Welcome to The Long Run. This is a podcast for biotech adventurers. I'm your host, Luke Timberman.
Today's guest is Carolyn Bertozzi. She's a professor of chemistry at Stanford University and an entrepreneur. More specifically, she's a chemical biologist. Even more specifically, you could call her a chemical glycobiologist or a bioorthogonal chemist. Now, what does that mean? Her research is focused on glycans, the beautiful and bewilderingly complicated sugar molecule structures attached to proteins. These carbohydrates are often underappreciated by biologists and orthogonal to the way many think. But glycans are known to play a significant role in how proteins behave and a wide variety of interactions between cells.
Whether you can aim drugs at some of these glycan targets and get the disease-modifying effects that a typical medicinal chemist desires — well, that's the sort of question that has driven much of Bertozzi's research over the years.
She took a gamble early in her career to get here. Bertozzi joined an immunology lab where it wasn't entirely obvious that a chemist would add much at first. By forcing herself to think outside one discipline, she ended up bridging fields in an interesting way. These raw and messy edges of disciplines are often where the big advances occur.
Now, without question, Bertozzi is an established star. She won a MacArthur Genius Grant early in her career, later won the prestigious Lemelson-MIT Prize for Invention, and was elected by peers into the National Academy of Sciences. She's known for leading teams that develop tools to provide better imagery — better information, really — about glycan behavior in live action. And when you develop tools or methods that lots of people can use and which advance an entire field, that's the kind of thing that gets you written up in the scientific history books.
Bertozzi is also an advocate of open science. Right before this interview, she published an interesting preprint article on lysosome-targeting chimeras, which she calls LYTAC. This one caught my immediate attention. These are conjugates that selectively degrade certain proteins, including APOE4, PD-1, and EGFR. Biotech people, you know, these are some very, very interesting targets. Shrewdly, Bertozzi publicized this preprint on Twitter, where she's an avid producer and consumer of scientific news and also a strong supporter of women's advancement in science.
She is also a warm and funny person to talk with. Bertozzi cares about open science as a way to speed up innovation. She cares about communicating science to the wider society at large and in supporting women's advancement within the field. I enjoyed asking her about how she got to this point in her career and how she thinks about biology evolving to embrace the kind of complexity that once deterred people from getting serious about her field.
Now, before we get started, I want to mention a couple events to mark on your calendars. The Boston Cancer Summit is coming up April 16 at Alexion Pharmaceuticals. David Shankine, John Reed, and Cindy Peretti are just a few of the cancer R&D leaders I've recruited to speak at this big charity fundraising event. Only a couple dozen tickets are left as of this recording.
But that's not all. A couple days later, on April 18th, I'll be flying west for a sister event in San Francisco. You can hear from Hal Baron at GSK, Ira Mellman of Genentech, and — drum roll, please — Carolyn Bertozzi of Stanford at the San Francisco Cancer Summit. Carolyn will speak more specifically there about Palleon Pharmaceuticals, a glycobiology-focused cancer drug developer that's been supported by SR One, Frazier Ventures, and others. You can see all the details on the speakers and how to buy tickets by going to Timberman Report and clicking on Kilimanjaro Climb. All proceeds from these events go to support cancer research at the Fred Hutchinson Cancer Research Center. Now, please join me and Carolyn Bertozzi on The Long Run.
Well, it's great to be here today at Stanford University with Carolyn Bertozzi, professor of chemistry here at Stanford. Thanks very much, Carolyn, for joining me on The Long Run.
Before I get started on sort of the classical biography stuff, which is typical on this show, I will say a couple things. I appreciate you are an avid user of Twitter. You communicate science — a lot of science, a lot of the joy of discovery — but you also bring up real issues pertinent to how we could do a better job in running the scientific enterprise. So on days when I feel a little sad about Twitter, I look at how you're doing it and I think that that's the right way to do it.
Well, coming from you that means something, because you're also obviously a very effective user of Twitter and social media. I'm actually a fairly newcomer to Twitter. You know, I actually knew nothing about Twitter or Facebook or any social media platform until I became a journal editor. And that was in 2015, right? Maybe late 2014. And I launched a new journal with the American Chemical Society and they said to me, you know, you should get on Twitter and promote the journal there. And I thought, oh, I don't know anything about Twitter and what would I even say on Twitter? I couldn't really conceive of how to use it. And they said, you know, we'll set it up for you and just start watching how other people use Twitter and then you'll get the hang of it.
