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June 17, 2020
About this episode
Dr. Terry Hébert wanted to be a microbiologist. Instead, he ended up getting interested in membrane protein as he followed the biology of a bacterial toxin that affects a mammalian ion channel. Today he and his team are working on understanding receptor signaling in specialized cellular environments to gain a better grasp of receptor function in pathophysiological settings with a special interest in the cardiovascular system. His favorite GPCR is the angiotensin 1 receptor, especially for its ability to activate a large variety of signaling pathways. Terry is also very active on social media. With over 2000 followers on Facebook and Twitter, he shares the latest available information on GPCR research daily.
Dr. Terry Hébert on the web
Episode transcript
Dr.Yamina Berchiche 0:00
There we go. Hi, Terry, thank you for being here today.
Dr. Terry Hebert 0:05
My pleasure, Yamina.
Dr.Yamina Berchiche 0:06
Thank you. You are currently a pharmacology professor at the Department of pharmacology and therapeutics at McGill. Can you tell us a little bit more about your background and how you got to where you are today?
Dr. Terry Hebert 0:16
Sure, I really didn't think I'd end up in a pharmacology department. I thought I would be a microbiologist. That was my training that was where my interests lay when I was a young fella. And then I kind of got waylaid by a microbial toxin that happened to act as an ion channel in mammalian cells. And that led me to become interested in membrane proteins generally, and then more specifically in voltage and in gated ion channels, and that sort of translated to an interest in GPCRs as kind of another interesting class of membrane proteins and so many years ago after that, here I am.
Dr.Yamina Berchicher 1:04
Awesome, awesome. And you trained in as a postdoc in Michel Bouvier's lab, where were you before that? Where did you do your Ph.D.?
Dr. Terry Hebert 1:12
So I did my Ph.D. at the University of Toronto and I was studying voltage-gated sodium channels and so that movement from the channel world to the GPCR world was really not driven by any desire to work on GPCRs It's just that I didn't want to leave where I was. And I stayed. I stayed in the city where I live so and just switch universities and then ended up working on GPCRs that way.
Dr.Yamina Berchiche 1:39
Wow, interesting. Since you've been working in the GPCR field for quite some time now, do you have a favorite GPCR that you're, you can say that's your favorite?
Dr. Terry Hebert 1:51
Yeah, that was a hard one. But I think I have to admit, despite the fact that I was trained, you know, on beta-adrenergic receptors that my favorite GPCR has to remain the angiotensin 1 receptor. I like that. I like that one a lot.
Dr.Yamina Berchiche 2:05
Any particular reasons that you could share with us?
Dr. Terry Hebert 2:09
I think because it's, it's why I'm interested in its role in the cardiovascular system for sure. That's a simple answer. But I think because it's such an interesting interacting protein, it is an interaction hub for many other GPCRs. It's coupled to many different signaling pathways. And it remains despite all we know about it, kind of a mystery because we're used to studying these things in isolation. And I think that the more we think about them as parts of networks that the more interesting they become, right, I think that that's still for me the big question is how, how large are these networks downstream of a single GPCR and for the angiotensin receptor, I think it's it's wired into everything.
Dr.Yamina Berchiche 2:58
Wow. And what is the current status, the need to know information that's recent that has been recently published on the angiotensin receptors?
Dr. Terry Hebert 3:07
Well, I think many people have started to realize that, you know, despite this sort of almost obsessive focus on G protein versus beta-arrestin, right, like the primary, downstream coupled G protein to a given receptor versus beta-arrestin while, while perhaps true in some cases, like opioid receptors, for example, where it's either-or, or, but for the angiotensin receptor, it's not just coupled to Gq or beta-arrestin, it's coupled to Gi it seems to be coupled to G12. It's probably wired into other signaling networks and, and then when you build in this idea that these receptors interact with each other, that kind of adds another layer of complexity to the story. So I think what we don't know is how much we don't know that we know that the AT1R interacts with a lot of different GPCRs. We know that it's wired into many different signaling pathways. But the biggest mystery for me is that we're still kind of focused on what it does in the HEK 293 cells. So that to me is the kind of central thing now to take all of the tools of modern pharmacology that we've built, but adapt them so that we can study these things in a more relevant physiological context or, or more importantly, even a more relevant pathophysiological context.
