Speaker 1: Pushkin. One of the most important technological breakthroughs so far
Speaker 1: this century is CRISPER aka Clustered regularly spaced palindromic repeats
Speaker 1: aka the extraordinary gene editing tool that is right now
Speaker 1: making its way to actual human patience. The FDA approved
Speaker 1: the first CRISPER produced drug last December, and now scientists
Speaker 1: are trying to improve on the original Crisper to bring
Speaker 1: more treatments to market. I'm Jacob Goldstein and this is
Speaker 1: What's Your Problem, the show where I talk to people
Speaker 1: who are trying to make technological progress. My guest today
Speaker 1: is Rachel Horowitz, the co founder and CEO of Caribou Biosciences.
Speaker 1: Rachel's problem is this, how can you make CRISPER work better?
Speaker 1: And how can you use it to engineer human immune
Speaker 1: cells to fight cancer. We started off talking about Rachel's
Speaker 1: graduate work at UC Berkeley. She studied with Jennifer DOWDNA,
Speaker 1: who would go on to win the Nobel Prize for
Speaker 1: her work on crisper. At the time, Rachel's work was
Speaker 1: focused on a protein called CAST six. Is it right
Speaker 1: that you spent five years studying one protein?
Speaker 2: I spent five years studying one small protein composed of
Speaker 2: only one hundred and eighty seven amino acids, So I
Speaker 2: was pretty far down the road hole.
Speaker 1: I mean, are you the world expert in that protein?
Speaker 1: Is there? Do you know more about that than anyone
Speaker 1: who has ever lived?
Speaker 2: There are probably three of us who know more than
Speaker 2: we ever wanted two about that protein.
Speaker 1: Just give me a little hit of that protein? Well, like,
Speaker 1: what is it? Why'd you spend five years studying it?
Speaker 2: It was my entry point to Crisper. I joined Jennifer
Speaker 2: dowdna's lab as a brand new baby PhD student in
Speaker 2: two thousand and seven. This was the dark ages of Crisper.
Speaker 2: There were three peer reviewed manuscripts that had been published
Speaker 2: at the time, so it took me about forty five
Speaker 2: minutes to get up to speed on the field. It
Speaker 2: was great, and I was joining a project headed up
Speaker 2: by a post doctoral fellow in the lab, and he
Speaker 2: had identified these Crisper associated or CAST proteins and he
Speaker 2: was trying to study all of them. Now he was
Speaker 2: able to make and study all but one. One was
Speaker 2: proving difficult in the lab, so he gave that one
Speaker 2: to me to see if I could sorted out. We
Speaker 2: did eventually sort it out, and in the end it
Speaker 2: turned out to be a very important little protein. It's
Speaker 2: actually responsible for making these small Crisper RNAs that are
Speaker 2: at the heart of Crisper biology. And so I had
Speaker 2: a lot of fun for many years really understand how
Speaker 2: that particular protein functioned, what it did, how it did
Speaker 2: it on a molecular level, and then ultimately zooming far
Speaker 2: far out how it fits into the broader use of
Speaker 2: Crisper systems.
Speaker 1: Yeah. I mean, if you're going to spend five years
Speaker 1: studying one protein, studying a protein that's essential to crisper,
Speaker 1: and doing it in like twenty ten, is as good
Speaker 1: as good as.
Speaker 2: It gets right right place, right time.
Speaker 1: And just to be clear briefly, just so we have it,
Speaker 1: what is crisper.
Speaker 2: Crisper is a technology for editing the genome. Crisper allows
Speaker 2: us to do a few different things to change genomes.
Speaker 2: We can hit the delete key. We can get rid
Speaker 2: of a gene that we don't want to express anymore.
Speaker 2: We can make a small change, maybe even as simple
Speaker 2: as a single nucleotide of DNA, and we can insert
Speaker 2: one or multiple new genes to actually give a cell
Speaker 2: new capabilities it didn't have. Before.
Speaker 1: So just in the last months, right order of magnitude months,
Speaker 1: there have been I guess the first drug approvals sort
Speaker 1: of based on Crisper, right, tell me about those.
Speaker 2: It's incredibly exciting. At the end of last year, the
Speaker 2: first ever Crisper edited therapy was approved by the FDA.