And so at first, you know, I was sort of awkwardly retweeting other people's tweets that didn't really have any of my own content. And then eventually I sort of realized that I was learning a lot from Twitter. You know, I was reading journals from their Twitter feeds. I was following news channels. I was following biotech and pharma channels. And suddenly within a few months I found that I was like really up on current events and I just felt very informed. And then I sort of found my voice on Twitter. But now that I, you know, have — I've been able to extract a lot of value from it. So I think I really appreciate it and hopefully I have something to contribute. But it's hard — I can't now live without it. So that's what happened.
Wow. Well, now the other thing that I did want to say at the start was, your area of expertise is one that — I mean, you can use social media and the journal to communicate some of this glycan biology, glycobiology, which, you know, I cover a lot of areas of biotech and I don't hear a lot of emphasis on this, not a lot of people talking about it. But I find it really — it brings me back thinking about what you do as an expert in this field to one of the very basic first things I learned in covering biotech like 20 years ago, and that is, you know, you can take a gene sequence and plug it into a host cell nucleus and out pops the protein that you want, and that can be the drug. Isn't that cool? Recombinant DNA. But there are these sugar molecules that are attached, that hang off in different ways and structures, and that can really affect how that protein behaves when you inject it into the body. Maybe it clumps together. Maybe it causes immunogenicity. And that's underappreciated, I think, by a lot of people, and this is like your world.
Yeah, that's right. First of all, I think your experience of not hearing much about glycoscience as you travel the biotech and pharma world — that's a common experience. So I think, and it's a reflection that a lot of people in the glycobiology field have been frustrated with, I think, you know, throughout the majority of their careers, because, you know, if you're in a space that is so clearly important and potentially rich with therapeutic targets and has implications for human health, and you find that there are barriers to having that science accepted in the more mainstream biopharma, you feel like the value is not being realized, right? And I think that's a common expression that I hear from people in the field.
And you're right that those people in the biopharma industry who are familiar with glycosylation usually start with an encounter with glycosylation of one of their protein therapeutics. In fact, the glycosylation of antibodies is now recognized as one of the important modulators of their effector functions. So that's a context where you might find more familiarity, right? People may or may not want their monoclonal to engage with Fc receptors, right, or to activate complement. And so that's a context in which they might want to engineer the glycosylation. But that's the tip of a, I think, gigantic iceberg.
And I'm actually very excited these days because it seems to me that finally, you know, for me, I've been working in glycoscience my entire independent career and even before that during my training. So if you add all that up, you know, we're talking like almost 30 years of work in glycobiology. And I find that the field is now becoming much more visible just recently. And I think it's an interesting convergence of, you know, you might ask yourself what might have been the intellectual deterrents to people in biology and biopharma to want to learn more and embrace glycoscience, right? What are the deterrents? And I think one of the main ones is the complexity. Especially when you start learning about glycoscience, it can easily feel like it's this quagmire of complex structures.
And there was a time in bioscience and biopharma — and that time was kind of post-molecular biology revolution — where I think there was a sort of reductionist mentality, right? So people thought, hey, now that we can go from the gene right to the protein and turn a protein on or turn it off, we now can make drugs and we can understand biology. And in a world that's driven by reductionist thinking, glycoscience has no chance.
Okay. Too complicated. It's too complicated. The structures — people don't, you know, it just seems like you can't find clarity in your biological mechanism. Whereas, you know, things seem clearer when you're talking about a single protein drug target. You can turn it off or on, right? You can inhibit it or agonize it, right? It seems very simple.
Fast forward to the modern era and I think now biologists and biopharma people have conceded that biology is very complicated. I think everything is complicated, not just glycoscience. And when you think about just cancer for a second, because I know you're involved in a startup company that's focusing on this area, the tumor microenvironment has been this hot term for the last few years. And there's all these things going on in that contextual environment there. It's low oxygen, it's high pressure, there's these thick stromal barricades. It's like you got your drug or your T cell has got to get through this whole gauntlet of things. Glycosylation is part of that series of obstacles, and that's one of the areas that you're focused on with Palleon. Am I reading that correctly?
That's absolutely right. Yeah.