Dr.Yamina Berchiche 4:38
Has there been any evidence of differential signaling of AT1R receptor depending on the tissue that it is expressed in?
Dr. Terry Hebert 4:49
I think, yes, I mean, if you look at what these things do in their native environment, which is in the cardio, cardiac myocyte, or in the vascular smooth muscle cell. They do things that are distinct from what they do in a HEK cell right? A HEK cell really kind of shows what's possible, but it doesn't really show what's happening. In our hands, and we've built a particular type of biosensor, which tracks receptor conformation. And we can see that when we express those sensors in Hek cells versus vascular smooth muscle cells, they give different outputs, depending on what ligand you challenge the receptor with. So, cellular context to me seems like it's the elephant in the room for all of us, right, but we don't pay much attention to it. But I think if we're going to maintain GPCRs as viable drug targets, we'd better start doing that.
Dr.Yamina Berchiche 5:49
Absolutely, absolutely. And so you had mentioned you had alluded to the bias signaling in the context of this angiotensin receptor. or other gpcrs as well, where you have G protein signaling versus beta rest in signaling. Where, on a higher level, where do you see bias signaling playing a role, in drug discovery?
Dr. Terry Hebert 6:14
So, I think you know, the idea of bias signaling is a powerful one. But um, I'll give you two examples, like, as I said, for the opioid receptor, it really does seem to be in some sense either-or, like the G protein signaling drives, the analgesic, you know, the therapeutic aspects of it, whereas beta-arrestin signaling seems to in large measure drive a number of the adverse consequences, although a paper came out last week saying that beta-arrestin in isn't responsible for all the adverse consequences. In the case of the angiotensin receptor, you know, we kind of got tripped up by the simple dichotomy between Gq and beta-arrestin. And the drug that was tested in clinical trials failed and didn't meet it didn't meet any of its primary endpoints. Now, I think that's probably for two reasons. If you're asking me for a bigger picture view of what, what's going on. One is I think that the bias or the signaling downstream of the angiotensin receptor, that's actually you want to block in disease is the Gq. But the one that you want to preserve the one that's cardioprotective, the one that may actually have some disease-modifying properties? I'm not sure that's just beta-arrestin. Right. That was the hypothesis but in a paper that we helped Stephane Laporte and Michel Bouvier publish in this in 2018, it kind of showed that the ligand that was just viewed as a pure beta-arrestin bias ligand, and no Gq signaling that part was true, but it also was true that those ligands activated Gq activated Gi. So I think We need to know kind of more of the molecular context and how it relates to disease. And, and I think if we're going to test these molecules as what they're designed to be, which I think is disease-modifying, we need to have, again, coming back to a more relevant physiological context in which to do that. I mean, I don't think that the Travena compound for the angiotensin receptor is a failure. I think it's the starting point to think about a better, better version of a clinical trial. But the company, you know, for probable reasons that made sense, at the time, closed down the program. So, but I think that bias is not a simple either-or it has to be more nuanced, right. And so I think that if we don't study these things in the right cell type, we're going to lose all of that nuance, and it's going to lead us to failures.
Dr.Yamina Berchiche 8:59
Do you think We now have or need more tools to be able to study the angiotensin receptors, for example, in a more physiologically relevant setting?
