB like Synthego here, you got a lot of inbound requests for Cas13 around SARS-CoV-2 diagnostics, therapeutics. It was the same for us. And it was really inspirational actually to see the scientific community kind of come together and especially labs to just completely pivot from what their normal comfort zone is into researching therapeutics or even the biology of the virus.

Including yours Neville. So it was really inspirational to see that. And that's definitely a silver lining for me.

Neville Sanjana:
Yeah, we had never actually done a drug screen. We always just did CRISPR screens. And so we did CRISPR screen and we were like, we can't stop here. Once we figure out what are the vulnerabilities of this virus genetically, let's target it with some actual drugs. And so yeah, you are totally right, 100%.

Lydia Morrison:
I think this is the longest silver linings discussion we've had in one of the podcast episodes yet, and I love it. I think that that means that there's actually a lot to celebrate amongst the tragedy. So with that, I would say, thank you so much to you all.

Thank you Neville for taking the time out of your schedule. Thanks so much Kevin and Brett for taking the times out of your busy schedules to be here with us today. And it was such a pleasure talking with you all.

Brett Robb:
Thanks so much.

Neville Sanjana:
Thank you.

Kevin Holden:
Yeah, thanks everyone. Looking forward to working all together again in the future.

Lydia Morrison:
Thanks for joining us for this episode of the Lessons from Lab & Life Podcast. Check back soon for a new episode.


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