So, you know, it's interesting because on the one hand, the contribution of glycosylation to diseases like cancer — many others as well — I think that, you know, the information has been kind of hiding in plain sight, but I think people have had a hard time finding clarity around how to understand the mechanism and how to drug it. And so Palleon was formed around our realization that there are changes in glycosylation in the tumor microenvironment that engage immune-suppressive mechanisms.
And, you know, in my own lab we sort of achieved clarity on that over the last 10 years, both from work that we were doing but also work that was being published in other labs. And, you know, we were able to basically mobilize a very experienced team of, you know, biopharma executives and scientists to come together and to basically make therapeutics that are based on this information. And it's very exciting because the molecules we're making, which, you know, admittedly we're still preclinical, so we have a long way to go in proving this hypothesis in humans, but hopefully within the next few years we'll have clinical candidates that can go into clinical testing and see if we're correct. But right now all the preclinical data are looking very exciting. And I think this is a really new axis of biology that just has been completely overlooked.
Now, was this one of those areas where, like everyone else, you're reading the literature and you read about these checkpoint inhibitors, you know, the PD-1s, these proteins expressed on the T cells that are immune-dampening mechanisms, and if you can release the brakes — I mean, how cool is this, right? It's pretty exciting. But not everybody responds. And, you know, often the tumor's crafty and finds other ways to dampen that immune response. And that's where you thought, okay, we may have something to contribute here too. We have a piece of the story that's not been included.
That's right. In fact, you know, I think — I mean, it may be that history will look back on the discovery of the checkpoint receptors and the development of checkpoint inhibitors, the anti-PD-1 and PD-L1 drugs, as one of the most important discoveries for glycobiology, ironically, because it was that biology that gave people in the glycoscience area clarity on these changes in glycosylation in the tumor microenvironment. Because it turns out that the way that PD-1 delivers its inhibitory signal to the T cell is exactly how another family of immune-modulatory receptors called the Siglecs deliver their inhibitory signals. But whereas PD-1 signals in response to PD-L1 engagement, the Siglec receptors signal in response to sugar engagement.
And when we saw the parallels between the PD-1 biology and these carbohydrate receptors and their signaling biology, that's where the clarity came from. And that's where we started working on it in several other labs. So now, you know, we come to see this family of Siglec receptors that are binding their carbohydrates as being functionally analogous to the PD-1/PD-L1 axis and potentially acting synergistically with that axis in many tumor settings.
Very cool. Well, I'm going to come back to this a little bit later. Longtime listeners are probably thinking, tell us about Carolyn and where she comes from, because this is like — I like to cover people's classical background. File this under the header of scientists are people too, and they are. And I think this is important for another aspect of your career that's important to you, which is teaching and communication, because I think the fact that scientists often don't communicate on personal levels very much with the wider public, you know, creates this distance that causes a lot of downstream problems, this disconnect between science and society. So let's try to bridge that gap a little bit. Carolyn Bertozzi, you're from Boston. I know your dad was a professor, or still is, at MIT, a physicist. He's retired. But yeah, he was a nuclear physicist at MIT. So you've got academia running in the family.
Yeah. And also entrepreneurism, because after my dad retired in his 70s, he started a company, and that company is called Passport Systems. It's a homeland security company.
Wow. Huh. Well, I'm a little out of my wheelhouse there with physics. But okay, so you're growing up in Boston in this academic family. I mean, obviously education must be a big value. How did he get you and your siblings excited about science?
Well, you know, to be honest, my father and my mother — I think they probably hoped that their children would grow up and want to be scientists. But I can't honestly say that they kind of drove us to science, other than we always had access to gadgets and stuff. You know, my dad would bring home from work — like he brought a computer terminal home back in the 70s before it was a thing, and we were playing with it. And he brought — I think the funnest thing he brought home was a giant magnet, and we used to have all kinds of crazy fun with this huge magnet. But it's not like he — he certainly didn't do what I see parents today doing, which is driving their kids around to science fairs and, you know, entering them in competitions and dragging them to science events and stuff. That was really not the case.
You had a lot of unstructured time.
Yeah. I mean, back right back in the 60s and 70s, right, when I was growing up, you just kind of ran around the neighborhood with the neighborhood kids, and that's what we did. And I didn't really contemplate like a focus on science until when I was maybe in college.
Wow. Okay. And now, how many siblings do you have?
