Michael Strainic podcast

Ken Mullinix: Welcome to The Exchange Podcast from Biomere. I’m Ken Mullinix. Our next guest is Dr. Michael Strainic. Dr. Strainic is an immunologist and has a PhD in pathology. Dr. Strainic is very detailed in this podcast with items such as COVID-19 Messenger RNA vaccines. We talk about ALS, we talk about Alzheimer’s. We also talked about the need for better transparency as far as sponsors and CROs are concerned so that we can provide them with better service. Dr. Strainic is a wealth of knowledge when it comes to immunology, and it was wonderful to pick his brain about these topics. So sit back, relax, and enjoy this podcast with Dr. Michael Strainic. Mike, I’ll let you talk a little more about yourself.

Michael Strainic: Thank you, Ken. I received my PhD from Case Western Reserve University. I worked in academia for around 22 years. I was in the Department of Pathology for 17 of those years, where I earned my PhD. And I worked in the fields of complement biology and immunology. I really focused on the interface between innate immunity and T-cell activation and T-cell differentiation. So, when you go from a naive T-cell to a T-effector cell or a regulatory T-cell in the different subsets in those two groupings.

Then after that, I joined industry, doing novel drug development, focusing on autoimmune disorders. This is a large part of what my PhD focused on. I was studying how you can control T-cell activation in immune systems to bias either to cool down for autoimmune disorders or to activate T-cells for immuno-oncology, which is where a lot of my immuno-oncology experience comes from.

The company I was working for then moved on to become clinically focused with their pipelines. So, their R&D team all moved on, and then I joined at that point. And I’ve been working here now for nearly a year on immuno-oncology models and running our in vitro lab here.

Ken: Interesting. Great. So, we do a lot of work in things like drug delivery to treat conditions such as ALS. I’ve always wondered if there’s an immune response to ALS and I kind of wonder, is that also just an overreaction of the immune system potentially?

Michael: Yeah, I think so. Particularly when you talk about neurobiology, one of the expertises that was at my university was their pathology departments, which are really well known for degenerative brain disorders. They have a huge program on PreOn diseases, but they also do a lot of Alzheimer’s work. I think a similar thing is happening in a lot of those cases where it’s a failure of the immune system’s control. I think both of those, ALS and Alzheimer’s, in a lot of ways, have a lot of immune and autoimmunity going on.

I remember I was at a conference, probably about 10 years ago now, and they were showing GWAS data on patients. One of the highest expressed proteins that was popping out was complement factor three, or C3. At the time, I was deeply involved in studying that protein because it’s part of the complement system and its effects on T-cells. When you have lots of complement, you get lots of T-cell activation; it really helps drive the process from the innate side of the equation.

I think what I’ve been seeing more and more in the literature, starting at the fringes and slowly working its way inward for Alzheimer’s, for example, and I’ve seen this recently on ALS as well, is where we’re seeing involvement of autoimmunity. I think it’s really beginning to be appreciated that those two diseases may actually be autoimmune diseases.

Ken: Interesting. Everyone talks about beta-amyloid plaques. I wondered to myself, is that a cause or is that a symptom of the disease? And that’s interesting. It’s interesting that science is still, you know, it’s up in the air.

Michael: Yeah, and especially with beta-amyloid, even years ago when I was just leaving university, they were still debating if it was a cause or just a symptom. Is it a biomarker? Is it even related? It’s there in every patient, so it’s probably at least a symptom of the disease, if not the cause. My feeling has always been that it is a downstream effect of the disease. The processes that trigger the disease are probably different. Once you’ve lost control of certain regulatory processes, that’s when the plaques start showing up.

Now, whether or not they’re the reason that we have cognitive impairment, I don’t know. But I think when you see a lot of articles about over-activation of macrophages, the specialized ones in the brain, and the microglia, you can envision that they’re trimming the neurons. And that’s what’s disrupting all the memory pathways because the neurons just aren’t attached anymore. But you don’t see that at a macroscopic scale. When a patient goes in for imaging, it’s not fine-tuned enough these days.

Ken: Right. I kind of think about an MRI being like a view from the space station. You can look down and you can see the planet, but you don’t see the individual cars and the people. It feels too zoomed out, as a layman’s way of putting it.

