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Fighting Cancer with CRISPR · What's Your Problem?

0:15
Speaker 1: Pushkin. One of the most important technological breakthroughs so far
0:23
Speaker 1: this century is CRISPER aka Clustered regularly spaced palindromic repeats
0:30
Speaker 1: aka the extraordinary gene editing tool that is right now
0:35
Speaker 1: making its way to actual human patience. The FDA approved
0:40
Speaker 1: the first CRISPER produced drug last December, and now scientists
0:45
Speaker 1: are trying to improve on the original Crisper to bring
0:48
Speaker 1: more treatments to market. I'm Jacob Goldstein and this is
0:56
Speaker 1: What's Your Problem, the show where I talk to people
0:59
Speaker 1: who are trying to make technological progress. My guest today
1:02
Speaker 1: is Rachel Horowitz, the co founder and CEO of Caribou Biosciences.
1:07
Speaker 1: Rachel's problem is this, how can you make CRISPER work better?
1:12
Speaker 1: And how can you use it to engineer human immune
1:15
Speaker 1: cells to fight cancer. We started off talking about Rachel's
1:19
Speaker 1: graduate work at UC Berkeley. She studied with Jennifer DOWDNA,
1:23
Speaker 1: who would go on to win the Nobel Prize for
1:26
Speaker 1: her work on crisper. At the time, Rachel's work was
1:29
Speaker 1: focused on a protein called CAST six. Is it right
1:35
Speaker 1: that you spent five years studying one protein?
1:39
Speaker 2: I spent five years studying one small protein composed of
1:44
Speaker 2: only one hundred and eighty seven amino acids, So I
1:48
Speaker 2: was pretty far down the road hole.
1:50
Speaker 1: I mean, are you the world expert in that protein?
1:53
Speaker 1: Is there? Do you know more about that than anyone
1:55
Speaker 1: who has ever lived?
1:57
Speaker 2: There are probably three of us who know more than
1:59
Speaker 2: we ever wanted two about that protein.
2:01
Speaker 1: Just give me a little hit of that protein? Well, like,
2:03
Speaker 1: what is it? Why'd you spend five years studying it?
2:05
Speaker 2: It was my entry point to Crisper. I joined Jennifer
2:10
Speaker 2: dowdna's lab as a brand new baby PhD student in
2:14
Speaker 2: two thousand and seven. This was the dark ages of Crisper.
2:18
Speaker 2: There were three peer reviewed manuscripts that had been published
2:22
Speaker 2: at the time, so it took me about forty five
2:25
Speaker 2: minutes to get up to speed on the field. It
2:26
Speaker 2: was great, and I was joining a project headed up
2:31
Speaker 2: by a post doctoral fellow in the lab, and he
2:34
Speaker 2: had identified these Crisper associated or CAST proteins and he
2:40
Speaker 2: was trying to study all of them. Now he was
2:42
Speaker 2: able to make and study all but one. One was
2:46
Speaker 2: proving difficult in the lab, so he gave that one
2:49
Speaker 2: to me to see if I could sorted out. We
2:52
Speaker 2: did eventually sort it out, and in the end it
2:55
Speaker 2: turned out to be a very important little protein. It's
2:58
Speaker 2: actually responsible for making these small Crisper RNAs that are
3:03
Speaker 2: at the heart of Crisper biology. And so I had
3:06
Speaker 2: a lot of fun for many years really understand how
3:10
Speaker 2: that particular protein functioned, what it did, how it did
3:14
Speaker 2: it on a molecular level, and then ultimately zooming far
3:18
Speaker 2: far out how it fits into the broader use of
3:21
Speaker 2: Crisper systems.
3:22
Speaker 1: Yeah. I mean, if you're going to spend five years
3:24
Speaker 1: studying one protein, studying a protein that's essential to crisper,
3:27
Speaker 1: and doing it in like twenty ten, is as good
3:32
Speaker 1: as good as.
3:32
Speaker 2: It gets right right place, right time.
3:36
Speaker 1: And just to be clear briefly, just so we have it,
3:39
Speaker 1: what is crisper.
3:41
Speaker 2: Crisper is a technology for editing the genome. Crisper allows
3:47
Speaker 2: us to do a few different things to change genomes.
3:52
Speaker 2: We can hit the delete key. We can get rid
3:54
Speaker 2: of a gene that we don't want to express anymore.
3:58
Speaker 2: We can make a small change, maybe even as simple
4:02
Speaker 2: as a single nucleotide of DNA, and we can insert
4:07
Speaker 2: one or multiple new genes to actually give a cell
4:10
Speaker 2: new capabilities it didn't have. Before.
4:13
Speaker 1: So just in the last months, right order of magnitude months,
4:16
Speaker 1: there have been I guess the first drug approvals sort
4:20
Speaker 1: of based on Crisper, right, tell me about those.
4:23
Speaker 2: It's incredibly exciting. At the end of last year, the
4:26
Speaker 2: first ever Crisper edited therapy was approved by the FDA.