I have two sisters. One older sister, one younger sister.
Okay. So you're the middle. Your older sister, I think I read, she's a mathematician.
Yeah. She was a math whiz from birth, you know, as they often are. And she's now a professor at UCLA in applied math.
Uh-huh. Uh-huh. So is that a hard act to follow?
Absolutely. Yeah. And we're only one year apart, right? So the typical situation for me is that she would, you know, have a teacher in elementary school and blow away the teacher in the class with her brilliance, and then I would come along and the teacher would say, 'Oh, hey, are you as smart as your sister?' And I would just kind of look at my feet and kick the dirt around. And then the answer was no. So that was my typical experience. So, you know, I had to differentiate myself in other ways.
Sports mostly. I think that was the big difference between us.
Soccer, softball, you name it. Anything with a racket or a ball or a glove or anything.
Yeah. Uh-huh. Team oriented.
Everything. Yeah. Team. Yep. Anything I could get into.
Mhm. Now, but you did pretty well in school too. You were not like a middle-of-the-pack student.
I was not a slacker. No, I wasn't like one of those standout, skip-a-grade kind of kids. And they existed in where I grew up. And my sister was sort of one of those types. But I just, you know, was trying. I was diligent. You know, I did my homework and got pretty good, though not perfect, grades.
Uh-huh. Uh-huh. But you go off to Harvard.
And did you — I know you majored in chemistry. Did you decide early on that chemistry was the field for you?
No, I had no — I had no interest in chemistry, honestly. You know, high school chemistry was a torture experience for me, as it is for many people, I've learned. And then in college I didn't really think about chemistry, but I took chemistry classes because I was a, you know, potential premed. I was thinking about med school, and so you have to take chemistry, right? And unexpectedly I fell in love with organic chemistry. It was the subject that clicked.
Uh-huh. Which is usually the weed-out class.
That's what everyone told me, and I fully expected to hate it and hold my nose. And the only good thing was it would be the last chemistry class I'd ever have to take, I thought. And it was the complete opposite for me.
What was it about it that made it click, you think?
You know, it was very visual. And that was a good match for my brain, I guess. The way, you know, I was sort of a visually minded person. I really loved the way that you could distill it all down to a few very fundamental principles that just applied to all these different situations. But if you got the principles, then you could explain so much of the observation of how molecules react with each other. It seemed very — it had a very personal feeling to me, like the molecules had little personalities. And they, you know, I started to look at people in a different way. And I would like — I'm looking at you and I'm thinking, what molecule best describes you, right? I could find a molecule that kind of embodies your qualities.
On the periodic table? No, those are elements. Those are atoms.
But if you combine the atoms together, you make a molecule. And the interesting thing is you could have two molecules with exactly the same atoms, right? The same number of carbons, nitrogens, oxygens, hydrogens, but link those atoms together in different ways, and those molecules are different, have different personalities, and can behave differently, very differently. So that's what was so cool to me about it.
I'm afraid to ask you what kind of molecule you think I am.
I don't know. Well, let's wait till after the interview. I get to know you better.
Fair enough. Now, you also had an interest in the arts. I think you played in some bands as an undergrad?
Yeah, you know, I played keyboards in a rock band. And that was actually — you know, when I was in high school I performed with a lot of my high school bands. You know, like I accompanied the musicals and with a jazz ensemble and a chorus. And so I played in a lot of groups. And I honestly thought in college I might even want to be a music major. So that was on my potential list of things. But I don't think my parents were that keen on the idea because, you know, it was not very pragmatic. And they were both, you know, children of the Depression, really. They were born in the 30s and lived through the Second World War. And, you know, they were of the mind that if you're going to spend all this money to go to college, right, you should leave with an education that situates you for some kind of practical career. And I totally understood that.
But so I figured if I wasn't going to major in music and do music as a vocation, maybe I could as an avocation at least stay active, right? So I got recruited to join a college band, and we played, you know, frat parties at local colleges in New England.
It was a combination of — we covered 80s music because that's how you got your jobs, playing parties, right? Popular music. So, you know, Prince and Michael Jackson and Billy Idol and whoever was popular. You know, I'm trying to think. We actually did a lot of — I'm blanking on the music we played. I mean, we played heavy metal. We played some AC/DC and Black Sabbath. But then we also played kind of R&B, you know, whatever the dance music was. But we always mixed in now and then original compositions, which, you know, the kids didn't recognize, but it was an outlet for our lead — the band leader, who was also our lead guitar player, who was a gifted musician, both as a player and a composer. And he wrote original compositions for us that we tried to kind of slot in there when nobody was noticing.