Michael: Yeah. And I think it’s the same way. It’s just like we can’t see enough resolution. Even when we’re looking at transgenic animal models and we’re trying to use a two-photon microscope that can achieve some of those resolutions, even then we’re still not seeing enough of it because those processes are really happening at an electron microscope level to see bits of a cell getting chewed up. You would need that kind of resolution to see.

Ken: Right. Do you think our models are accurate in the sense that if you open a textbook and you’re looking at a cell and these processes, that’s kind of an analogy of how things work? But if you were to actually zoom in, do you think it would be different? Are we pretty close on that, kind of like the atom? The atom is not an electron as we see it, you know, an electron going around an atom; it looks much differently.

Michael: Yeah, and I think it’s very similar to textbooks. There are two things we always have to remember about a textbook. One, it’s about five years out of date. Most information doesn’t get put into a textbook until it’s been confirmed. Nowadays, it takes longer and longer for consensus to be built on what is now a textbook piece of information. I think if you look in the most recent immunology books, they’re starting to talk deeply about innate immune system interactions with T-cell biasing. That’s something that even five years ago was not showing up in any textbooks. You weren’t seeing citations from the different groups who contributed information in the literature that says that.

When you talk about the diagrams themselves, the second thing you need to bear in mind is that they’re made to be simple and easily digested for a young trainee. Textbooks are meant for trainees; they’re not meant for experts. The experts have already read that book; they should know it by heart and they’re working on the deeper knowledge. When you look at textbook information, it really is like reading a subway map. They don’t show you every twist and turn of the tracks, but it says, you know, “go from this station to this station”. I think a textbook diagram on certain cellular processes is very similar. Whereas a real understanding would require you to understand the tracks, the electricity that runs the stations, the fueling systems, and all of those little details that are not on that diagram. They’re just completely obfuscated for a simple ease for the common person to digest. I think you see a similar thing with textbooks.

Ken: So, with all the knowledge you’ve gained on the immune system and all the papers you’ve written, what are you targeting these days?

Michael: These days, that’s a tricky question for me. A lot of the stuff I did in the past five years when I was working in drug development is still under NDAs. My ability to talk freely about stuff I worked on would technically expire in the summer of this coming year. But even then, because I’m working in the same family of companies, they were doing research and development from JOINN Laboratories, Biomere’s parent company. And then joined our parent company. I think even then I have an obligation. So, I’m kind of limited in what I can talk about. What I do focus on now, though, is providing in vitro lab support and model support for where I’m at right now with animal models and consulting for clients. I focus on appropriate model selection and what questions can we answer, what services we can provide.

So one of the things that I focus on is, for example, what can I do with the equipment I have that gets as close to an academic answer that a lot of companies may want when they don’t necessarily have access to those these days. Most pharmaceutical companies, especially in the startup realm, their capabilities are much lower because they just can’t afford to buy every piece of equipment, like someone says Eli Lilly could or Genentech. They can run full academic research programs to drive and support their products, but smaller companies can’t necessarily do that. And those people work very closely with their disease, but they’re not necessarily familiar with all the models that could be done in an industry setting. So I try to focus on helping them choose the appropriate model these days, including things like delivery routes, which refers to how a drug is administered to an animal.

And, uh, you know, I work a lot on what’s the best way to dose the brain, and, you know, what’s the best way to get a global transduction into the central nervous system. 

Ken: Would you say you’re primarily working with AAV vectors? 

Michael:  I can tell you what I’m seeing right now is that the hot topics are delivery vectors and delivery methods. Delivery vectors are the hot thing. We see a lot less specific molecules, like for immuno-oncology and checkpoint therapy. We don’t see as many of those anymore. Since the advent of COVID-19, because of the vaccine and its unique way it was being delivered with the lipid nanoparticles, now everybody is testing their compound with that delivery method. The advantage to a lipid nanoparticle is that you can change it. You have your lipid, but then you can paint molecules on the surface by expressing molecules that can be incorporated into the surface. Or you can purify them, and then you can target those to certain tissues. So, that’s the thing I’m seeing a lot of, both with that delivery method and the science that’s targeting those things. But also, what are they delivering? Are they delivering a drug or are they delivering AAV? I’m seeing both. We see lots of drugs being encapsulated, and we also see lots of AAV. Lots of different companies are doing this now, and they’re starting to get into the ability to target specific tissues and do gene therapy much more targeted than previously has been achievable. We are seeing those types of things, and that’s one of the things that we’re trying to find support for people is how they can measure their target. We can do a lot of that stuff here with expression vectors that the clients already have in their targets sometimes. Then we can image that in vivo in some models for small rodents. For the larger animals, when they’re trying to start doing their PK studies, for those, it’s usually that you get an animal dose and they do the timing, and then we send the tissues out for analysis. This is so that people can figure out what organs their target is getting to, and if it’s getting to the organ they have targeted with their engineering. 