Speaker 2: It's now but approved by other regulatory agencies outside the
Speaker 2: US too. So this is a cellular therapy for the
Speaker 2: treatment of sickle cell and beta thalacemia. So this is
Speaker 2: the use case where you take cells, you use Crisper
Speaker 2: to change them, and then you deliver the cells as
Speaker 2: the therapy back to these patients and the vision is
Speaker 2: to try to actually cure sickle cell disease.
Speaker 1: It's quite remarkable and really fast from when you were
Speaker 1: in grad school and this kind of wasn't quite the
Speaker 1: original work, but this early work was happening. Right. It's
Speaker 1: twelve years, which for go from a lab and kind
Speaker 1: of just basic proof of concept to a thing in
Speaker 1: the world seems wildly fast.
Speaker 2: It's lightning speed. I'm not aware of any other life
Speaker 2: science technology that went from really important publication in science
Speaker 2: magazine to approved therapy anywhere near that fast. There are
Speaker 2: probably a few things to thank for That. One is
Speaker 2: Crisper's actually not the first genomediting technology. Genomediting has been
Speaker 2: around for a while, but the other approaches are much
Speaker 2: harder to use, and so this really unlocked a much faster,
Speaker 2: broader scale of genomediting. So there was a lot of
Speaker 2: resident expertise and capability that could be turbocharged by the
Speaker 2: introduction of chris per Gino mediting.
Speaker 1: It's like there were people who sort of knew how
Speaker 1: to do it already and then this incredible tool kind
Speaker 1: of fell out of the sky and was like, Oh,
Speaker 1: we can just do the thing. We're doing way better
Speaker 1: exactly we're saying there were a couple of reasons. Was
Speaker 1: that one reason was there another reason.
Speaker 2: That's one, and I think another is that there were
Speaker 2: things developed for other fields or biology well understood that
Speaker 2: could quickly be taken advantage of. So, for example, the
Speaker 2: genetic cause of sickle cell disease has been known for decades,
Speaker 2: and yet there hasn't been the right tool to do
Speaker 2: much of anything about it. And so this was sort
Speaker 2: of the perfect marriage of this incredible enabling technology and
Speaker 2: its ability to solve a biology problem that's been well
Speaker 2: understood for a very long time.
Speaker 1: Can you give me a sense of the landscape of
Speaker 1: how crisper is being used in drug therapies Now, broadly.
Speaker 2: Crisper is being used in two very fundamental ways for
Speaker 2: drug development. The first is basic research and the second
Speaker 2: is actually designing and doing new therapies, and that falls
Speaker 2: largely into two categories. One is the kind of work
Speaker 2: that we are doing here at Caribou, where we use
Speaker 2: crisper to actually modify or engineer cells, and the cells
Speaker 2: are the therapy. So by the time we deliver, for example,
Speaker 2: our Carte cell therapy CEB tend to patients, there's no
Speaker 2: Crisper inside of those cells anymore. Crisper is gone. It
Speaker 2: has modified the genome in multiple ways, and the cell
Speaker 2: is the therapeutic. The other strategy that some companies are
Speaker 2: using is to actually deliver Crisper inside the human body,
Speaker 2: and the idea is to try to correct a gene
Speaker 2: that causes a rare genetic disorder, and so in that case,
Speaker 2: crisper itself is the therapy.
Speaker 1: So in that latter case, I mean that is gene
Speaker 1: therapy essentially what people have therapy, and what's what seems
Speaker 1: to be next in line what's farthest along anyways in
Speaker 1: terms of other crisper derived therapies.
Speaker 2: Yeah, there's some very exciting work coming out of a
Speaker 2: company called Intellia Therapeutics where they're actually using crisper as
Speaker 2: the drug. So they are delivering it packaged inside these
Speaker 2: little fat particles to go directly to a patient's liver
Speaker 2: to correct a gene that causes a disease. And they
Speaker 2: are running what's called a phase three trial for one
Speaker 2: of those medicines right now.
Speaker 1: So I feel like this is a dumb question, But
Speaker 1: as I imagine that, like, does that mean that the
Speaker 1: therapy has to get to like every cell in the liver?
Speaker 1: Like is it going to change the genome of every
Speaker 1: cell in your liver? Is that the way that works?