Dr. Terry Hebert 9:10
I think the tools are there. There are two types of tools that we've needed for a long time one is the one that many GPCR people have invested in developing which is you know, signaling biosensors, conformational biosensors way to track you know, in ways that are amenable to high throughput screening. We have those biosensors, all the resonance energy-based biosensors, FRET and BRET flavors, lots of biosensors that are based on the production of second messengers. And we have those but we've mostly been using them in Hek cells. So the other tools that people have been developing I think are ways to get those biosensors into something like an induced pluripotent stem cell where you could put the biosensors in, put them in a way that that they're not interfering with the dominus of those cells, and then turn those stem cells into something else. And you could turn those stem cells into more than one something else, right? You could actually make cardiac fibroblasts, you could make cardiac myocytes. And then you could look at paracrine signaling between the cell types, you know, the way it actually happens in the heart. Studying cells in isolation is not the best way forward anyway, but using the wrong cell is definitely the wrong way forward. So I think that now, we have the possibility to put all of these really amazing tools that the field has developed into a more relevant physiological setting, right? The stem cells not only can be generic in the sense that they come from a human, but they can also come from patients now, right. So we can model what's going on in the patient context by using biosensor approaches or any other type of phenotypic drug discovery approaches in patient-derived stem cells and those cells derived, differentiated, into relevant target tissues. So I think we're in the early days of that, but I, I think that's the way forward.
Dr.Yamina Berchiche 11:24
Absolutely. It's very important to have the right relevant cell cellular background, sometimes we spend too much time working on our Hek cells and we cultivate them in these generated media. But we don't even know what exactly is in the media and hex tube of HEK tube of HEK cells, there are variations.
Dr. Terry Hebert 11:42
We're finding that out when we knock out G proteins in those HEK 293 cells, it's like, we thought that would be a really simple way to ask about the role of a particular G protein but in the HEK cell context anyway, we know now that those cells rewire, they rewire in ways that allow workarounds for missing a particular protein, right? Because the receptors are coupled to so many different signaling pathways, they find workarounds to that, you know, so that this cell without that G protein is now intrinsically different than the cell with that G protein. And I think that that type of thinking makes me think that we need to do it in the right cell type all the time.
Dr.Yamina Berchiche 12:24
Absolutely, absolutely. And are you currently working on using these biosensors in more native-like, cellular environments? In the lab?
Dr. Terry Hebert 12:35
Yeah, so we've gone two routes. One is that we're doing a lot more things in primary cells. So primary myocytes primary fibroblasts to make sure that the context of our biosensor outputs is right. And we've also gone down the road now of slowly, you know, retooling to become an IPSc lab, right, so we're now growing and differentiating human induced pluripotent stem cells. We're starting to establish collaborations to get them from patients where we would look at patients with both rare diseases and patients who have more common diseases like cardiac cardiomyopathy, which are all driven by different mechanisms, but all kind of are sensitive to the drugs we use to treat heart failure, right, but they're differentially sensitive. So how can we pick a therapeutic approach, you know, targeting the angiotensin 1 receptor system targeting the alpha-adrenergic system targeting the beta-adrenergic system? Now we have a way to test that in individual patients before we ever have to try it in the patients themselves. So I think that that's kind of where we're going.
Dr.Yamina Berchiche 13:51
Absolutely. And I'm in the same context. So now that you'll have the right tools, the right seller context. Are you Gonna plan on screening libraries of compounds or how are you gonna address this?
Dr. Terry Hebert 14:06
Yeah, I'm, I'm, I'm old. You know, I think that so there's not, we can't do everything right. So I think that for us, the screens will be either in collaboration with people who are set up to do larger, larger throughput screens. But for us, we think that we have enough like the angiotensin receptor is so interesting because there's enough chemistry around it, that we already have a few dozen ligands that we can test pretty easily going forward. So, um, whether we're going to do the high throughput screening, that will depend on funding on collaborators, but the medium-throughput screening, yeah, we're going to do it and the and, and, and in different cell types. I think that's what we're after. Like the minimum number of molecules, we would need to look at, that would allow us to understand the role that cellular context plays in determining what those ligands do.
Dr.Yamina Berchiche 15:09
Fantastic. And so you're going to be looking at the cellular context, looking at multiple compounds, are you also going to be looking at different signaling pathways in parallel?