Now, at the time, of course, when you're young, you have no idea where any of this stuff is going. But looking back now, do you think that that was a useful side of your brain to exercise and that it helped in getting the humanities and the science mixture?
It was. Yeah, I think so. Because, I mean, first of all, like playing with that band is one of the things I remember. You know, I mean, you forget most of what you learn in college. But those experiences I will remember forever, right? So it was very memorable to be able to perform with those guys and the crazy stories that we have of like taking the rented van up to Maine to play a gig at a college. We did a gig there. We got lost and it was a snowstorm. And, you know, that's all part of my experience.
But really, I'll say that the most incredible part of that was just being able to play and get to know as a young person our lead guitarist, who ended up being a very famous musician, actually. So that was Tom Morello, who graduated from Harvard two years ahead of me. And then he went and made it in the music industry in Los Angeles, and he formed Rage Against the Machine, which I don't know if you're — you're young, maybe you don't know. I'm old enough to know those guys. And then Audioslave was the next band. And he's right now still touring. I mean, he performs, and I follow him on Twitter, you know, just to kind of see what he's doing. And I listen to his recordings. You know, I get the MP3s, and I'm still a longtime fan.
So you get to be a fan, but at some point, like, you buckle down, you figure out what you want to do with the rest of your life, and it's chemistry. You just — so you major in this, you end up going to Berkeley for your PhD.
Great tradition of chemistry at Berkeley. How did you end up going there?
Well, you know, honestly, first of all, it was a top-ranked graduate program. Not that I knew that at the time. I mean, someone told me, 'Oh, you should apply to Berkeley and Stanford and Caltech, and these are the best places.' I said, 'Okay.' But honestly, during my senior year, one day I was walking to class in the morning from my dorm, you know, with my backpack, and I was crossing Mass Ave, which cuts right through the middle of Harvard Square. And all of a sudden a car like drove by and honking, honking. And I looked, and it was my dad, who was on his way to work at MIT, right? And that's the moment when you realize that you really ought to get out of this town and try something new, because, you know, I grew up in Lexington, Massachusetts, which is like 20 minutes from Harvard Square, right? So I really hadn't gone anywhere in my whole life. And I was like, okay, you know, so, you know, when I was applying to graduate schools, I kind of rolled out the map and I said, okay, what is there way out there, you know, on the left side of the map? And so I had in my mind, I say, got to get to California. And so then that kind of narrowed down the options. And so then I, you know, I got into Berkeley and Stanford and Caltech. Those were the big three at the time on the West Coast. And so I came to visit.
And Berkeley was the place back then that had kind of a growing and also quite substantial representation in what we then called bioorganic chemistry. So that's chemistry at the interface with biology. Now it's kind of been rebranded chemical biology. You probably have heard that term. But before that we called it bioorganic chemistry. And I sort of felt like that would be the place where I could, you know, both learn organic chemistry, which I loved, but also be able to apply it in a biological context. And I also had a strong affinity to biology because I had started as a bio major. Actually, I had switched my major to chemistry halfway through college.
Oh, so you were thinking premed. That got you some of those biology classes, right?
But I loved those classes, right? I loved them. Biochemistry was great, and I took a neurobiology class that I loved. And what I loved about them was thinking about right down to the molecules, like what is happening when the ion channel opens, right? You know, and so it seemed like the right fit.
And this would have been around the time of the beginnings of what was called rational drug design, structure-based — Stu Schreiber's group at Harvard, Pete Schultz at Berkeley, and a whole bunch of others.
Absolutely. And I met with them when I was looking at grad schools. Right. I mean, I was a grad student. Pete Schultz was a rising star at Berkeley, and Stu Schreiber was at Yale at the time. And I got to meet with them and hear about their visions. And I thought, 'Wow, yeah, this is where it's at.' Synchrotron radiation had become available to structural biologists. And back then, you're right, in the 80s, there was this incredible wave of excitement around, you know, if you could solve the structure, then you could make the drug. And of course, you know, it turned out to be more difficult than that.