4:30
Speaker 2: It's now but approved by other regulatory agencies outside the
4:35
Speaker 2: US too. So this is a cellular therapy for the
4:38
Speaker 2: treatment of sickle cell and beta thalacemia. So this is
4:42
Speaker 2: the use case where you take cells, you use Crisper
4:46
Speaker 2: to change them, and then you deliver the cells as
4:49
Speaker 2: the therapy back to these patients and the vision is
4:54
Speaker 2: to try to actually cure sickle cell disease.
4:56
Speaker 1: It's quite remarkable and really fast from when you were
5:00
Speaker 1: in grad school and this kind of wasn't quite the
5:03
Speaker 1: original work, but this early work was happening. Right. It's
5:07
Speaker 1: twelve years, which for go from a lab and kind
5:12
Speaker 1: of just basic proof of concept to a thing in
5:14
Speaker 1: the world seems wildly fast.
5:17
Speaker 2: It's lightning speed. I'm not aware of any other life
5:21
Speaker 2: science technology that went from really important publication in science
5:27
Speaker 2: magazine to approved therapy anywhere near that fast. There are
5:32
Speaker 2: probably a few things to thank for That. One is
5:36
Speaker 2: Crisper's actually not the first genomediting technology. Genomediting has been
5:41
Speaker 2: around for a while, but the other approaches are much
5:45
Speaker 2: harder to use, and so this really unlocked a much faster,
5:51
Speaker 2: broader scale of genomediting. So there was a lot of
5:54
Speaker 2: resident expertise and capability that could be turbocharged by the
5:59
Speaker 2: introduction of chris per Gino mediting.
6:01
Speaker 1: It's like there were people who sort of knew how
6:02
Speaker 1: to do it already and then this incredible tool kind
6:05
Speaker 1: of fell out of the sky and was like, Oh,
6:06
Speaker 1: we can just do the thing. We're doing way better
6:09
Speaker 1: exactly we're saying there were a couple of reasons. Was
6:13
Speaker 1: that one reason was there another reason.
6:15
Speaker 2: That's one, and I think another is that there were
6:18
Speaker 2: things developed for other fields or biology well understood that
6:24
Speaker 2: could quickly be taken advantage of. So, for example, the
6:27
Speaker 2: genetic cause of sickle cell disease has been known for decades,
6:32
Speaker 2: and yet there hasn't been the right tool to do
6:36
Speaker 2: much of anything about it. And so this was sort
6:39
Speaker 2: of the perfect marriage of this incredible enabling technology and
6:44
Speaker 2: its ability to solve a biology problem that's been well
6:47
Speaker 2: understood for a very long time.
6:50
Speaker 1: Can you give me a sense of the landscape of
6:54
Speaker 1: how crisper is being used in drug therapies Now, broadly.
7:00
Speaker 2: Crisper is being used in two very fundamental ways for
7:04
Speaker 2: drug development. The first is basic research and the second
7:08
Speaker 2: is actually designing and doing new therapies, and that falls
7:14
Speaker 2: largely into two categories. One is the kind of work
7:17
Speaker 2: that we are doing here at Caribou, where we use
7:20
Speaker 2: crisper to actually modify or engineer cells, and the cells
7:26
Speaker 2: are the therapy. So by the time we deliver, for example,
7:30
Speaker 2: our Carte cell therapy CEB tend to patients, there's no
7:34
Speaker 2: Crisper inside of those cells anymore. Crisper is gone. It
7:37
Speaker 2: has modified the genome in multiple ways, and the cell
7:41
Speaker 2: is the therapeutic. The other strategy that some companies are
7:46
Speaker 2: using is to actually deliver Crisper inside the human body,
7:51
Speaker 2: and the idea is to try to correct a gene
7:55
Speaker 2: that causes a rare genetic disorder, and so in that case,
7:59
Speaker 2: crisper itself is the therapy.
8:02
Speaker 1: So in that latter case, I mean that is gene
8:05
Speaker 1: therapy essentially what people have therapy, and what's what seems
8:11
Speaker 1: to be next in line what's farthest along anyways in
8:14
Speaker 1: terms of other crisper derived therapies.
8:18
Speaker 2: Yeah, there's some very exciting work coming out of a
8:20
Speaker 2: company called Intellia Therapeutics where they're actually using crisper as
8:25
Speaker 2: the drug. So they are delivering it packaged inside these
8:30
Speaker 2: little fat particles to go directly to a patient's liver
8:34
Speaker 2: to correct a gene that causes a disease. And they
8:37
Speaker 2: are running what's called a phase three trial for one
8:41
Speaker 2: of those medicines right now.
8:44
Speaker 1: So I feel like this is a dumb question, But
8:46
Speaker 1: as I imagine that, like, does that mean that the
8:49
Speaker 1: therapy has to get to like every cell in the liver?
8:53
Speaker 1: Like is it going to change the genome of every
8:55
Speaker 1: cell in your liver? Is that the way that works?