Speaker 2: Thank goodness, No, that's not requite.
Speaker 1: It couldn't be that, right, It couldn't be that most
Speaker 1: of them like what like what? But it's sell by cell.
Speaker 1: It's like that the particle hits one liver cell and
Speaker 1: changes the genome, and then another one hits another one
Speaker 1: and then is there some kipping point? Like how does
Speaker 1: it work?
Speaker 2: It's a wonderful question, and I think there are a
Speaker 2: lot of people who sit in a lot of conference
Speaker 2: rooms staring at whiteboards trying to understand what is that
Speaker 2: tipping point? Because I think it's biologically unrealistic to think
Speaker 2: you can edit one hundred percent of cells in the liver,
Speaker 2: and if that's what's needed for a therapy, you're probably
Speaker 2: out of luck, and instead focusing on diseases where there's
Speaker 2: some model or suggestion that you know, maybe editing ten
Speaker 2: percent of the cells or fifteen or twenty percent of
Speaker 2: the cells would be enough, and there's confidence that the
Speaker 2: technology might be able to accomplish that.
Speaker 1: Well, what you mentioned that there's a therapy and did
Speaker 1: you say phase three in the final stage of clinical trials?
Speaker 1: What disease is that targeting?
Speaker 2: So Intellia is working on a disease called transthyretin amyloidosis
Speaker 2: or a TTR. For sure. It's a disease caused by
Speaker 2: misfolded proteins and it leads to neurodegeneration and cardiomyopathies.
Speaker 1: That's the one in the liver.
Speaker 2: They are editing liver cells because the liver produces the
Speaker 2: misfolded protein that causes problems elsewhere in the body.
Speaker 1: So, okay, clearly Crisper is this wildly useful breakthrough, but
Speaker 1: it's not perfect. And your company was founded in a
Speaker 1: way to address this key weakness of Crisper as originally developed.
Speaker 1: So what is the weakness in particular that your company
Speaker 1: is focusing on?
Speaker 2: Specificity? When I say specificity, I mean editing the one
Speaker 2: site in the genome that we intend to and not
Speaker 2: accidentally making changes anywhere else. Right in Microsoft Word, you
Speaker 2: put the cursor exactly where you want to write new text,
Speaker 2: not a mystery where the new text is going to land.
Speaker 2: Using a biological tool like Crisper, more often than not,
Speaker 2: you edit the site that you intend to. But biology
Speaker 2: is noisy, and sometimes the system lands in places you
Speaker 2: didn't expect and can make changes in places you didn't want.
Speaker 2: That could be a problem for what you're trying to do.
Speaker 2: And so our team for years has been focused on
Speaker 2: the challenge of specificity and ultimately developing new technologies to
Speaker 2: address this head on.
Speaker 1: What percent of the time does Crisper get it wrong?
Speaker 1: It's the question I want to ask, and I'm sure
Speaker 1: that's too broad a question, But how do you think
Speaker 1: about that? How should I think about that?
Speaker 2: It varies dramatically so the way Crisper actually works, it's
Speaker 2: usually a specific protein called CAST nine that cuts the
Speaker 2: genome at the site that you're trying to edit. But
Speaker 2: CAST nine on its own can't do anything. It's inert.
Speaker 2: If you will, it needs an RNA, a piece of
Speaker 2: RNA that's actually specifically designed to match the sequence of
Speaker 2: the genome that you're trying to modify. It partners with
Speaker 2: this RNA and the RNA takes it to the right place.
Speaker 2: So depending on which RNA you've designed, the edits could
Speaker 2: be more or less specific. There are plenty of examples
Speaker 2: of first generation Crisper cast nine where you could get
Speaker 2: really efficient editing at the site you want, and really
Speaker 2: efficient editing at several other sites as well that you
Speaker 2: did not want. And then there are many of us,
Speaker 2: my company Caribou bios Sciences included, who have invented, developed
Speaker 2: access to new technologies that can overcome some of these
Speaker 2: specificity challenges.
Speaker 1: I mean, it seems like in your case that particular
Speaker 1: technology is sort of the core proposition that the company
Speaker 1: is founded on. Right, Can we take crisper and make
Speaker 1: it work more reliably?
Speaker 2: Absolutely?
