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HomeInVivo Biosystems Blog17 Minutes of ScienceSeventeen Minutes of Science: A Stepwise Approach to Model Organisms and Drug Discovery

Seventeen Minutes of Science: A Stepwise Approach to Model Organisms and Drug Discovery

Tune in weekly to our virtual series "Seventeen Minutes of Science" every Tuesday at 11am PST / 2pm ET where we go live on Facebook with a new guest each week to talk about how science and biotechnology is woven into their lives for (you guessed it) 17 minutes!

This week on 17 Minutes of Science we are joined by Dr. Alex Parker (Assistant Professor at University of Montréal, CHUM Research Center, CSO of Modelis).

Dr. Parker has a broad background in genetics, with specific training and expertise in neuroscience, science of aging and hereditary diseases. He uses the model organism C. elegans to construct simple genetic models of these diseases and then confirms his findings in mice.

Dr. Parker joins us to talk about how he uses multiple models in his research and how this stepwise approach is implemented at Modelis.

Transcript

Dr. Kat McCormick (Host): [00:00:10] Hello, everybody, and welcome to 17 minutes of Science. This is the InVivo Biosystems Show, where we interview scientists and thought leaders who have something to tell us about science. And today, I am very excited to be talking to Alex Parker. Alex Parker is an associate professor in the Department of Neuroscience at the University of Montreal, and he is a researcher at CRCHUM (University of Montreal Hospital Research Center). Alex is also a medical geneticist by training and he has an interest in late onset neurodegenerative diseases. He uses the model organism C. elegans in combination with mice to confirm his findings. A major focus of his successful academic career has been the development of models of ALS or Lou Gehrig's disease. These studies have led the way to identify new therapeutic targets and strategies directly usable in the patients. And among them, a drug has been discovered in his lab that has proven successful in a clinical trial for ALS. So welcome, Alex.

 

Dr. Alex Parker (Guest): [00:01:11] Oh, thanks a lot. Thanks for having me. This is a fun idea. I'm happy to be here and talk a little bit today, so thanks.

 

Dr. Kat McCormick (Host): [00:01:18] Wonderful. Yeah. So my first question is pretty broad, but how about you tell us about your research and what's going on in your lab right now?

 

Dr. Alex Parker (Guest): [00:01:26] Yeah, so I, I work with worms. I've worked with C. elegans my whole career since being a grad student, a postdoc to PI now. For a while now, I guess like 13 years. And I've always been interested in, in neurodegenerative diseases. I don't know why. It was just — I just got into that field and all along I've been trying to use worms to make models. And from there, really, we spent a lot of time making all kinds of different models. Like in my lab now, the main focus is ALS. But we've been developing models more broadly for neuromuscular disorders as well as branching into things like dementia and whatnot. And we were really interested in seeing if we could use the worms for drug discovery because it was like a situation where everybody knew very well that worms are great for modifier screening. Genetic screens obviously are invaluable and they discovered so many things. But why not drug screening? So we just thought we would give it a try and it turned out to work rather well in the end. So we do a lot of drug screening in parallel. We've probably only done a handful of genetic screens and like, I don't know, probably over two dozen small molecule screens now with the various models.

 

Dr. Kat McCormick (Host): [00:02:37] Wow, that is really incredible. I know that in our work we get asked a lot about the translatability of C. elegans for human diseases. And one of the things that I really love about your work is that it proves that worms really do have a lot to say about human disorders, especially with neurodegeneration, it seems.

 

Dr. Alex Parker (Guest): [00:02:58] Yeah, so that's the thing, right, because you will have get those comments like "well, what are worms good for what have you done for us lately?" But that's not true. It's like there is a lot of potential still there. And the fact that we were able to relatively recently move, like, develop a model in worms, do a drug screen, and with our collaborators move through fish, to mice, and ultimately to a clinical trial means it's possible. Right. We're not the only people who are going to do this in history, hopefully. Right. So, I mean, there's a lot of room out there. So it's proof that you can do this. I think it's just — I don't know what it was. People thought there's not enough translatability. I think it really, really depends on what your plan for translation is. Like, do you have appropriate or good complementary models to move things beyond the worms? Because if you do, then you can quickly tell if what you're working on is worth it or not. So I think that's it. I think the main thing is that C.elegans are fantastic for discovery, of course. But some of its powers is that — if you pair it up with other systems you can move through things quickly.