8:58
Speaker 2: Thank goodness, No, that's not requite.
9:01
Speaker 1: It couldn't be that, right, It couldn't be that most
9:04
Speaker 1: of them like what like what? But it's sell by cell.
9:07
Speaker 1: It's like that the particle hits one liver cell and
9:11
Speaker 1: changes the genome, and then another one hits another one
9:13
Speaker 1: and then is there some kipping point? Like how does
9:15
Speaker 1: it work?
9:17
Speaker 2: It's a wonderful question, and I think there are a
9:19
Speaker 2: lot of people who sit in a lot of conference
9:22
Speaker 2: rooms staring at whiteboards trying to understand what is that
9:26
Speaker 2: tipping point? Because I think it's biologically unrealistic to think
9:31
Speaker 2: you can edit one hundred percent of cells in the liver,
9:34
Speaker 2: and if that's what's needed for a therapy, you're probably
9:36
Speaker 2: out of luck, and instead focusing on diseases where there's
9:41
Speaker 2: some model or suggestion that you know, maybe editing ten
9:46
Speaker 2: percent of the cells or fifteen or twenty percent of
9:49
Speaker 2: the cells would be enough, and there's confidence that the
9:52
Speaker 2: technology might be able to accomplish that.
9:54
Speaker 1: Well, what you mentioned that there's a therapy and did
9:57
Speaker 1: you say phase three in the final stage of clinical trials?
10:00
Speaker 1: What disease is that targeting?
10:03
Speaker 2: So Intellia is working on a disease called transthyretin amyloidosis
10:08
Speaker 2: or a TTR. For sure. It's a disease caused by
10:13
Speaker 2: misfolded proteins and it leads to neurodegeneration and cardiomyopathies.
10:20
Speaker 1: That's the one in the liver.
10:21
Speaker 2: They are editing liver cells because the liver produces the
10:26
Speaker 2: misfolded protein that causes problems elsewhere in the body.
10:31
Speaker 1: So, okay, clearly Crisper is this wildly useful breakthrough, but
10:37
Speaker 1: it's not perfect. And your company was founded in a
10:41
Speaker 1: way to address this key weakness of Crisper as originally developed.
10:47
Speaker 1: So what is the weakness in particular that your company
10:51
Speaker 1: is focusing on?
10:53
Speaker 2: Specificity? When I say specificity, I mean editing the one
10:58
Speaker 2: site in the genome that we intend to and not
11:01
Speaker 2: accidentally making changes anywhere else. Right in Microsoft Word, you
11:06
Speaker 2: put the cursor exactly where you want to write new text,
11:09
Speaker 2: not a mystery where the new text is going to land.
11:12
Speaker 2: Using a biological tool like Crisper, more often than not,
11:17
Speaker 2: you edit the site that you intend to. But biology
11:21
Speaker 2: is noisy, and sometimes the system lands in places you
11:24
Speaker 2: didn't expect and can make changes in places you didn't want.
11:29
Speaker 2: That could be a problem for what you're trying to do.
11:31
Speaker 2: And so our team for years has been focused on
11:35
Speaker 2: the challenge of specificity and ultimately developing new technologies to
11:40
Speaker 2: address this head on.
11:42
Speaker 1: What percent of the time does Crisper get it wrong?
11:44
Speaker 1: It's the question I want to ask, and I'm sure
11:45
Speaker 1: that's too broad a question, But how do you think
11:48
Speaker 1: about that? How should I think about that?
11:50
Speaker 2: It varies dramatically so the way Crisper actually works, it's
11:56
Speaker 2: usually a specific protein called CAST nine that cuts the
11:59
Speaker 2: genome at the site that you're trying to edit. But
12:02
Speaker 2: CAST nine on its own can't do anything. It's inert.
12:06
Speaker 2: If you will, it needs an RNA, a piece of
12:09
Speaker 2: RNA that's actually specifically designed to match the sequence of
12:14
Speaker 2: the genome that you're trying to modify. It partners with
12:17
Speaker 2: this RNA and the RNA takes it to the right place.
12:20
Speaker 2: So depending on which RNA you've designed, the edits could
12:24
Speaker 2: be more or less specific. There are plenty of examples
12:28
Speaker 2: of first generation Crisper cast nine where you could get
12:32
Speaker 2: really efficient editing at the site you want, and really
12:36
Speaker 2: efficient editing at several other sites as well that you
12:39
Speaker 2: did not want. And then there are many of us,
12:42
Speaker 2: my company Caribou bios Sciences included, who have invented, developed
12:48
Speaker 2: access to new technologies that can overcome some of these
12:52
Speaker 2: specificity challenges.
12:54
Speaker 1: I mean, it seems like in your case that particular
12:56
Speaker 1: technology is sort of the core proposition that the company
13:00
Speaker 1: is founded on. Right, Can we take crisper and make
13:02
Speaker 1: it work more reliably?
13:05
Speaker 2: Absolutely?