Speaker 1: So, what do you do to make it work better?
Speaker 2: So? At the heart of our company is what we
Speaker 2: call the Shardona technology. Now, Shardona is an acronym. Cchr
Speaker 2: DNA stands for a mouthful crisper hybrid RNA DNA technology.
Speaker 2: You now see why we use an acronym.
Speaker 1: But each of those words, I mean, it's like a
Speaker 1: relatively sort of you know, comprehensible acronym, right, like crisper
Speaker 1: hybrid RNA DNA. It's like, that's not wildly complicated.
Speaker 2: Fair, I appreciate that, And to be fair, it does
Speaker 2: actually describe what the technology is. So I just told
Speaker 2: you usually CAST nine or other crisper proteins need an
Speaker 2: RNA partner to get to the right side in the genome.
Speaker 2: What some of my colleagues did is actually develop hybrid guides,
Speaker 2: guides that are part RNA and part DNA. And it
Speaker 2: turns out the inclusion of DNA improves the specificity dramatically.
Speaker 2: We can measure this in a very quantitative way and
Speaker 2: see that it improves the specificity of editing by many
Speaker 2: orders of magnitude.
Speaker 1: A huh, So it's not like ten percent better, it's
Speaker 1: like one hundred times better.
Speaker 2: A thousand times better, even more. In some cases.
Speaker 1: Is there a sort of layperson's answer to why.
Speaker 2: Absolutely. It all has to do with what we would
Speaker 2: call it biochemistry affinity, meaning what is the binding tightness
Speaker 2: of the crisper system for the target genome? And it
Speaker 2: might intuitively feel like higher binding, higher affinity is better,
Speaker 2: but it actually turns out the opposite is true, huh,
Speaker 2: And that by including DNA we actually decrease the affinity
Speaker 2: of the complex for the target. And the reason you
Speaker 2: want to decrease the affinity is that really the entire
Speaker 2: human genome resents a laundry list of potential off target
Speaker 2: sites we don't want to edit. So you want low
Speaker 2: enough affinity that you're not accidentally grabbing all these other
Speaker 2: pieces of the genome and instead grabbing the one site
Speaker 2: that you actually want to modify.
Speaker 1: So is the challenge then to see how low you
Speaker 1: can get the affinity and have it still work. I mean,
Speaker 1: I get that you don't want it to not bind
Speaker 1: things that it's not supposed to bind to, or not
Speaker 1: cut things that it's not supposed to cut, but you
Speaker 1: do want it to bind to or cut the thing
Speaker 1: that it is supposed to cut. So presumably there's some
Speaker 1: optimal spot or maybe what's optimal depends on the use case.
Speaker 1: But how do you strike that balance.
Speaker 2: It's a very careful balancing act. You're absolutely right. Our
Speaker 2: research team has spent a huge amount of time working
Speaker 2: on this and has found ways to really develop the
Speaker 2: appropriate way to balance these two needs for each time.
Speaker 2: We need to make an.
Speaker 1: Edit still to come on the show. How Rachel and
Speaker 1: her colleagues are using this new kind of Crisper technology
Speaker 1: to create new treatments for cancer. There's this promising new
Speaker 1: kind of cancer treatment called car T cell therapy. T
Speaker 1: cells are a key part of the immune system, and
Speaker 1: the basic idea here is to engineer T cells to
Speaker 1: attack cancer cells. As you'll hear, a few car T
Speaker 1: cell therapies have been approved, but they're complicated and expensive.
Speaker 1: So Rachel and her colleagues are using Crisper to try
Speaker 1: to come up with a new kind of car T
Speaker 1: cell therapy that is both simpler and cheaper. So let's
Speaker 1: talk about some of the some of the projects you're
Speaker 1: working on with the technology. We'll start with what's farthest
Speaker 1: along clinically.
Speaker 2: Furthest along is a cell therapy that we call CB ten,
Speaker 2: and we are developing this to treat relapsed or refractory
Speaker 2: B cell non Hodgkin lymphoma. So that's a kind of
Speaker 2: blood cancer, and it's when B cells, part of the
Speaker 2: immune system, become diseased. And so we are using our
Speaker 2: Crisper genomeediting, our Chardonnay technology to actually take healthy T
Speaker 2: cells from healthy donors and then modify them through Crisper
Speaker 2: to teach them how to find and kill these kinds
Speaker 2: of diseased B cell cancers. These therapies are called car
Speaker 2: T cell therapies. We're not the first to work on them.