Dr. Terry Hebert 15:19
Well, I think that's where the toolkits are already built, right. So we have, we have the tools to look at a large amount of what's downstream of a G protein. And that's not to say that we know when we move, the other concern about moving to these different cellular contexts is that maybe the signaling context is different there too. So that may tell us that we need to build an additional number of biosensors as we realize that while this G protein Coupled Receptor in this cell is now wired into a number of signaling pathways that we didn't know about before, but I, I think that the way, the way that that problem is, is, is pretty simple to solve. We've become pretty good at building biosensors for signaling pathways as we identify them. But I think that the hard work will be in, in making sure that we get all of that in each relevant cellular context. And maybe it won't be so hard, maybe we'll see pretty easily that a lot of the signaling is conserved as we move from one cell type to another, but I think some of it is going to change. So I think it's important to start looking outside of the HEK so
Dr.Yamina Berchiche 16:31
I tend to agree with that. What's your take on forming partnerships with pharma, for example, with Travena now or bigger companies that could help you with, you know, larger screens once you establish you once you have observations in these different models?
Dr. Terry Hebert 16:49
Yeah, I mean, I think that if we're really going to, if we're really going to impact medicine, there have to be partnerships with pharma. Right. So we have a small farm partnership with Domain Therapeutics in our consortium for biosensor development. And they are interested in moving beyond the HEK 293 cells as well. And I think that you know, I think it's the smaller pharma and the smaller biotech companies that really are going to be able to, to kind of take the risk of, of, of what we're doing and try to kind of build the tools to then scale up so that larger pharmaceutical companies can engage right there they're waiting to, I think they're waiting for two things. They're waiting for somebody to demonstrate that bias is a really actionable property of GPCR that can be exploited clinically. And they're waiting for someone to show that there's a way to model that in a simple, simpler way that captures the complexity but captures it in a way that can be used for the high-throughput screen. Right. So those are the challenges in attracting pharma support. I think that we're thinking small for the time being. But I think regardless of whether the idea of bias loses some of its impacts, the idea of doing drug discovery in relevant cell types is still, I think, an important pursuit.
Dr.Yamina Berchiche 18:22
Yeah, I absolutely agree with that. I think it's, it's kind of a step by step, the way I see it a step by step event, if you can show it in the lab, you can show it in smaller biotech, then you might be able to sell the idea to bigger Pharma where most likely there is a more hierarchical system that takes more time to get through these funnels. So I know that we've talked about it. GPCRs are complex, just the ATR1 one receptor consumable through different signaling pathways by coupling to different partners. given the complexity of GPCR signaling and their importance in physiological settings. What is your take on them on being drug targets? We agree that they're good drug targets we keep on showing these in PowerPoints, but where should we focus on GPCR? Or should we focus on some other enzymes or some kinases that do other things? And in cancer cells, for example?
Dr. Terry Hebert 19:17
You know, I think they remain tractable because they're expressed at the cell surface, and a lot of their downstream signaling machinery isn't so I think they're attractive for drug discovery in that sense. I also think that the low hanging fruit has essentially been picked already. Right. So what's left is the sort of complicated biology that that only kind of in situ drug discovery would allow us to do so going back to the physiological context is going to help us push things forward. I mean, how many GPCR are there that aren't in your nose? About 400 that we don't have drugs for us. a fair number of them right, they remain orphans, or if not orphans under characterize because, you know, we can't get the information we need from HEK cells. So I think that yes, there are definitely still good drug targets. But they that, that we're now at the stage where we need to make a kind of I won't say evolutionary but but but we need to make a leap away from the simple models and sort of embrace the complexity a bit more to get at the next generation of targets. And then the final thing I have to say about that is that now we realize that they don't just signal at the cell surface, right. So is there a way to, to drug receptors that are inside the cell, not just the ones that come in through endocytosis, which seemed like a reasonable, a still tractable target, but what about the ones that show up in places like the nuclear membrane or the mitochondria? membrane how do we? How do we get at those? Right? So I think those are interesting drug targets too. And one thing I've learned over the years is that chemists, chemists can make molecules that go anywhere and do anything. So it's just a matter of engaging pharma and in academic chemists in that regard to the kind of think about getting GPCRs where they live, getting GPCR is how they live and then not being focused so much on the simple systems we've been using.
