CRISPR has emerged as a powerful tool for altering DNA sequences with incredible precision, opening up new avenues of research into the treatment of disease. In this episode, we explore the science behind CRISPR, as well as its potential. From curing genetic disorders to creating new crop varieties, the possibilities seem endless. Our four guests today are scientists working to push these gene editing tools to the next frontier.
CRISPR has emerged as a powerful tool for altering DNA sequences with incredible precision, opening up new avenues of research into the treatment of disease. In this episode, we explore the science behind CRISPR, as well as its potential. From curing genetic disorders to creating new crop varieties, the possibilities seem endless. Our four guests today are scientists working to push these gene editing tools to the next frontier.
Speaker 1 (00:06): The Royal Swedish Academy of Sciences has today decided to award the 2020 Nobel Prize in Chemistry, jointly to, Emmanuelle Charpentier and Jennifer Doudna for the development of a method for genome editing.
Speaker 2 (00:22): CRISPR/Cas9, or simply, the genetic scissors were discovered just eight years ago, but have already benefited humankind greatly. Only imagination sets the limits for what this chemical tool, that's too small to be visible with our eyes, can be used for in the future.
Rachel King (00:49): Jennifer Doudna and Emmanuelle Charpentier won the Nobel Prize in Chemistry for their discovery, in 2011, of CRISPR/Cas9.
(00:58): CRISPR has emerged as a powerful tool for altering DNA sequences with incredible precision, opening up new avenues of research into the treatment of disease.
(01:08): In this episode, we explore the science behind CRISPR, as well as its potential. From curing genetic disorders to creating new crop varieties, the possibilities seem endless. But, are the expectations too high? Will CRISPR really improve health outcomes?
(01:26): Our four guests today, are scientists working to push these gene editing tools to the next frontier. Yes, there are challenges, but all four believe we're on the cusp of a biotechnology revolution.
(01:39): I'm Rachel King, and you are listening to, I Am BIO.
(02:01): As soon as Jennifer Doudna and Emmanuelle Charpentier published their ground-breaking paper, describing CRISPR, scientists were immediately seized by its possibilities.
(02:12): Our first guest says CRISPR changed the scientific landscape.
Leah Sabin (02:16): My name is Leah Sabin, and I am an Executive Director at Regeneron.
(02:22): CRISPR has changed everything about the way that we do science. The ability to make genetically engineered mice, for instance, has been really enhanced by the ability to create specific cuts in the mouse genome.
(02:35): The ability to model human mutations in cell lines in order to study them more effectively has been dramatically enhanced by CRISPR.
(02:43): Even the ability to quickly as, does this gene matter in a specific disease context, in a disease model organization? We can very quickly interrogate the role of different genes, in different diseases by quickly creating a knockout, using this technology.
(03:00): The ways in which it has advanced science, are too many to list. It has been, for sure, the most exciting advance, in science, in my career, absolutely.
Rachel King (03:11): And how exactly does CRISPR work? Leah describes it this way?
Leah Sabin (03:17): Let's say, if you're on an airport runway, and you wanna hit a specific site on that runway, what happens is, the Cas9 nucleus paired with its guide RNA, and it can scan along that runway, and it's constantly checking to see if it has a match.
(03:34): And once the guide RNA sees its match, it can bind and signal to the protein, the nucleus, that it's time to create a cut. And so, the nucleus is controlled, it will not cut unless it gets that exact match, that will tell it, it has permission to cut.
(03:52): And that's a huge advantage, because, control of where exactly the nucleus cuts, particularly if you're editing a human genome, is essential.
Rachel King (04:01): Although there are a number of different applications of the technology, Leah says, most scientists are aware that it will take a lot of work to convert this elegant and exciting scientific idea, into something that could actually help a human.
Leah Sabin (04:15): And the challenges there are, delivery. So, how do you introduce these editing components into human cell? What kind of cells are you able to get to in a human being? What is the efficiency? Even if you can get to the right cells, can this enzyme actually do its job in a human being's cell?
(04:35): Many of the disease that one would want to treat with this type of technology would require a fairly high efficiency to actually make a difference in patient's life. So, all of these were unknowns. And, for that reason, a lot of early therapeutic applications of CRISPR tech was in ex vivo editing.