Speaker 2: There are many who are advancing these kinds of therapies.
Speaker 2: And CAR again is an acronym. It stands for chimeric
Speaker 2: antigen receptor, and it describes a special protein that we
Speaker 2: can encourage the T cells to express that gives them
Speaker 2: the ability to specifically recognize and kill these B cells.
Speaker 1: As I understand it, other companies have developed car T
Speaker 1: cell therapies that take an individual patient's own immune cells
Speaker 1: and develop them in the lab essentially, and then put
Speaker 1: them back into the patient to target cancer. Right. That
Speaker 1: is unsurprisingly, very very very expensive, right, because it's sort
Speaker 1: of like you're developing a custom drug for each patient,
Speaker 1: which is great in a way, but also it's like
Speaker 1: this bespoke, sort of individually tailored drug that it just
Speaker 1: costs a lot to make and it costs a lot
Speaker 1: to buy. And so my understanding is that you're trying
Speaker 1: to develop a version that is more like a traditional
Speaker 1: drug that doesn't have to be customized to every patient.
Speaker 2: Is that right, That's exactly correct. So there are today
Speaker 2: in the United States six approved car te cell therapies,
Speaker 2: and each one of them is what's called anatologous cell therapy,
Speaker 2: which is scientific fancy word for patient specific.
Speaker 1: And so those drugs, just to be clear, those are approved,
Speaker 1: they're in use, they exist in the world.
Speaker 2: Those are approved commercial products today.
Speaker 1: And they cost like hundreds of thousands of dollars per patient.
Speaker 2: Correct. Yeah, So they are proof positive that the immune system,
Speaker 2: specifically T cells, can be incredibly powerful anti cancer agents.
Speaker 2: They also demonstrate how challenging it is to develop one
Speaker 2: batch of therapy for each and every patient. That is
Speaker 2: not scalable. That is not going to be something that
Speaker 2: delivers this kind of therapy to broader and broader patient populations,
Speaker 2: and it's also restricted to cancer patients who have sufficiently
Speaker 2: good T cells to make the product in the first place.
Speaker 1: Oh, that's interesting, Like if you're a patient in your
Speaker 1: immune system is just totally beat down by having cancer
Speaker 1: or being treated for cancer, then you don't have the
Speaker 1: T cells to generate this therapy.
Speaker 2: That's exactly correct. There's also quite a lot of complexity
Speaker 2: and almost handholding, if you will, necessary to make these
Speaker 2: patient specific therapies, and so cancer centers like MD Anderson
Speaker 2: or the University of Pennsylvania, they have tremendous expertise and
Speaker 2: they have the staff to really work with patients to
Speaker 2: shepherd them through this process to ensure that they can
Speaker 2: actually support them provide any additional therapies they need while
Speaker 2: they're waiting for their therapy to be manufactured, to give
Speaker 2: them access to this kind of therapy. But that's not
Speaker 2: where the majority of patients are treated. The majority of
Speaker 2: patients are treated in community hospitals and community clinics that
Speaker 2: don't have the resources to shepherd patients through this kind
Speaker 2: of very complex stuff.
Speaker 1: So, so what do you have to do to make
Speaker 1: a one size fits most version of this, right you
Speaker 1: want to? It would be good for the world if
Speaker 1: we could move away from having to design this drug
Speaker 1: literally for each patient and have a drug that'll work
Speaker 1: for almost everybody. That's what you're trying to do. How
Speaker 1: do you do it?
Speaker 2: Yeah, the vision is to develop what the field would
Speaker 2: call allogeneic or off the shelf car T cell therapies.
Speaker 1: Which is what most drugs are, right, Like just a
Speaker 1: drug and the doctor gives you the drug and hopefully
Speaker 1: it makes you better.
Speaker 2: Right right, So step one is we need to use
Speaker 2: healthy T cells from healthy donors instead of T cells
Speaker 2: from cancer patients.
Speaker 1: Okay.