Ken: Interesting. Do you see a path forward for messenger RNA vaccines as a whole? Do you think COVID was kind of the initial push for that? 

Michael:  Yeah, I think COVID was the push to show that something we’ve been achieving in the lab can be done in a clinical setting at a large scale. That is now going to be, as I think, a very strong shift in vaccines in that direction over time. My concern as an immunologist is the packaging systems and tolerance against the packaging systems. In some ways you want to have an immune response against them because that’s what you’re trying to do; you’re trying to immunize people. So you want their immune system to be boosted. But if it’s too strong and it clears out the vaccine before it can be effectively expressed, you could run into problems there. As an immunologist, that’s the only theoretical barrier I can envision right now. With lipid nanoparticle delivery, it shouldn’t be too big of a problem because there are only a few specialized subsets that do that, and clearly, they’re not involved with these first-generation delivery systems. I’m more worried about the tissue-specific targeting ones, like, will patients develop immune reactions against those targeted molecules? For example, if you’re trying to target something to a brain cell so it’ll clear the blood-brain barrier, it might work the first time or two, but on the third time, does it get through? Or you correct one disease, and then they develop another disease later, and can you use that same delivery factor? Will it still work? I think that’s where the frontier is in delivery methods. 

Ken:  Gotcha. I recently saw in the news they’ve been talking about DNA contamination with the COVID vaccine. 

Michael:  I don’t know if that’s part of the manufacturing process or if that’s just something they can work out. I haven’t seen that specifically in that article, and I’ve not heard that. I would suggest that contamination during the manufacturing process is probably sloppy because these things are being made in multiple manufacturers. Quality controls are usually very tight in FDA-regulated manufacturers, but I could see cases where you’re getting some DNA through purification. This is because messenger RNA and DNA purification methods are so close to each other in terms of how you do it. Most in-vitro labs, their purification method is going to pull mRNA out, and they’re going to pull DNA out too. It’s just the way the patients are to the methods that are available to people, so at the commercial scale, I could see how that might be linked through. I don’t know if it’s a huge issue, though, because the DNA that’s likely contaminating is probably just from the cells that they’re using to manufacture it in the first place. Most of those are a mammalian cell line, and that shouldn’t have any effects. I would think, but I’d have to look at the article to see, and more importantly, the FDA report to see what actually happened in those cases. 

Ken:  You mentioned Prion diseases like Creutzfeldt-Jakob disease, things like that. Are there, would you say that’s a small number of cases of that, like versus Alzheimer’s and different neurological degenerative diseases? 

Michael:  The number of cases of those are very small, especially with tighter controls on agriculture now; we’re not seeing so much mad cow disease. I’m more familiar with it just because the center for collecting all the samples from patients who had encountered it was at Case Western, on a floor above me. So we were on the third floor, and that was on the fourth floor. That whole floor was the Prion floor, so everyone was always worried about going up there and touching a single doorknob because you never know with that disease. It takes like ten years for it to manifest. I used to harvest spines at the anatomy lab, and some of the older dementia patients would always worry me. I’d think, “I don’t want a needle stick here” because you never know when you’re working with brain tissue. I think that’s the same thing, even when you’re working with Alzheimer’s. The same facility also does all the Alzheimer’s work, which is stored up there too. They’re a big center for biobanking, and so I always worried about that as well. Whenever I had to do a study, I’d think, “I don’t want a needle stick here”. Those are the ones you’re really worried about because you know, if even a little bit gets on you, you’re not going to know forever. It takes like 10 years before you know. 

Ken:  So there’s not even a way to trace patients who have that? 