(04:54): So, applying the technology to cells outside of a human being. Cells that were removed from a patient, modified, and then, put back into a patient. But, that is, in itself, a very expensive process, a really difficult process.
Rachel King (05:06): Regeneron and Intellia teams were the first to have clinical data showing that targeted cells could be edited within the body, with a single, intravenous, infusion of CRISPR.
Leah Sabin (05:18): So, what we sought to do with our collaborators at Intellia Therapeutics, was to develop a method whereby we could deliver the CRISPR machinery directly into a human being, and that this delivery would happen only one time, and this single dose would create a therapeutic edit, that would help a patient for the rest of their life.
(05:39): The first disease that we applied this technology to, is a disease called, transthyretin amyloidosis. Transthyretin amyloidosis is caused by the misfolding of a protein called transthyretin, which is shortened to TTR. And so, what happens in these patients who are suffering from transthyretin amyloidosis is that, their TTR protein becomes aggregated when it's circulating, and becomes lodged in organs where it doesn't belong.
(06:13): We aim to reduce the source of this protein, which is coming from the liver. Our therapy targets the DNA encoding TTR in the patient's hepatocytes of their liver, in order to reduce the supply of misfolded protein.
(06:29): Clinically, several patients have received a single administration of our experimental drug, which is called NTLA-2001, and it is a lipid nanoparticle that targets the liver, and delivers the CRISPR machinery to the liver, which creates a edit in a specific location, within the disease-causing gene, with a goal of disrupting expression of the disease-causing gene, in order to reduce the amount of misfolded protein in that patient's circulation.
(07:04): What's really exciting is that, the publication just describing how to use CRISPR as a programmable nucleus, was in 2012, and by 2021 Regeneron and Intellia together, already generated some very promising, first in human, data, suggesting that this CRISPR technology can work to treat human disease.
Rachel King (07:29): Building upon this breakthrough, Regeneron is going beyond using CRISPR to knock out or modify disease-causing genes. The company is researching whether the technology could durably replace genes that might be missing.
Leah Sabin (07:42): We are aiming to use CRISPR in two specific ways. One is to disrupt disease-causing genes. On the flip side, we also are aiming to use CRISPR to allow us to permanently replace a missing factor in a given disease, whether it be hemophilia or Pompe disease, or any other disorder where gene replacement or gene correction in the liver would be beneficial to the patient.
(08:08): But, you can imagine, there are many diseases outside of the liver, that could benefit from either a gene editing approach or a gene replacement approach. And so, and interest of ours is to develop deliver technologies, and the next generation of CRISPR technologies in order to have a suite of technologies that would allow us to perform any edit that might be required to treat a given disorder, in any tissue in the body.
(08:38): The potential to be able to modify a patient's DNA in order to permanently correct the source of the disease is extremely powerful.
Rachel King (08:49): Leah's colleague, David Gutstein, is helping to test Leah's work in clinical trials.
David Gutstein (08:54): I'm David Gutstein, and I'm the Program Head for bleeding and clotting disorders, here at Regeneron.
Rachel King (09:00): Regeneron is working on several disease targets, but is making the most progress with TTR.
David Gutstein (09:06): The one that's the furthest along in the clinic is addressing transthyretin amyloidosis, and with that program, we're currently in the clinic, studying that CRISPR therapeutic in patients that have either the heart disease phenotype, conferred by transthyretin amyloidosis, or the peripheral nerve phenotype that is caused by this rare disorder.
(09:36): We have treated patients with either the heart or nerve phenotype, and we have seen upwards of 90% reduction in this transthyretin protein in the circulation. So, very substantial reduction in transthyretin protein.
(09:55): But we're continuing to monitor these patients, we work very closely in collaboration with our partners at Intellia, for clinical responses from these patients. These are early days for this platform, but we have very encouraging results to this point.
Rachel King (10:13): Although not as far along as the TTR program, Regeneron is also working on developing a gene insertion program, targeting patients with the rare bleeding disorder, hemophilia, which is debilitating and potentially life-threatening.
David Gutstein (10:28): These patients are deficient in a specific blood factor, and they are unable to clot their blood normally. And so, they can have spontaneous bleeds. Because of this, they can develop bleeds into their joints, that can cause progressive disability, into their soft tissue, that can cause very substantial pain syndromes, and, occasionally, they can even have life-threatening bleeds.