Speaker 2: Step two is you have to make this safe. Right, Typically,
Speaker 2: if you take a T cell from one person and
Speaker 2: put it in another person, you are probably going to
Speaker 2: cause what is called graft versus host disease, which is
Speaker 2: where the other person's T cells attack parts of your.
Speaker 1: Body, analogous to what is that transplant patients have. Basically,
Speaker 1: it's like yeah.
Speaker 2: Correct, correct, So right off the bat, we have to
Speaker 2: prevent that, and we do that through genome editing by
Speaker 2: getting rid of something called the T cell receptor. It's
Speaker 2: the thing on the surface of the T cell that
Speaker 2: would usually empower it to cause graph versus host disease.
Speaker 2: So that's hitting the delete key once to get rid
Speaker 2: of that.
Speaker 1: Okay.
Speaker 2: The second step is you have to give the T
Speaker 2: cells the CAR so it knows what it's looking for
Speaker 2: on the surface of cancer cells to appropriately identify and
Speaker 2: kill them. And many of our peers stop there. Those
Speaker 2: two combined would be what they envision as a product,
Speaker 2: but our team looked at that and said, that will
Speaker 2: never be enough.
Speaker 1: And so just to be clear, when you see people stop,
Speaker 1: there are people trying that, like, is that version of
Speaker 1: this drug in trials? Now?
Speaker 2: Yes, multiple human clinical trials are being run with something
Speaker 2: that looks like.
Speaker 1: That, and so if that works, that would be a
Speaker 1: off the shelf, one sized, fistmost normal drug kind of drug.
Speaker 1: You're skeptical that it's going to work.
Speaker 2: Correct, We think you have to take it a step
Speaker 2: farther and I'll tell you why. Okay, Yeah, these off
Speaker 2: the shelf T cells, they are foreign to the patient's
Speaker 2: immune system, and the patient's immune system is going to
Speaker 2: figure that out fairly quickly and actually kill off the
Speaker 2: CAR T cells. And that's very different from when you've
Speaker 2: had a product made from your very own T cells.
Speaker 2: They can last for a very long time, and so
Speaker 2: we look at that differential in time and say that's
Speaker 2: a problem we have to solve.
Speaker 1: Why doesn't everybody agree with you?
Speaker 2: I would say more and more people agree with us
Speaker 2: if you look at what's happening in the field. In fact,
Speaker 2: many of the first off the shelf car T cells
Speaker 2: that have been tried in human clinical trials have been
Speaker 2: retired because they didn't work as well as people had hoped.
Speaker 2: And I think many are now going back to the
Speaker 2: drawing board to think about what are other things we
Speaker 2: can do to empower or enhance these T cells to
Speaker 2: overcome these challenges.
Speaker 1: So what do you do, you were getting to the
Speaker 1: sort of next steps, what do you do to make
Speaker 1: it better tolerated by the patient's immune system.
Speaker 2: Yeah, we think about how to bridge that gap, both
Speaker 2: very literally and in ways that are more about boosting
Speaker 2: the biology than necessarily entangling with the patient's immune system. So,
Speaker 2: for example, in some of our other cell therapies that
Speaker 2: we're developing for other blood cancers like multiple myeloma and AML,
Speaker 2: we actually deploy what we call immune cloaking, and so
Speaker 2: this is where we use our genomeediting to change what
Speaker 2: is or is not decorating the surface of the car
Speaker 2: T cells to try to slow down how the patient's
Speaker 2: immune system could recognize and clear the therapy. So that's
Speaker 2: a very literal way of addressing this challenge.
Speaker 1: Cloaking is a cool name for it, to basically make
Speaker 1: the cell better at hiding from the immune.
Speaker 2: System exactly exactly Is.
Speaker 1: There an example of a particular change you make to
Speaker 1: that end.
Speaker 2: Yes, So what we do is actually get rid of
Speaker 2: some of the proteins that would usually sit on the
Speaker 2: surface of a Carte cell. These are called HILA class
Speaker 2: one molecules, and it helps to prevent the patient's immune
Speaker 2: system from readily recognizing and clearing the therapy. It's a
Speaker 2: little more complex than that. There's actually a special kind
Speaker 2: that we then decorate the surface with to help ensure
Speaker 2: that all parts of the immune system cannot rapidly recognize it.