 

Dr. Kat McCormick (Host): [00:03:59] What has been your strategy to taking the work that you do in C. elegans and moving it through mammalian models?

 

Dr. Alex Parker (Guest): [00:04:07] That's, that's always tough. And it's an ongoing question because we want to find models that are good for testing therapeutics. And what does this mean? So, I mean, with the technology that we have and the approaches and, you know, with working with worms, you use huge numbers. Right. So you can get the variability down. So there are a lot of good models. Let me put it this way, for any particular disease field. Right. I don't know how long it takes for people to develop a consensus as for what is the best mouse model for this disease. It could take decades. And why is that? Because they show phenotypes, but not all the phenotypes are useful for like reliable drug testing. So there are some models that are great or it's too hard to do. So if we can find a model that shows — for example, most recently we've been using an ALS model, the SOD1 mouse model, the G93A, its a classic model. Some people say it's a very specific form of ALS, that's fine, but for us, on one hand it shows reliable neurodegeneration and that's what we want. We don't want it to be — is this really working or not? It's like these, these mice show a great phenotype. So that's it. Something that can show reliable phenotypes in a relatively short amount of time. I mean, it's a lot to ask, but — there's not always the best model. There's not always a good disease model for our needs at any given time. So it depends. But we talk about this all the time. And any time we try to embark on a new project, that's one of the things — what can we do? How far can we actually go? And we're at the mercy of others in this aspect.

 

Dr. Kat McCormick (Host): [00:05:39] Hmm. And what do you think has been the role of CRISPR transgenesis and some of the other genetics methods that are available in worms in creating appropriate genetic models of diseases?

 

Dr. Alex Parker (Guest): [00:05:51] Yea, so this, this is great. I'm a big fan of this approach and I honestly think it is probably — will be the standard and it'll be the future. I mean, the classic approach of using a transgenics is still great, but you're always hindered by — sometimes people will say, and they're not wrong, that sometimes there's massive overexpression of a region of interest will give rise to phenotypes that are not necessarily relevant to what's happening in humans. So it's a tradeoff, right? The transgenics are often -you have a strong phenotype in a short amount of time. So it's great for screening. But you might be picking up things that are hitting on expression problems, whereas the CRISPR gene-editing models, if you can do that, I believe that's the way, way to go forward, because you have, you know, it's genetically relevant. But again, you don't know because that's the thing. Well, with any of these models, I would say probably — let me see, for every model we make about 60 to 70 percent of the time we have a phenotype we can use and some just show nothing. So you have to move on. But I think that if you can gene edit patient relative mutations in the C.elegans genes, that — that is the way to go. The trade-off usually is that the phenotypes are not as strong as what you are used to if you're working with transgenics, but you know, you adapt. That's my feeling anyway.

 

Dr. Kat McCormick (Host): [00:07:20] Yeah. You've mentioned a few times that the worms show phenotypes and that they've been good for you in terms of phenotypic based screens or phenotype drug discovery. What do you think is the role for this Phenotype drug discovery, PDD, over target-based drug discovery or as complementary to?

 

Dr. Alex Parker (Guest): [00:07:41] Yeah, so that's that's the thing. Right. So it's a big issue of debate, obviously. And in the end, I'd like to probably say that they're complementary, right? Because if you if you can narrow down a mechanism and it's like, I guess you can say — is this mechanism highly penetrant to the disease? I'm not sure use the terms this way, but then yeah that's a great mechanism because you can't get much beyond that. But a lot of the time we don't have this information and we just don't know yet. I mean, genes that will be identified for diseases are still being identified all the time. And so if you don't have a clear consensus on what the mechanism is, then you're somewhat limited in trying to develop a targeted based approach, even for something like ALS. I don't know. There's over two dozen genes involved. They're all linked to all these different processes. Is there any one key mechanism or is it likely a mix? So the phenotypic screens, you know, you come in and you're basically, as we like to say, we're somewhat agnostic about the mechanism at this point because we don't know. So you basically know what you know, the genetics, this this gene, this variant will cause the disease. You put it in your animals and they're sick. Then you go off and do the work, do the phenotypic screening. And then once you have a drug that rescues your phenotype and your animals, this is basically a tool at the same time, because then you can go back and drill down on the mechanisms using the genetics and whatever. And I would say that people shouldn't be afraid of phenotypic screening. I think it's actually a very powerful way and can complement or even lead to further like target-based approaches. But, you know, we do phenotypic screening basically non-stop because that's sort of the space we're in, because genes are identified. No main cause is known. We need to get the work anyway.