If you enjoy listening to these revealing interviews with biotech newsmakers, you will love the in-depth reports that you can get two to three times a week on Timberman Report. You can subscribe to Timberman Report for $149 a year per person. Discounts are available for companies and universities. Ask me about a group license at luketimbermanreport.com. And have you heard about the cancer summit events I'm organizing this spring as a volunteer for the Fred Hutchinson Cancer Research Center? These events are big fundraisers, part of the $1 million Kilimanjaro Climb to Fight Cancer campaign I'm leading this year. Hal Baron, David Shankine, Ira Mellman, Mary Lynn Headley, Cindy Peretti, Christina Burrow, and many others are part of this Ocean's 11-style ensemble cast of cancer R&D movers and shakers coming together at these events. For tickets, go to timbermanreport.com and click Kilimanjaro Climb. Once again, go to timbermanreport.com and click Kilimanjaro Climb.
Okay. So you get in there at Berkeley and you're working on your PhD. Was this the time when the light bulb turns on around glycosylation, glycobiology? What was it about that that excited you as a problem worth diving into?
Well, for that I have to thank my PhD adviser, whose name was Mark Bednarski. And Mark had come out of his own training with a natural products and carbohydrate chemist named Sam Danishefsky, who's still at Columbia and Sloan Kettering, still active, still, you know, publishing amazing things, and one of the legends of organic synthesis. And so Mark had learned about carbohydrates as an interesting class of synthesis targets. And then he had done a postdoctoral fellowship with George Whitesides at Harvard. And at that time George was very active in understanding how multivalency contributes to interactions between cells and between viruses and cells. And in George's lab, Mark had worked on the influenza virus, right? And George was part of a consortium of biochemists at Harvard, including Don Wiley, that were trying to understand the molecular basis of flu binding to target host cells, which occurs through hemagglutinin interacting with a sugar called sialic acid. So Mark had learned about glycobiology through the window of this influenza project.
And so when he joined the Berkeley faculty, it was the same year that I started as a grad student. So he was this young new assistant professor, you know, full of energy and wanting to recruit students. And he kind of gave me a hard sell. And I, you know, started reading papers he had given me about the beauty of carbohydrates and how their structures were so complicated and interesting and cool. And, you know, it's interesting that you mentioned structure-based drug discovery as like a big thing in the 80s. And the one place where structure-guided drug design in fact gave the drug was in the flu, right? So the structure of the neuraminidase had been solved, and it was based on that structure that the two flu drugs that really are still the two that are on the market today, which are Relenza and Tamiflu, they were designed based on the information from that structure. So that was like an outrageous success of structure-guided drug design, one of the early ones. And these were the papers that Mark was giving me to read, you know, and I was like, 'Wow, this incredible stuff.' And so I joined his lab and I just got hooked.
And I think my affinity to the field has persisted. I'm what you'd call a lifer, you know, in glycobiology. It's persisted because, first of all, the chemistry is beautiful and challenging and interesting. But second of all, the biology was so uncharted. So it was — it's kind of like, I imagine, you know, when early explorers got on their boats and departed from the ports of Portugal, you know, headed for North America, and you get there and it's a wilderness, right? But it's a wilderness that's fertile, right? It's teeming with sea life. And, you know, I picture people landing in North America and seeing like lobsters and crabs, you know, crawling around on the beaches and like open fields of vegetation. And to me, that's what the field of glycoscience looked like. That's what it felt like back then.
This wasn't an area where you might get bored, where you'd solve one structure and figure something out and then it was sort of like rinse and repeat, right? This was going to lead you toward more and more difficult, interesting problems.
Yeah, that's what I thought. And also it seemed like a field that really needed the help of chemists. You know, the biology was pretty challenging. And, you know, there was so much going on with the molecular biology revolution, right? PCR, you know, was in the 80s, and then all these cool recombinant technologies and protein expression technologies and mutagenesis technologies. And then there was high-throughput stuff coming online in the late 80s, phage display. And I mean, it was so much going on. And the green fluorescent protein technologies for imaging, you know, in the early 90s. And like none of it seemed to be transportable to glycoscience, right? It's a different class of biomolecules and difficult to study. And I think, you know, honestly, part of today's generation's ignorance in glycoscience you can relate back to the time when there was — it was so much easier to do everything else, right? So, you know, that's where the flock moves.