Michael:  It’s, “Where’d you get it?” “We have no idea”? Because it’s all, even if the misfolded protein triggered it in yourself, it takes so long for it to build up. By the time it builds up, it’s all yours. The nucleating factor is not something you’re going to be able to trace out of trillions in your brain. And I’ve heard that they’re not even autoclavable, some of those misshapen proteins. I don’t know if that’s accurate or not. If anything, that could cause more unfolding and then just make more of them. Because it’s really just unfolded proteins that then can’t refold. The autoclave doesn’t break that. The only thing that breaks it is heavy UV and bleach. And those are the only things that can really kill a protein; things that totally kill a protein are going to be the only things that do that. An autoclave just melts stuff; it doesn’t actually break any bonds. You need something to covalently modify the target. 

Ken: It’s fascinating to talk to someone with such a wealth of knowledge in this field. I mean, I feel like I can ask you anything about it. It’s very enlightening. Thanks for doing this podcast and for your time here. Is there anything else you’d like to go over as far as Biomere is concerned or the CRO business as a whole?

Michael:   The only thing is, when I was thinking about our conversation, because I’m an immuno-oncologist, one of the things I’ve really realized since I’ve joined is that for people out there who are studying tumor models and they want to do work in vitro and in vivo, it’s interesting how few are aware of some of the limitations in industry and in the CRO business. Choosing the correct model can be critical to success or failure for them. So, when you’re working with a partner, whether it’s Biomere or one of our competitors, you have to drill down very carefully with them on what you’re trying to achieve. A lot of pharmaceutical industries are trying to keep things close to their vest. They don’t want to disclose their target, their molecule, or their therapeutic because they don’t want someone to steal it.

But that is not generally going to happen when you’re working with someone like us because we work with dozens of companies every year, and we have to keep all of their stuff secret. Some fully disclose, others don’t tell us next to nothing that comes to us as “therapeutic A”, and that’s all we hear. When they’re choosing their models, we have had an experience where someone will send a therapeutic, we will run it, and we will see lots of toxicity in the small animal where they’re trying to do their efficacy study and trying to prove that their therapeutic works. They will run it again and again, but when you go back and you look at it, what they have is a molecule that is fully humanized. It’s ready to go into a human being, but they’re giving it to an animal that is generating an immune response.

In the case of cancer, most drugs are designed specifically to poke the immune system forward; they want to get a hot immune response. But when you do that in an animal, you start getting a toxic effect. 

Ken:  So then your drug looks toxic and you can’t use it. 

Michael:  It really has nothing to do with the drug; it’s the way they designed it for their initial test in vivo. People need to be more forthcoming with their CRO, like ourselves, to say, “What do you have?” so we can drive you toward the model that works. If you do it in the mouse, there are types of mice, such as the syngeneic mouse model of tumors, where it’s a mouse tumor cell being implanted into a mouse so that the tumor will not be rejected by an immune system and grow. But then your therapeutics need to have more. If it’s an antibody-based one, it needs to be a mouse antibody so it doesn’t get rejected and doesn’t trigger the immune response. If you have a human therapeutic, then you should use a humanized mouse, which they make. Ultimately, the best system is patient-derived tumor models, where they take cells from a patient and put them into a mouse that has a human immune system or a human immune system analog, which would be more accurate.

Then, the therapeutic is much less likely to trigger any immune response, and it should function the way it is supposed to. You’re not going to see rejection and toxic effects where the mouse gets so sick it dies within hours of administration. So those are the things I think, when you’re working with CROs, you need to think about your model, and you need to think about and discuss with the CRO what you’re trying to achieve, what system you are studying, and what effects you’re expecting to see. A second example would be, we had a client who didn’t want to tell us anything. They gave us a drug, and we saw something, and someone only offhand noted it in a report. It’s not something that normally would’ve been mentioned, but the client was like, “Oh, yeah, we were expecting to see that.” It’s like, “We almost stopped this study because we saw that.” If you expect to see something, you shouldn’t be scared that the CRO is going to tell you no. You should be more forthcoming so that we can say, “Okay, we’re seeing things you’re expecting to see. We’re seeing this, we’re seeing this.” Or at least tell us what we should pay attention to. For example, “We should be monitoring metabolism,” or “We should be looking at this area.”