 

Dr. Kat McCormick (Host): [00:09:22] Have you ever dovetailed your approaches to phenotype based drug discovery with later target identification using some of those genetic modifier screens that you were talking about earlier?

 

Dr. Alex Parker (Guest): [00:09:33] We haven't completed that completely. We've done a few things. None of this is — this is in various states of projects. Right. I think we've done a couple of things where basically you have a situation where the drug rescues and then you do, you test the candidate genes. I don't believe we've done a classic genetic screen yet to block the effect. Right. And then go in and clone it. But that's something I've been I've been bugging people in my lab about for a while. And it's just like you have to, it has to be set up right. I think if you can reliably screen that way, that's something we are interested in. We talk about it frequently. It's like - cause you have the drugs. So, yeah, we're just not there yet. But it's something we talk about.

 

Dr. Kat McCormick (Host): [00:10:18] Yeah, I think it does seem like there should be opportunity for that, right? That there should be some kind of opportunity to follow up on hits that you find and perform some kind of modifier screens to really pin down the target with C.elegans because you do have these tools available. We do.

 

Dr. Alex Parker (Guest): [00:10:37] Yeah, I agree. I think that's a powerful way. And there's a handful of papers where people have done this, with like a well-known drug. I guess maybe the metformin experiments are good examples of this from the work literature where they've identified new mechanisms. What is known to be like a well-known drug.

 

Dr. Kat McCormick (Host): [00:10:52] Right, a very widely used drug.

 

Dr. Alex Parker (Guest): [00:10:57] Yeah.

 

Dr. Kat McCormick (Host): [00:10:57] Including off-label uses for people who want to live to one hundred and twenty. So, yeah, I tend to agree with you. I think that's really pretty powerful. So I also wanted to talk to you a little bit about since you're using a patient specific variants to model diseases, do you think that looking into the future, that there is a role for C. elegans, maybe Drosophila and some of the other lower organisms in finding precision medicines, medicines that really are specific to particular genetic variants that cause disease?

 

Dr. Alex Parker (Guest): [00:11:34] Yeah, so we do think that because we think that while some of these genes that exist in pathways maybe all have common pathways, they probably — each specific variant or gene gets there a very specific way. So we're starting to see this where you think that perhaps some of the drugs that you're identifying for one particular gene may be effective overall, but it might be better if you do a second screen for a different variant. So we think you can actually mix, mix and match this up. But I do think there's something there. And some people say, well, you know, the worm is sick. It's sick. Is it really sick because that's too much of this gene or not enough of that? But I think there are differences. So I think this is something that we can — this is something you can probably do. You could scale this up in C. elegans because we all probably talk to, well, I talked to many clinicians, and researchers, and they have bags and bags of variants that need testing. And so they'll talk to somebody like me and say, you could do this and we can. So we just have to basically set up a more of a pipeline approach. And because you'll hear that certain patients with certain variants are — they don't respond to certain well-known drugs. So why is that? So perhaps we can screen again against these variants and find something more specific to each patient. So that's something. Yeah, I think there's a huge, huge potential there.

 

Dr. Kat McCormick (Host): [00:12:54] Yeah, that's great. I think that's really good news for the precision medicine community as a whole. You just mentioned you have clinical geneticists knocking on your door of your lab and asking you to take on projects. And I'm wondering, I know that you also have an appointment at Modelis, which is a company that does some of this modeling. Is that related to your founding of models?

 

Dr. Alex Parker (Guest): [00:13:15] Yeah, I mean, it was basically directly related to this because I was — when we started doing the drug screening, it worked out pretty well. And at that time we started publishing. And when the paper came out showing that with the full story, like the worms up to the clinical trial, we were getting a lot of requests to like try this and try that. But it was becoming too much for my lab to handle in an academic setting. So I thought there was an opportunity there to set this up formally. And that was the the birth of Modelis where we were like, why can't we, well, can we do this? And we set the company up and so far so good. And we do this all the time now at various levels, for various people, because it was just, it's just too much. And I thought we have to do something because it works. I think the approach works.

 

Dr. Kat McCormick (Host): [00:14:03] Now, going back to your involvement in this ALS clinical trial, how did you see this progressing and what was really the timeline of moving from the primary screen in C.elegans all the way to clinical trial.