13:06
Speaker 1: So, what do you do to make it work better?
13:09
Speaker 2: So? At the heart of our company is what we
13:12
Speaker 2: call the Shardona technology. Now, Shardona is an acronym. Cchr
13:18
Speaker 2: DNA stands for a mouthful crisper hybrid RNA DNA technology.
13:23
Speaker 2: You now see why we use an acronym.
13:25
Speaker 1: But each of those words, I mean, it's like a
13:27
Speaker 1: relatively sort of you know, comprehensible acronym, right, like crisper
13:32
Speaker 1: hybrid RNA DNA. It's like, that's not wildly complicated.
13:37
Speaker 2: Fair, I appreciate that, And to be fair, it does
13:41
Speaker 2: actually describe what the technology is. So I just told
13:44
Speaker 2: you usually CAST nine or other crisper proteins need an
13:48
Speaker 2: RNA partner to get to the right side in the genome.
13:52
Speaker 2: What some of my colleagues did is actually develop hybrid guides,
13:57
Speaker 2: guides that are part RNA and part DNA. And it
14:01
Speaker 2: turns out the inclusion of DNA improves the specificity dramatically.
14:07
Speaker 2: We can measure this in a very quantitative way and
14:10
Speaker 2: see that it improves the specificity of editing by many
14:14
Speaker 2: orders of magnitude.
14:16
Speaker 1: A huh, So it's not like ten percent better, it's
14:18
Speaker 1: like one hundred times better.
14:21
Speaker 2: A thousand times better, even more. In some cases.
14:24
Speaker 1: Is there a sort of layperson's answer to why.
14:27
Speaker 2: Absolutely. It all has to do with what we would
14:32
Speaker 2: call it biochemistry affinity, meaning what is the binding tightness
14:39
Speaker 2: of the crisper system for the target genome? And it
14:44
Speaker 2: might intuitively feel like higher binding, higher affinity is better,
14:50
Speaker 2: but it actually turns out the opposite is true, huh,
14:55
Speaker 2: And that by including DNA we actually decrease the affinity
15:00
Speaker 2: of the complex for the target. And the reason you
15:03
Speaker 2: want to decrease the affinity is that really the entire
15:07
Speaker 2: human genome resents a laundry list of potential off target
15:12
Speaker 2: sites we don't want to edit. So you want low
15:15
Speaker 2: enough affinity that you're not accidentally grabbing all these other
15:18
Speaker 2: pieces of the genome and instead grabbing the one site
15:21
Speaker 2: that you actually want to modify.
15:24
Speaker 1: So is the challenge then to see how low you
15:27
Speaker 1: can get the affinity and have it still work. I mean,
15:29
Speaker 1: I get that you don't want it to not bind
15:32
Speaker 1: things that it's not supposed to bind to, or not
15:34
Speaker 1: cut things that it's not supposed to cut, but you
15:36
Speaker 1: do want it to bind to or cut the thing
15:37
Speaker 1: that it is supposed to cut. So presumably there's some
15:41
Speaker 1: optimal spot or maybe what's optimal depends on the use case.
15:44
Speaker 1: But how do you strike that balance.
15:47
Speaker 2: It's a very careful balancing act. You're absolutely right. Our
15:50
Speaker 2: research team has spent a huge amount of time working
15:53
Speaker 2: on this and has found ways to really develop the
15:57
Speaker 2: appropriate way to balance these two needs for each time.
16:03
Speaker 2: We need to make an.
16:03
Speaker 1: Edit still to come on the show. How Rachel and
16:10
Speaker 1: her colleagues are using this new kind of Crisper technology
16:13
Speaker 1: to create new treatments for cancer. There's this promising new
16:27
Speaker 1: kind of cancer treatment called car T cell therapy. T
16:31
Speaker 1: cells are a key part of the immune system, and
16:33
Speaker 1: the basic idea here is to engineer T cells to
16:36
Speaker 1: attack cancer cells. As you'll hear, a few car T
16:41
Speaker 1: cell therapies have been approved, but they're complicated and expensive.
16:45
Speaker 1: So Rachel and her colleagues are using Crisper to try
16:48
Speaker 1: to come up with a new kind of car T
16:50
Speaker 1: cell therapy that is both simpler and cheaper. So let's
16:56
Speaker 1: talk about some of the some of the projects you're
16:59
Speaker 1: working on with the technology. We'll start with what's farthest
17:02
Speaker 1: along clinically.
17:03
Speaker 2: Furthest along is a cell therapy that we call CB ten,
17:08
Speaker 2: and we are developing this to treat relapsed or refractory
17:12
Speaker 2: B cell non Hodgkin lymphoma. So that's a kind of
17:15
Speaker 2: blood cancer, and it's when B cells, part of the
17:19
Speaker 2: immune system, become diseased. And so we are using our
17:24
Speaker 2: Crisper genomeediting, our Chardonnay technology to actually take healthy T
17:29
Speaker 2: cells from healthy donors and then modify them through Crisper
17:35
Speaker 2: to teach them how to find and kill these kinds
17:39
Speaker 2: of diseased B cell cancers. These therapies are called car
17:44
Speaker 2: T cell therapies. We're not the first to work on them.