(10:57): If we can intervene somehow, and CRISPR may give us that opportunity, we may be able to substantially improve the lives of people who suffer from this disease, and from other genetic diseases.
(11:13): What we've come up with is a system, using CRISPR, to insert a functional copy of the missing factor, into the cells, in their liver, so that they can produce therapeutic levels of the factor, thereby prevent these spontaneous bleeds.
(11:31): That program is currently in the pre-clinical stages, but we're hoping that we can progress that into clinical studies in the not too distant future.
Rachel King (11:41): As with any novel therapeutic, there will always be challenges in taking in through clinical trials.
David Gutstein (11:46): We are very focused on prioritizing safety for our patients.
(11:53): Another challenge in bringing forward novel therapeutic, like transthyretin, is that, while we have very robust pre-clinical characterization, we have very limited translation into the clinic. And so, selecting doses to go forward, is going to be an area where we pay tremendous amount of attention.
(12:15): And we're going to be looking very closely at how we can translate data from our pre-clinical models, to predict how we should be dosing in the clinic, at what levels, and in what, sort of, format.
(12:32): So, there are numerous challenges for taking this forward into the clinic. We're working very diligently, pre-clinically, to understand all of the aspects that we can possibly glean at that stage, before we transition into the clinic, with these therapeutics.
Rachel King (12:56): After our break, we'll meet two scientists whose companies are trying to design new CRISPR tools for therapeutics, and researching the safest and most effective ways to deliver CRISPR into the human body.
(13:19): It's not too early to start planning for the world's most influential biotech meeting, BIO 2023. Held in Boston from June 5th through June 8th, the conference will highlight our theme, Stand Up For Science. Come join us to learn, network, and stand up for innovation. Register today at bio.org/events.
(13:52): Our next guest works at a company that has put eight different therapies into the clinic across 10 different trials.
Julie Bruno (13:59): I'm Julie Bruno. I am the SVP of Programs and Portfolio at CRISPR Therapeutics.
(14:06): I think that, what it means to translate CRISPR technology into a transformative therapy is, really making sure that you've tailored the technology to the disease target.
(14:16): And I think that translation and execution of that science, is in the bones of CRISPR Therapeutics as a company.
(14:24): The company has been around for less than 10 years, and thus far, put eight different therapies into the clinic across 10 different trials. It's a level of translation and execution of the science and the technology into therapies that, in my opinion, it's pretty unmatched for the size and stage of development.
(14:42): I think that, that pace of innovation is only going to continue to be quite rapid, as you think about next generation technologies that are building off of CRISPR/Cas9.
(14:50): I am personally very excited to see where all of that goes, and how it really impacts and moves the needle for patients who, from their suffering from som every serious diseases.
(15:00): But, what CRISPR is really opened up the possibilities for is the actual ability to go in, and, perhaps, correct the underlying disease. And so, I think that's what makes it really special and exciting. Is, it provides this basis for treatments to be developed, for diseases that are very serious, that there historically has not otherwise been a meaningful therapy for.
Rachel King (15:23): CRISPR Therapeutics is developing a potential therapy with CRISPR, for severe sickle cell disease.
Julie Bruno (15:30): At CRISPR Therapeutics, one of the programs that we have that's furthest along in terms of development is the Exa-cel program, and ex vivo therapy for the treatment of severe sickle cell disease.
(15:40): We partner the development of that program with Vertex. And sickle cell disease is one of those disease that we talk about when we talked about those that have very high unmet medical needs.
(15:52): So, despite the fact that patients suffering from sickle cell disease have significantly earlier mortality, and just the ongoing quality of life for patients suffering from this disease, they're, they're having incredibly painful crises and, kind of, very disruptive ongoing symptoms.
(16:10): Even in spite of all of that, there hasn't been a lot of innovation for treatments for these patients. And so, the potential for a treatment, like Exa-cel, is to have life free of pain. If you look at the most recent data update for Exa-cel, the patients that have been treated with it, have had a cessation of those pain crises going out, past three years now, which is really remarkable.
(16:34): I do think that, that really speaks to the transformational power of the platform.
(16:39): And if you just take a step back, diabetes, cancer, heart disease, those three disease areas, they account for nearly 50% of the mortality in the world, and that's why, for us, at CRISPR Therapeutics, working, not just to address rare diseases, but also thinking where the biggest unmet needs for patients, is what motivates us on a day-to-day basis.