 

Dr. Alex Parker (Guest): [00:14:17] Ok, so, it's getting fuzzy. Now, let me see. I think it was we did something like, I believe it was, and somebody will correct me if I'm wrong I'm sure. I think it was the from the time we started the screen to the beginning of a clinical trial, like with the recruitment of Lawrence Korngut basically and the clinician researcher at University of Calgary, was two years. Now, that's not with everything, right. That's like we have this we come to this point to the clinical trial. And in the meantime, we were working out some more of the mechanisms. So it was two years. Yeah. However, to publish the entire story, took like five or seven. You know that's another thing. So.

 

Dr. Kat McCormick (Host): [00:14:55] Why does publication always lag so far behind.

 

Dr. Alex Parker (Guest): [00:15:00] I don't know. I don't know. I mean we, so something that's interesting or maybe, you know, something to consider is that this type of academic drug discovery approach — don't get me wrong. It's great. And you want to translate it as far as you can for everybody. But I'm not - I'm not convinced that the system is set up to do this properly for the trainees. Because sometimes by the time - for example, we talk about this often, it's like when our paper came out, all the people who had done the work had moved on. Right. So it's a little hard to run these huge things because it's, you know, it's the thing you're supposed to do. That's what everybody says. It's like you want to start with basic discovery with the model organisms and get it to a clinical trial. That's great. But it's hard and it can be long. It can be long for everybody involved. But that's just something to consider. Something to consider.

 

Dr. Kat McCormick (Host): [00:15:53] Hmm. There's a recent trend, I guess, towards patient advocacy groups becoming more involved in the pursuit of scientific research. And I'm wondering if you have experience in working with scientific, sorry,- patient advisory groups and what do you think about their role in moving science and treatment forward?

 

Dr. Alex Parker (Guest): [00:16:12] I, yeah, I think it's I think it's good. I mean they're organized and they have their own voice and they want to see things get done quickly for their families and whatnot, and this makes sense. And we work with several groups where, for example, we will, not to name any details, there's a specific variant with somebody in this group of families or whatnot. We'll develop models and start to get to work right away. And sometimes this will be funded by these private foundations and it just moves at a quicker rate than a traditional grant granting agency. It depends. But this allows us also to develop preliminary data and drug hits that might be interesting to this group in the meantime. Well, let me put it this way. Sometimes they'll be like, well, you can develop worms and or fish model relatively quickly and do a complete drug screen by the time they develop a mouse model. So there's room here to like, just get things going quickly. Get the whole package in a short amount of time. But I think it makes sense, especially for these rare diseases, because people. Yeah, that's my answer I guess. I think it's worthwhile. They do good work.

 

Dr. Kat McCormick (Host): [00:17:25] Yeah. And our time here is almost up. So —just one last question.

 

Dr. Alex Parker (Guest): [00:17:28] Oh wow.

 

Dr. Kat McCormick (Host): [00:17:30] I know, seventeen minutes, goes by fast. So my last question for you, I think is just around — oh, woah, a bird just hit my window.

 

Dr. Alex Parker (Guest): [00:17:38] Oh, boy.

 

Dr. Kat McCormick (Host): [00:17:41] It's just around that, that speed question. So you said it took two years. And I think that when we hear from patient advocacy groups, they're also really concerned with speed. And do you think it is a viable strategy to start these screens in and lower organisms with the idea that they will move?

 

Dr. Alex Parker (Guest): [00:18:03] Yeah, I think it will, because for one reason, it's like nobody has — in terms of time. People don't have all the time on the planet to wait for these things. The second thing is, if you do these drug screens in worms or whatnot, you can find drugs that might be good for just like pure translational repurposing later on but they're also informative of mechanisms sometimes right. Because these drugs are also tools, for the most part because they're well known if you're repurposing. So sometimes it gives you clues about the mechanisms of the disease. Yeah, I think it's it's good to do this stuff. In the meantime, there's no sense to wait like do it linearly. You can do things in parallel. I think it helps everybody.

 

Dr. Kat McCormick (Host): [00:18:42] That's great. Well, Alex, thank you so much again for joining us on 17 Minutes of Science and we look forward to seeing more publications from your lab in the future.

 

Dr. Alex Parker (Guest): [00:18:51] Thanks a lot. Have a good day.

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