17:47
Speaker 2: There are many who are advancing these kinds of therapies.
17:51
Speaker 2: And CAR again is an acronym. It stands for chimeric
17:55
Speaker 2: antigen receptor, and it describes a special protein that we
18:00
Speaker 2: can encourage the T cells to express that gives them
18:05
Speaker 2: the ability to specifically recognize and kill these B cells.
18:10
Speaker 1: As I understand it, other companies have developed car T
18:15
Speaker 1: cell therapies that take an individual patient's own immune cells
18:21
Speaker 1: and develop them in the lab essentially, and then put
18:25
Speaker 1: them back into the patient to target cancer. Right. That
18:28
Speaker 1: is unsurprisingly, very very very expensive, right, because it's sort
18:32
Speaker 1: of like you're developing a custom drug for each patient,
18:36
Speaker 1: which is great in a way, but also it's like
18:40
Speaker 1: this bespoke, sort of individually tailored drug that it just
18:45
Speaker 1: costs a lot to make and it costs a lot
18:47
Speaker 1: to buy. And so my understanding is that you're trying
18:50
Speaker 1: to develop a version that is more like a traditional
18:52
Speaker 1: drug that doesn't have to be customized to every patient.
18:56
Speaker 2: Is that right, That's exactly correct. So there are today
19:00
Speaker 2: in the United States six approved car te cell therapies,
19:05
Speaker 2: and each one of them is what's called anatologous cell therapy,
19:10
Speaker 2: which is scientific fancy word for patient specific.
19:14
Speaker 1: And so those drugs, just to be clear, those are approved,
19:17
Speaker 1: they're in use, they exist in the world.
19:19
Speaker 2: Those are approved commercial products today.
19:21
Speaker 1: And they cost like hundreds of thousands of dollars per patient.
19:24
Speaker 2: Correct. Yeah, So they are proof positive that the immune system,
19:29
Speaker 2: specifically T cells, can be incredibly powerful anti cancer agents.
19:35
Speaker 2: They also demonstrate how challenging it is to develop one
19:40
Speaker 2: batch of therapy for each and every patient. That is
19:44
Speaker 2: not scalable. That is not going to be something that
19:48
Speaker 2: delivers this kind of therapy to broader and broader patient populations,
19:53
Speaker 2: and it's also restricted to cancer patients who have sufficiently
19:57
Speaker 2: good T cells to make the product in the first place.
20:00
Speaker 1: Oh, that's interesting, Like if you're a patient in your
20:04
Speaker 1: immune system is just totally beat down by having cancer
20:07
Speaker 1: or being treated for cancer, then you don't have the
20:09
Speaker 1: T cells to generate this therapy.
20:12
Speaker 2: That's exactly correct. There's also quite a lot of complexity
20:18
Speaker 2: and almost handholding, if you will, necessary to make these
20:23
Speaker 2: patient specific therapies, and so cancer centers like MD Anderson
20:29
Speaker 2: or the University of Pennsylvania, they have tremendous expertise and
20:34
Speaker 2: they have the staff to really work with patients to
20:38
Speaker 2: shepherd them through this process to ensure that they can
20:41
Speaker 2: actually support them provide any additional therapies they need while
20:45
Speaker 2: they're waiting for their therapy to be manufactured, to give
20:48
Speaker 2: them access to this kind of therapy. But that's not
20:51
Speaker 2: where the majority of patients are treated. The majority of
20:54
Speaker 2: patients are treated in community hospitals and community clinics that
20:59
Speaker 2: don't have the resources to shepherd patients through this kind
21:03
Speaker 2: of very complex stuff.
21:07
Speaker 1: So, so what do you have to do to make
21:11
Speaker 1: a one size fits most version of this, right you
21:13
Speaker 1: want to? It would be good for the world if
21:15
Speaker 1: we could move away from having to design this drug
21:20
Speaker 1: literally for each patient and have a drug that'll work
21:23
Speaker 1: for almost everybody. That's what you're trying to do. How
21:25
Speaker 1: do you do it?
21:26
Speaker 2: Yeah, the vision is to develop what the field would
21:29
Speaker 2: call allogeneic or off the shelf car T cell therapies.
21:34
Speaker 1: Which is what most drugs are, right, Like just a
21:37
Speaker 1: drug and the doctor gives you the drug and hopefully
21:40
Speaker 1: it makes you better.
21:41
Speaker 2: Right right, So step one is we need to use
21:44
Speaker 2: healthy T cells from healthy donors instead of T cells
21:48
Speaker 2: from cancer patients.
21:49
Speaker 1: Okay.