Speaker 2: I also want to be clear, we don't think this
Speaker 2: creates a perfect stealth cell that lasts forever. There are
Speaker 2: lots of things about these cells that we expect the
Speaker 2: patient's immune system to ultimately recognize and cause it to reject.
Speaker 2: This is about buying additional time with a hope that
Speaker 2: that allows additional anti tumor activity.
Speaker 1: And is there is there a balance you have to
Speaker 1: strike there where, well, the cell still has to work, right,
Speaker 1: I mean, is there a universe where you do so
Speaker 1: much to try and cloak the cell that it can't
Speaker 1: whatever do its cellular business and persist as a cell
Speaker 1: until it finds the tumor?
Speaker 2: Right? I think there's some extreme world where you try
Speaker 2: to put so many different genometics into the T cell
Speaker 2: that you break it, maybe both on a cell specific level,
Speaker 2: but also a population level. So if you think about it,
Speaker 2: we're trying to take this population of millions and millions
Speaker 2: of T cells and provide three, four five different genometics. Now,
Speaker 2: genomeediting is very efficient, but it's not one hundred percent efficient.
Speaker 2: You know, some medits might be eighty percent, otherre's ninety percent,
Speaker 2: maybe ninety five percent. So that means, as you now
Speaker 2: look at this whole population of T cells, every time
Speaker 2: you add a new edit, it means a fraction of
Speaker 2: a fraction of a fraction of the cells actually have
Speaker 2: all the edits that you desire. So we set a
Speaker 2: pretty high bar for ourselves. We only bring a program
Speaker 2: forward into the clinic if we can manufacture it in
Speaker 2: such a way that at least half of all of
Speaker 2: the T cells have all the edits that we're going for,
Speaker 2: and we've been able to do that with three different
Speaker 2: therapies so far.
Speaker 1: So you're saying that even with your improved version of Crisper,
Speaker 1: it's still sufficiently error prone. Not that it's highly error prone,
Speaker 1: but it still makes enough mistakes that something like half
Speaker 1: of the cells you're creating won't be exactly the way
Speaker 1: you want them to be.
Speaker 2: I would say, it's not that it's making mistakes, meaning
Speaker 2: it's not making off target changes elsewhere that we didn't want.
Speaker 2: It's instead that in some fraction of the cells, they're
Speaker 2: just not getting.
Speaker 1: The edit right of omission rather than a sinecommission. Yes, exactly.
Speaker 1: So it's the affinity, like you nailed the low affinity.
Speaker 1: So does that suggest just to sort of zoom out
Speaker 1: for a sec I mean it suggests that there is
Speaker 1: room for improvement on the kind of platform level. Presumably.
Speaker 2: I think so. And I'll give an example of even
Speaker 2: the work we've done over the past few years. So
Speaker 2: our first program, which is for lymphoma, benefits from three edits.
Speaker 2: Fast forward now to our third program for AML. It
Speaker 2: has five different genomeedics in it. We're able to hit
Speaker 2: the delete key on three different genes in two different places.
Speaker 2: We can insert new genes to give new functionality to
Speaker 2: the T cells. And I think this already represents really
Speaker 2: pushing the envelope in terms of what you can accomplish.
Speaker 2: And I think there's further room to run with that
Speaker 2: as well.
Speaker 1: If things go well, When when might you be, you know,
Speaker 1: submitting a drug for approval?
Speaker 2: Fantastic question. We hope to start a phase three trial
Speaker 2: with CB ten next year. If you look at the
Speaker 2: kinds of phase three trials that have been run for
Speaker 2: these cell therapies before, they usually take two years or
Speaker 2: more to run, and then there's some time after that
Speaker 2: put all the documents together for the regulatory agencies. So
Speaker 2: a lot of work yet to be done. Very excited
Speaker 2: about what's coming next.
Speaker 1: We'll be back in a minute with the lighting round.
Speaker 1: Let's have a lightning round. Let's finish with the lighting round.
Speaker 1: What's more frustrating pipetting or knitting?
Speaker 2: Knitting?
Speaker 1: What's the hardest thing you ever knit?
Speaker 2: Mittens?
Speaker 1: Tell me about pipe petting. I feel like you and
Speaker 1: pipetting have history.