Dr.Yamina Berchiche 21:31
Speaking of targeting, GPCR, and accelerating drug discovery, what's your take on using AI artificial intelligence and machine learning to accelerate the knowledge drug discovery targeting GPCRs.
Dr. Terry Hebert 21:46
I've been thinking a lot about that lately because I'm actually teaching about AI and drug discovery and where I think it has value is in exploring chemical space in the context of structures that we have now, like, since 2007, the number of GPCR structures has literally exploded, right? I mean, I mean, you've seen on my Facebook page, I put up at least one or two new structures every week, it seems. So I think AI and machine learning in general will kind of have a role in kind of identifying sites outside of the orthosteric binding site that might be targeted for new drugs, right. We haven't had much luck finding allosteric sites because they generally have lower affinities and we don't have a starting point of places to look because anywhere can be anywhere on the receptor surface can be a site for an allosteric ligand or even anywhere on an interacting protein could be a site for an allosteric ligand. I think AI will help us kind of find targets that we could approach in that sense. Beyond that, I don't think AI has much use in drug discovery. It's still a hard slog right getting through, you know, pharmacokinetics and pharmacodynamics, you know, does the drug get metabolized this way or that way? I think maybe down the road, it might have an impact there as well. But, I think there are still things we just have to do the old fashioned way, empirically. And, and, you know, in that hypothesis-driven way that that, that we do better than AI, but AI can do some things better than us in terms of speed and capacity,
Dr.Yamina Berchiche 23:37
Definitely in processing all that information that you're going to acquire from those native-like cell lines
Dr. Terry Hebert 23:46
That's absolutely right to Yes.
Dr.Yamina Berchiche 23:49
Great. Thank you so much. Um, so just to sum up, working on GPCR is not easy. It's not ideal to do it in Hek cells, but now we have many different biosensor tools that allow us to understand their function in a more physiological context. There is still a lot of work to do, what would be your advice to young scientists who want to study GPCRs?
Dr. Terry Hebert 24:13
Well, don't be afraid of that complexity, and don't be afraid of the, you know, the fact that your mentors might be afraid of that complexity, right. I mean, my own road was, you know, a totally serendipitous observation about proteins that interact with GPCR's being other GPCRs right, that that we still struggle with that in the field, are they real? Are they stable? Are they just homo or just heterodimers? Right, but I think that you know, I kind of liked the idea that it was scary to everyone else at the time. Right and I think that, that my own students have kind of had those, those certain moments of serendipity where they, they couldn't understand what they thought was a negative control gone horribly wrong, right. So you have to be open to discovery by being open to the kind of being wrong.
Dr.Yamina Berchiche 25:22
It sounds like an infinite game that's worth playing.
Dr. Terry Hebert 25:25
Yeah, very much.
Dr.Yamina Berchiche 25:29
And during your trajectory, as a scientist, were there any AHA moments when you realize, well, GPCRs are very interesting, but they're complex, and you've learned something that changed your perspective on them.
Dr. Terry Hebert 25:42
I think like, you know, the dimer story was an AHA moment, right? I mean, that, that anyone was ever able to replicate that to me was, Oh, thank goodness, right. I mean, because it was we took a risk kind of thinking about them as dimers. You know that was when I was a postdoc. And as a PI, I've had several AHA moments when we first realized that, you know, GPCRs weren't just going to the cell surface. I mean, I didn't have that idea. First, that was, you know, people like Sylvain Chemtob and Bruce Allen, they were thinking about that in a way that really kind of transformed the field. But we got into it, our AHA moment was realizing that we could actually drug them on the nuclear membrane, right. So we could build molecules that we could, we could cage them, they could get across the cell membrane, and then we can uncage them. That was really cool. And related to that the, I guess, almost the biggest AHA moment for me was not because of a G Protein-Coupled Receptor, it was more because of a G protein when we realized that or when we observe that that G protein into the nucleus, the G Proteins interact with transcriptional regulators and that G protein might actually be regulating the expression of genes in a way that's completely distinct from their normal function at the cell surface. So that's a that's an ongoing story in my lab, we're hoping to submit that in the next couple of weeks. But that’s been a real eye-opener as to, you know, how evolution uses different things for different purposes, right, the things that that they originally came into place for, get sampled for many other functions, and some of those functions get conserved and some of those functions get further modified to serve completely different roles than then than what we're used to thinking and doing. So. I guess those are the three dimers, nuclear localization of GPCRs and the drug ability they're in, and then you know, G proteins acting as transcriptional regulators.