21:50
Speaker 2: Step two is you have to make this safe. Right, Typically,
21:54
Speaker 2: if you take a T cell from one person and
21:56
Speaker 2: put it in another person, you are probably going to
22:00
Speaker 2: cause what is called graft versus host disease, which is
22:03
Speaker 2: where the other person's T cells attack parts of your.
22:07
Speaker 1: Body, analogous to what is that transplant patients have. Basically,
22:11
Speaker 1: it's like yeah.
22:13
Speaker 2: Correct, correct, So right off the bat, we have to
22:16
Speaker 2: prevent that, and we do that through genome editing by
22:19
Speaker 2: getting rid of something called the T cell receptor. It's
22:22
Speaker 2: the thing on the surface of the T cell that
22:24
Speaker 2: would usually empower it to cause graph versus host disease.
22:27
Speaker 2: So that's hitting the delete key once to get rid
22:30
Speaker 2: of that.
22:30
Speaker 1: Okay.
22:32
Speaker 2: The second step is you have to give the T
22:34
Speaker 2: cells the CAR so it knows what it's looking for
22:38
Speaker 2: on the surface of cancer cells to appropriately identify and
22:42
Speaker 2: kill them. And many of our peers stop there. Those
22:46
Speaker 2: two combined would be what they envision as a product,
22:50
Speaker 2: but our team looked at that and said, that will
22:53
Speaker 2: never be enough.
22:54
Speaker 1: And so just to be clear, when you see people stop,
22:56
Speaker 1: there are people trying that, like, is that version of
23:00
Speaker 1: this drug in trials? Now?
23:02
Speaker 2: Yes, multiple human clinical trials are being run with something
23:05
Speaker 2: that looks like.
23:06
Speaker 1: That, and so if that works, that would be a
23:09
Speaker 1: off the shelf, one sized, fistmost normal drug kind of drug.
23:13
Speaker 1: You're skeptical that it's going to work.
23:15
Speaker 2: Correct, We think you have to take it a step
23:17
Speaker 2: farther and I'll tell you why. Okay, Yeah, these off
23:21
Speaker 2: the shelf T cells, they are foreign to the patient's
23:25
Speaker 2: immune system, and the patient's immune system is going to
23:28
Speaker 2: figure that out fairly quickly and actually kill off the
23:32
Speaker 2: CAR T cells. And that's very different from when you've
23:35
Speaker 2: had a product made from your very own T cells.
23:38
Speaker 2: They can last for a very long time, and so
23:41
Speaker 2: we look at that differential in time and say that's
23:44
Speaker 2: a problem we have to solve.
23:45
Speaker 1: Why doesn't everybody agree with you?
23:49
Speaker 2: I would say more and more people agree with us
23:52
Speaker 2: if you look at what's happening in the field. In fact,
23:55
Speaker 2: many of the first off the shelf car T cells
23:58
Speaker 2: that have been tried in human clinical trials have been
24:00
Speaker 2: retired because they didn't work as well as people had hoped.
24:04
Speaker 2: And I think many are now going back to the
24:06
Speaker 2: drawing board to think about what are other things we
24:09
Speaker 2: can do to empower or enhance these T cells to
24:13
Speaker 2: overcome these challenges.
24:14
Speaker 1: So what do you do, you were getting to the
24:17
Speaker 1: sort of next steps, what do you do to make
24:19
Speaker 1: it better tolerated by the patient's immune system.
24:21
Speaker 2: Yeah, we think about how to bridge that gap, both
24:25
Speaker 2: very literally and in ways that are more about boosting
24:29
Speaker 2: the biology than necessarily entangling with the patient's immune system. So,
24:35
Speaker 2: for example, in some of our other cell therapies that
24:38
Speaker 2: we're developing for other blood cancers like multiple myeloma and AML,
24:43
Speaker 2: we actually deploy what we call immune cloaking, and so
24:47
Speaker 2: this is where we use our genomeediting to change what
24:51
Speaker 2: is or is not decorating the surface of the car
24:54
Speaker 2: T cells to try to slow down how the patient's
24:57
Speaker 2: immune system could recognize and clear the therapy. So that's
25:00
Speaker 2: a very literal way of addressing this challenge.
25:03
Speaker 1: Cloaking is a cool name for it, to basically make
25:05
Speaker 1: the cell better at hiding from the immune.
25:07
Speaker 2: System exactly exactly Is.
25:10
Speaker 1: There an example of a particular change you make to
25:14
Speaker 1: that end.
25:16
Speaker 2: Yes, So what we do is actually get rid of
25:20
Speaker 2: some of the proteins that would usually sit on the
25:23
Speaker 2: surface of a Carte cell. These are called HILA class
25:26
Speaker 2: one molecules, and it helps to prevent the patient's immune
25:31
Speaker 2: system from readily recognizing and clearing the therapy. It's a
25:36
Speaker 2: little more complex than that. There's actually a special kind
25:39
Speaker 2: that we then decorate the surface with to help ensure
25:42
Speaker 2: that all parts of the immune system cannot rapidly recognize it.