Speaker 2: You know. Pipeetting is about moving clear liquids from one
Speaker 2: to another. I spent many, many years where that is
Speaker 2: what I did every day, and obviously it gave me
Speaker 2: the ability to do hands on wet lab research. And
Speaker 2: there's a piece of it that I desperately miss, which
Speaker 2: is being the first to know the answer to an
Speaker 2: interesting biological question. Right, there's a magical aha moment when
Speaker 2: you see the results first. Now these days, I'm not
Speaker 2: that far away from the people who get to do
Speaker 2: the really cool work in our lab, So I'm at
Speaker 2: peace with the balancing act of not having to pipette
Speaker 2: and you know, being the third, fourth, tenth person who
Speaker 2: learns the cool news.
Speaker 1: Worthwhile trade off at the end. Indeed, did you go
Speaker 1: to grad school assuming you would work in industry? Is
Speaker 1: there some moment when you are making a leap off
Speaker 1: of this path? You know you're getting a PhD? You
Speaker 1: clearly have been very good at school. Lots of people
Speaker 1: just stay in school all their lives and become professors
Speaker 1: and have wonderful careers. Was there some moment when you
Speaker 1: decided to step off of that path? Leap off of
Speaker 1: that path?
Speaker 2: I was probably one of the few people in my
Speaker 2: PhD program who came to school knowing I didn't want
Speaker 2: to be a professor when I grew up. I actually
Speaker 2: thought I wanted to be a patent attorney when I
Speaker 2: grew up. However, we started working with patent attorneys because
Speaker 2: of all the cool technology that was coming out of
Speaker 2: the lab, and I pretty quickly realized that's not the
Speaker 2: job that I want to do.
Speaker 1: Good figure figured that out.
Speaker 2: Indeed before I went to three years of law school.
Speaker 2: So it created sort of this moment of well, I
Speaker 2: don't know what I'm going to do when I grew up.
Speaker 2: Now know a few things I don't want to do,
Speaker 2: and it meant I started thinking a lot about the
Speaker 2: industry side of science. I took a lot of business
Speaker 2: school classes at that point in time to try to
Speaker 2: learn and learn a new vocabulary. But I think that
Speaker 2: made it easier to take the entrepreneur or a leap,
Speaker 2: because I wasn't on a different path than I had
Speaker 2: to jump off to.
Speaker 1: Go on basically your way out of going to law school. Indeed,
Speaker 1: so you were on the Forbes thirty under thirty, the
Speaker 1: Fortune forty under forty. As far as I know, there's
Speaker 1: no fifty under fifty. So do you have like a
Speaker 1: next move, Well.
Speaker 2: There is a fifty over fifty, but I've got to
Speaker 2: wait a few more years for that.
Speaker 1: I'm glad that you've got it lined up, though it's
Speaker 1: important to have a goal and you've got time. What's
Speaker 1: one thing that you wish people understood better about genes?
Speaker 2: I think many people expect there's a very clear one
Speaker 2: to one connection that a gene means X. There are
Speaker 2: very few genes in our genome that result in one
Speaker 2: specific outcome. We as human beings are the product of
Speaker 2: this incredibly complicated cross signaling across every gene in our genome,
Speaker 2: and any one trait, even as simple as how tall
Speaker 2: we are, is the output of many, many, many different genes.
Speaker 2: And so I do wish there was a better understanding
Speaker 2: of just the rich complexity of our own biology, because
Speaker 2: then I think it feeds directly into how do you
Speaker 2: use a technology like crisper to change disease biology? And
Speaker 2: there are some examples, but not a ton of examples
Speaker 2: where one edit is enough.
Speaker 1: It's like the the Mendelian pea plants maybe do more
Speaker 1: harm than good as a teaching to a like No, no,
Speaker 1: it's not usually like that.
Speaker 2: Fair.
Speaker 1: Yes. Rachel Horwitz is the co founder and CEO of
Speaker 1: Caribou Biosciences. Today's show was produced by Gabriel Hunter Chang.
Speaker 1: It was edited by Lyddy jeene Kott and engineered by
Speaker 1: Sarah Bruguier. You can email us at problem at Pushkin
Speaker 1: dot FM. I'm Jacob Goldstein and we'll be back next
Speaker 1: week with another episode of What's Your Problem.