Rachel King (17:02): Julie says her company has created a new team that focuses solely on developing the next generation of CRISPR technology.
Julie Bruno (17:10): We have a team within the company, called CRISPR X, which, um, was established a little less than a year ago at this point. CRISPR X is a team that we've set up within the company, that's, kind of, been carved out to be able to look at what are next generation editing technologies that might make sense for specific disease targets.
(17:33): What they're doing is, trying to push forward the scientific frontier for what CRISPR and all of the next gen editing technologies could be used for.
Rachel King (17:43):
Julie's goal is to use CRISPR to address common diseases, such as cancer and diabetes.
Julie Bruno (17:48): So, from the elucidation of CRISPR/Cas9 to today, the world is a completely different place. I actually don't know what there's anything that seems impossible in the future, that I would hope that this pace of innovation continues, or even quickens. Hopefully, 35 years from now, we're sitting here and we're saying those three big disease areas, cancer, diabetes and cardiovascular, that we've really been able to come up with meaningful therapeutic approaches for them, that have changed, kind of, the way that we think about them.
(18:20): So, we've gone from those being accountable for 50% of mortality, to really being manageable diseases. That's the sort of thing that the elucidation of CRISPR/Cas9 has really made possible for the world, which is really exciting.
(18:34): This is an incredible scientific revolution of innovation that we're seeing right now, and CRISPR/Cas9 has really opened up the door for that type of impact on patients, and so, just continuing to watch how the field pushes forward, is going to be incredible over the next, you know, five, ten years.
Rachel King (18:54): Our next guest's company pushes the field forward, by designing CRISPR technology for specific diseases, and is developing new ways to deliver CRISPR to its targeted genes.
Benjamin Oakes (19:05): My name is Benjamin Oakes. I am the Co-founder and CEO of Scribe Therapeutics.
Rachel King (19:11): From Ben's perspective, CRISPR technology has progressed from that first discovery in 2011.
Benjamin Oakes (19:18): Well, we started out really focused on engineering better versions of CRISPR technologies, versions that were safer and more effective at therapeutically relevant doses, we've moved on to actually now taking those better CRISPR enzymes that we built, and we wholly own, and turning them into therapeutics.
(19:37): At Scribe, we're an engineering organization that's focused on engineering those CRISPR molecules, taking those back to our immune systems, and turning them into genetics scalpels, delivery not being a simple problem, has a multitude of solutions. And it actually depends on what type of disease and/or what type of cell you're trying to get into.
(19:57): We have good delivery technologies to get into the liver, and we have delivery technologies to get into the CNS, or the central nervous system, the brain, and the muscle. But there are still many organ systems that we can't deliver these, sorts of, CRISPR technologies into yet, with high efficiencies. And therefore, the search for additional ways to deliver is really continuing.
(20:18): We've now proven [inaudible 00:20:20] the ability of our enzyme systems to work in any deliver technology that we've tried them, and therefore, to actually edit the genome in animals. In any organ system that we've tried them in. So, this includes the CNS, the central nervous system, this includes the liver, this includes muscle, this includes in the eye.
(20:40): And we have program exploring how best to use genome editing technology in all of these areas. In some instances, for rare disease, as we've discussed, in other instances, looking at how we can start to modify the underpinnings of much more common diseases.
Rachel King (20:55): Scribe is creating a set of CRISPR tools that can be used to modify the underlying cause of diseases.
Speaker 7 (21:02): We have a diversification happening in the types of tools that are available. And what's interesting is that they're really non overlapping, right. CRISPR tool A is ideal for doing this specific task, CRISPR tool B is ideal for doing a different task, CRISPR tool C is ideal for doing a totally third task. And each one of them is uniquely adapted to fit a particular, what we think about, as a target product profile, or particular drug outcome, that you want to accomplish.
(21:33): In a autosomal dominant disease, you want to remove the toxic gene, you wanna break it, so, you have tool A that's good for that. In a recessive disease, you want to insert, potentially, a new copy of the broken gene, and there's CRISPR-based tools now for that. And then, in these broader patient populations, where we really want fine tune genetics so that you can have a healthier life, perhaps, there are even better tools for that. And that's perhaps where epigenetic modification, where we're not directly modifying the genome, but you're modifying how that genome is expressed, is the more ideal tool.