25:46
Speaker 2: I also want to be clear, we don't think this
25:49
Speaker 2: creates a perfect stealth cell that lasts forever. There are
25:53
Speaker 2: lots of things about these cells that we expect the
25:55
Speaker 2: patient's immune system to ultimately recognize and cause it to reject.
26:00
Speaker 2: This is about buying additional time with a hope that
26:03
Speaker 2: that allows additional anti tumor activity.
26:06
Speaker 1: And is there is there a balance you have to
26:11
Speaker 1: strike there where, well, the cell still has to work, right,
26:15
Speaker 1: I mean, is there a universe where you do so
26:17
Speaker 1: much to try and cloak the cell that it can't
26:20
Speaker 1: whatever do its cellular business and persist as a cell
26:23
Speaker 1: until it finds the tumor?
26:26
Speaker 2: Right? I think there's some extreme world where you try
26:30
Speaker 2: to put so many different genometics into the T cell
26:34
Speaker 2: that you break it, maybe both on a cell specific level,
26:39
Speaker 2: but also a population level. So if you think about it,
26:43
Speaker 2: we're trying to take this population of millions and millions
26:47
Speaker 2: of T cells and provide three, four five different genometics. Now,
26:53
Speaker 2: genomeediting is very efficient, but it's not one hundred percent efficient.
26:57
Speaker 2: You know, some medits might be eighty percent, otherre's ninety percent,
27:01
Speaker 2: maybe ninety five percent. So that means, as you now
27:04
Speaker 2: look at this whole population of T cells, every time
27:08
Speaker 2: you add a new edit, it means a fraction of
27:12
Speaker 2: a fraction of a fraction of the cells actually have
27:15
Speaker 2: all the edits that you desire. So we set a
27:18
Speaker 2: pretty high bar for ourselves. We only bring a program
27:22
Speaker 2: forward into the clinic if we can manufacture it in
27:26
Speaker 2: such a way that at least half of all of
27:28
Speaker 2: the T cells have all the edits that we're going for,
27:32
Speaker 2: and we've been able to do that with three different
27:34
Speaker 2: therapies so far.
27:35
Speaker 1: So you're saying that even with your improved version of Crisper,
27:43
Speaker 1: it's still sufficiently error prone. Not that it's highly error prone,
27:48
Speaker 1: but it still makes enough mistakes that something like half
27:52
Speaker 1: of the cells you're creating won't be exactly the way
27:55
Speaker 1: you want them to be.
27:56
Speaker 2: I would say, it's not that it's making mistakes, meaning
27:59
Speaker 2: it's not making off target changes elsewhere that we didn't want.
28:03
Speaker 2: It's instead that in some fraction of the cells, they're
28:06
Speaker 2: just not getting.
28:07
Speaker 1: The edit right of omission rather than a sinecommission. Yes, exactly.
28:12
Speaker 1: So it's the affinity, like you nailed the low affinity.
28:17
Speaker 1: So does that suggest just to sort of zoom out
28:20
Speaker 1: for a sec I mean it suggests that there is
28:23
Speaker 1: room for improvement on the kind of platform level. Presumably.
28:27
Speaker 2: I think so. And I'll give an example of even
28:29
Speaker 2: the work we've done over the past few years. So
28:32
Speaker 2: our first program, which is for lymphoma, benefits from three edits.
28:37
Speaker 2: Fast forward now to our third program for AML. It
28:41
Speaker 2: has five different genomeedics in it. We're able to hit
28:45
Speaker 2: the delete key on three different genes in two different places.
28:49
Speaker 2: We can insert new genes to give new functionality to
28:53
Speaker 2: the T cells. And I think this already represents really
28:57
Speaker 2: pushing the envelope in terms of what you can accomplish.
29:00
Speaker 2: And I think there's further room to run with that
29:02
Speaker 2: as well.
29:04
Speaker 1: If things go well, When when might you be, you know,
29:09
Speaker 1: submitting a drug for approval?
29:12
Speaker 2: Fantastic question. We hope to start a phase three trial
29:17
Speaker 2: with CB ten next year. If you look at the
29:22
Speaker 2: kinds of phase three trials that have been run for
29:24
Speaker 2: these cell therapies before, they usually take two years or
29:29
Speaker 2: more to run, and then there's some time after that
29:31
Speaker 2: put all the documents together for the regulatory agencies. So
29:35
Speaker 2: a lot of work yet to be done. Very excited
29:37
Speaker 2: about what's coming next.
29:42
Speaker 1: We'll be back in a minute with the lighting round.
29:55
Speaker 1: Let's have a lightning round. Let's finish with the lighting round.
30:01
Speaker 1: What's more frustrating pipetting or knitting?
30:07
Speaker 2: Knitting?
30:11
Speaker 1: What's the hardest thing you ever knit?
30:15
Speaker 2: Mittens?
30:16
Speaker 1: Tell me about pipe petting. I feel like you and
30:18
Speaker 1: pipetting have history.