Dr.Yamina Berchiche 27:58
That's fascinating. I can't wait to read that paper Good luck with submitting it. It'll go through peer review pretty quickly,
Dr. Terry Hebert 28:07
Yes, and come back and come back rejected. But you know, but I'm ready for that too.
Dr.Yamina Berchiche 28:13
That's all that matters as long as you're ready. I mean, you can only control so much. Having the right controls having the right, the right experiments were done and the rest you'll figure it out with time. Are there any conferences around GPCRs that you think young students or young scientists should attend?
Dr. Terry Hebert 28:34
You know, I, my own family situation has sort of limited my travel to meetings. And so the one that I go to religiously every year is the Great Lakes GPCR Retreat. It's small, it's cutting edge. It's a lot less expensive than say, a Keystone meeting or a Gordon Conference, but the quality of the science is equal to either of those and so If I were to tell students from anywhere to go to a meeting, it would be to the GPCR retreat you're going to meet in a really informal setting people who are are are like the thought leaders and in the field and you and you meet them over beer and potato chips. What can be better?
Dr.Yamina Berchiche 29:25
Absolutely. I've been at that meeting. It's like going home every year. Um, if you have any job openings for your lab for people to join your team, where can they find these ads?
Dr. Terry Hebert 29:37
I guess I thought about that question, too. The easiest way to find me and to find out what I want, what I need is to look on my Facebook page, right? So the GPCR Consortium page, or my lab page, those those those kind of have a sense of what we're after and what we're interested in where we're going and I don't even have a job opening in the sense that, you know, I'm always waiting for somebody to ask me a question. You know, are you looking for volunteers? Are you looking for graduate students? Are you looking for postdocs? I've kind of stopped looking because where I am at McGill University, we've been pretty lucky in the sense that we get a lot of interesting people coming through that I don't usually have to advertise, not that I'm so important that I don't have to advertise. But I get enough traffic just from teaching a lot and from going to the few meetings that I go to, and from having an active social media presence that I think that those are the places that I would look if you want to work in my lab.
Dr.Yamina Berchiche 30:44
I would highly recommend both of your Facebook pages and your Twitter accounts. I think it's up to date anyone who wants to know what's going on in the GPCR field, that's the place to go. How did you come up with the idea of having a Facebook page Or, you know, putting together the Consortium?
Dr. Terry Hebert 31:03
Yeah. So I was not an early adopter of Facebook, I got actually roped in by my wife to join Facebook because she sent me a link to look at some pictures she'd posted of my infant daughter on Facebook and the only way I could see them because she was out of town at the time was to become a member of Facebook. And what really made me think of using Facebook as a tool was initially because of teaching. And then I realized once I finally also was not an early adopter, once I got a smartphone, I realized I could post things related to my lab all the time. And then I realized that not everyone was interested in all the other stuff that goes on my lab page. So I thought I would devote one just to GPCRs and G proteins and signaling and that's how the GPCR Consortium came to be and I and I realized the power of those networks in just kind of getting people to think about what I think is important is because a lot of people visit them and and and I, I'm always struck by the fact that you know, people still come to see it every day and but I think there's real power in taking the few minutes to post things every day.
Dr.Yamina Berchiche 32:27
Absolutely agreed, I only keep my Facebook account open because of your page, too.
Alright, thank you so much, Terry, for being here today.
Dr. Terry Hebert 32:39
It was a great pleasure to be invited. Yamina and I really enjoyed our conversation.
Dr.Yamina Berchiche 32:43
Thank you so much. Thank you.
* The transcript has been minimally edited to improve readability