(22:13): At Scribe, really feel like we've cr- started to create a, a toolbox that is capable of accomplishing what we want.
Rachel King (22:21): One of Ben's colleagues is Jennifer Doudna. In fact, they're co-founders of Scribe. Ben has known Jennifer since he was a student in her lab, where she was his mentor.
(22:32): Ben says Jennifer has a unique perspective of what CRISPR can do in the present, and what it means for the future.
Benjamin Oakes (22:39): Working with many different mentors throughout my career, each one of them has their own unique strengths and skillsets. And, I think, working with Jennifer is an eye-opening experience, because she brings an incredible wholistic view. Some people will say it's a 30,000-foot view, but Jennifer understands, not only the details of the specific biochemistry, because that's where she's been focused for a very long time now, but also just the implications of what these incredibly small and detailed experiments mean, at a much broader and grander scale.
(23:13): And being able to go from understanding and looking at things that are at a scale that are too small to even see, all the way to how this is gonna impact human health, is an incredibly rare talent.
Rachel King (23:23): However, Ben says there are misconceptions about CRISPR. For example, some people think it's farther along than it really is. The reality is, there's still a lot of work to do in order to understand its potential, and how best to use it.
Speaker 7 (23:37): The most important misconception about CRISPR, in my mind, is that, the technology is more advanced than it actually is. When we think genome editing, and it, it is, in part, due to many of the metaphors we use, we think about, as I talk about, it's that control find function in a Word document. So, we find the word that's miss spelled, and we can go change that spelling.
(24:00): Well, that's not true, actually. In most cases, even in the cases of some of the more advanced technologies, that are specifically designed to fix the spelling of that word, in trying to do so, they might miss spell the word next to it, in this example.
(24:15): From the perspective of what CRISPR technology does when it creates a double strand DNA break, it usually creates, essentially, a mutation at the site of that double strand break. Now, as researchers and medical professionals, we can utilize that mutation to accomplish a goal. For example, like, turning on fetal hemoglobin to treat sickle cell disease.
(24:36): But, it is not yet... I have a (laughs) a piece of the genome that looks like X, and I want it to look exactly like Y, and I can make that happen a 100% of the time, every time. Because, even if I can make that happen, it's a probabilistic thing. So, it might happen 20% of the time, and then, the other 80% of the time, I get something else.
(24:56): And this is why we still do believe deeply, that there is a lot of room for improvement in CRISPR technology, and why we're dedicated to engineering these CRISPR tools to be better.
(25:06): This is one of the main misconceptions.
Rachel King (25:08): Despite such misconceptions, one thing is crystal clear to Ben, the future of medicine and biotech belongs to CRISPR.
Benjamin Oakes (25:17): For the first time, in an efficient way, we are at the precipice, if not already over the precipice, of an entirely new era in humanity. Something I like to think about, human progress has been defined by the tools and technologies that we engineer.
(25:34): You started out in the Stone Age, and then we moved on, and we got to the Iron Age, and now, we were, depending on who you talk to, you're in the Information Age. We're no longer there, we are in the age of the genome and the age of CRISPR.
(25:49): When we look back a a 100 years or a 1,000 years from now, are we gonna remember anything else? Is there gonna be anything else in the textbook, other than, in the early 2000s humanity learned how to modify its own genome?
(26:04): And I do not think that there will be anything as important as that. This is the future. Period.
Rachel King (26:12): We may be living in the age of CRISPR, but it's just the dawn of a new era. Despite its incredibly precise genome editing abilities, there's still a lot we don't know about CRISPR's potential as a tool for transformative therapeutics.
(26:27): But one thing is for sure, we should be excited about where CRISPR's going, and the possibilities that lie ahead for our society.
(26:35): We'd like to thank our guests, Leah, David, Julie, and Ben, for sharing their perspectives on this exciting new technology.
(26:44): Make sure to subscribe, rate and/or review this podcast, and follow us on Twitter, Facebook, and LinkedIn at I am Biotech, and subscribe to Good Day BIO at bio.org/goodday.
(26:58): This episode was developed by Executive Producer, Theresa Brady, and Producers Lynne Finnerty and Rob Gutnikoff. It was engineered and mixed by Jay Goodman, with theme music created by Luke Smith and Sam Brady.