30:20
Speaker 2: You know. Pipeetting is about moving clear liquids from one
30:24
Speaker 2: to another. I spent many, many years where that is
30:29
Speaker 2: what I did every day, and obviously it gave me
30:32
Speaker 2: the ability to do hands on wet lab research. And
30:36
Speaker 2: there's a piece of it that I desperately miss, which
30:39
Speaker 2: is being the first to know the answer to an
30:42
Speaker 2: interesting biological question. Right, there's a magical aha moment when
30:47
Speaker 2: you see the results first. Now these days, I'm not
30:52
Speaker 2: that far away from the people who get to do
30:54
Speaker 2: the really cool work in our lab, So I'm at
30:57
Speaker 2: peace with the balancing act of not having to pipette
31:00
Speaker 2: and you know, being the third, fourth, tenth person who
31:04
Speaker 2: learns the cool news.
31:05
Speaker 1: Worthwhile trade off at the end. Indeed, did you go
31:08
Speaker 1: to grad school assuming you would work in industry? Is
31:11
Speaker 1: there some moment when you are making a leap off
31:15
Speaker 1: of this path? You know you're getting a PhD? You
31:18
Speaker 1: clearly have been very good at school. Lots of people
31:21
Speaker 1: just stay in school all their lives and become professors
31:24
Speaker 1: and have wonderful careers. Was there some moment when you
31:27
Speaker 1: decided to step off of that path? Leap off of
31:30
Speaker 1: that path?
31:32
Speaker 2: I was probably one of the few people in my
31:34
Speaker 2: PhD program who came to school knowing I didn't want
31:38
Speaker 2: to be a professor when I grew up. I actually
31:41
Speaker 2: thought I wanted to be a patent attorney when I
31:44
Speaker 2: grew up. However, we started working with patent attorneys because
31:49
Speaker 2: of all the cool technology that was coming out of
31:51
Speaker 2: the lab, and I pretty quickly realized that's not the
31:55
Speaker 2: job that I want to do.
31:57
Speaker 1: Good figure figured that out.
31:59
Speaker 2: Indeed before I went to three years of law school.
32:02
Speaker 2: So it created sort of this moment of well, I
32:06
Speaker 2: don't know what I'm going to do when I grew up.
32:09
Speaker 2: Now know a few things I don't want to do,
32:12
Speaker 2: and it meant I started thinking a lot about the
32:15
Speaker 2: industry side of science. I took a lot of business
32:18
Speaker 2: school classes at that point in time to try to
32:21
Speaker 2: learn and learn a new vocabulary. But I think that
32:24
Speaker 2: made it easier to take the entrepreneur or a leap,
32:28
Speaker 2: because I wasn't on a different path than I had
32:30
Speaker 2: to jump off to.
32:31
Speaker 1: Go on basically your way out of going to law school. Indeed,
32:37
Speaker 1: so you were on the Forbes thirty under thirty, the
32:41
Speaker 1: Fortune forty under forty. As far as I know, there's
32:44
Speaker 1: no fifty under fifty. So do you have like a
32:47
Speaker 1: next move, Well.
32:50
Speaker 2: There is a fifty over fifty, but I've got to
32:52
Speaker 2: wait a few more years for that.
32:56
Speaker 1: I'm glad that you've got it lined up, though it's
32:58
Speaker 1: important to have a goal and you've got time. What's
33:03
Speaker 1: one thing that you wish people understood better about genes?
33:10
Speaker 2: I think many people expect there's a very clear one
33:14
Speaker 2: to one connection that a gene means X. There are
33:19
Speaker 2: very few genes in our genome that result in one
33:24
Speaker 2: specific outcome. We as human beings are the product of
33:29
Speaker 2: this incredibly complicated cross signaling across every gene in our genome,
33:37
Speaker 2: and any one trait, even as simple as how tall
33:41
Speaker 2: we are, is the output of many, many, many different genes.
33:46
Speaker 2: And so I do wish there was a better understanding
33:49
Speaker 2: of just the rich complexity of our own biology, because
33:53
Speaker 2: then I think it feeds directly into how do you
33:56
Speaker 2: use a technology like crisper to change disease biology? And
34:02
Speaker 2: there are some examples, but not a ton of examples
34:05
Speaker 2: where one edit is enough.
34:07
Speaker 1: It's like the the Mendelian pea plants maybe do more
34:11
Speaker 1: harm than good as a teaching to a like No, no,
34:13
Speaker 1: it's not usually like that.
34:16
Speaker 2: Fair.
34:16
Speaker 1: Yes. Rachel Horwitz is the co founder and CEO of
34:23
Speaker 1: Caribou Biosciences. Today's show was produced by Gabriel Hunter Chang.
34:28
Speaker 1: It was edited by Lyddy jeene Kott and engineered by
34:32
Speaker 1: Sarah Bruguier. You can email us at problem at Pushkin
34:35
Speaker 1: dot FM. I'm Jacob Goldstein and we'll be back next
34:39
Speaker 1: week with another episode of What's Your Problem.