You don’t have to tell us the specific proteins, but at least tell us, “Oh, these animals might have a change in their liver enzymes,” or “They might have a change here.” And this is so you should be looking at the pathology as you’re examining the animals and sacrificing the animals so that we can communicate to them, “Okay, we saw a discoloration in the liver,” or “We saw a spot.” Sometimes they just assume the CRO is going to report everything, but that’s really not feasible, especially if it’s only a minor change. But that minor change might be very important to them in their program and the indication that their drug is working the way they want it to. It’s that the assay wasn’t designed to show it.

Ken:  Is there a way to develop that greater transparency? 

Michael:  Part of what I’ve been trying to work on is when I meet with clients for the first time, I try to get them to give us a little bit more transparency, and I try to tell them why I would like to have a little bit more and how it benefits them. Like I said, if we know where to look, you don’t have to tell us what your drug is. We don’t need to know what protein it’s targeting. But if we know it’s an autoimmune, a tumor oncology, or a metabolic drug, we can then examine things much more carefully and give you more detailed reports, and I try to communicate that to clients.

Ken:  I think the other way is to just pass that word along to people through mechanisms like these podcasts where you can educate potential interested parties: “Here are some things you might not have been thinking of, or here’s how you might be short-circuiting your approach under your secrecy.” There are ways you can still be secret and still accomplish what you want to do and work better. 

Michael:  I run into the same issue. Someone will say, “What’s the best route for global transduction in the CNS?” and I say, “Well, we’ve done it a thousand times. We don’t always get the data back.” And again, that doesn’t really accompany letting us know, “Oh, you did a great job.” It doesn’t really benefit them; it might benefit the next company, so that might be more reason why they don’t tell us. 

Ken:  I can see that. I can see how they’re trying to avoid helping other potential competitors.

Michael:  But at the same time, a lot of companies, when they’re working with us, my involvement will be a lot of times on the small animal side because that’s the one where they’re doing their initial investigations. The techniques that we are doing for them tend to be exploited more in terms of looking at advanced immuno-readouts, phenotyping of the immune cells via flow, and activation markers. All of those sorts of things. We’re at an earlier stage, and when they come back later, we’re like, “Okay, here’s how this assay was done. Here’s how it looked last time. Maybe we should try tweaking it this way.” I’ve worked with some clients back and forth and really hammered in the assay. We had one who wanted to do something that was super expensive. When we showed it to him, he was like, “Oh, that’s not going to work.” And I said, “Well, what are you trying to show? And why do you need to show that?” and he laid out his reasoning and what his practical objectives were. And I was like, “You can get there with this, I think,” and then he looked at it and said, “Yeah, you’re right. I can get there with that method, and that will give me what I need to move forward.” They were able to change things dramatically and made it a much easier, much more feasible study, both from the actual practical doing the work but also from a cost-benefit standpoint. Like, they weren’t going to lay out the money they could, but they could achieve their goal nonetheless. That’s the thing I think most people need help understanding. When you work with the CRO, you can still achieve your goal, and you’re much closer if you’re more transparent. When you’re trying to play things too close to the vest, we can’t tell you the alternatives. We can always say, “Yeah, no, we can’t do that. We don’t have the facilities.” 

Ken:  Hopefully, things like this podcast lend themselves to greater discussion and discourse with sponsors and CROs. Progress for them helps progress in humanity as well. It’s great that we’re in a field where we can actually make a difference. 

Michael:  That’s the point. If you talk to any scientist in our field, that’s why they go into it. Because they want to develop cures, they want to do research, whether they are at the very early academic stage, in the middle drug discovery phase, or in a late stage like ourselves. We are testing molecules for clients where the next step is clinical trials in a lot of cases. So, you know, that’s why we’re here. We’re here to help these people and we’re here to help move those things forward because that’s what we want to do.

My experience has always been that most people who work in our industry could have become medical doctors if they had wanted to. For my personal reasoning, I could be a doctor and I could help 10 to 20, maybe upwards of 30 people a day. Or I could go and do research work for five to ten years and help millions. That is where my decision ended up being made, which was developing something that could move forward. Some of the work I did has been translated into an FDA-approved drug, and patients are benefiting from it. 

Ken:  Wow. That’s great. I think research is a great field to go into, especially if you like variety.

Michael:  The number of surgeries I do now versus the number of types of surgeries I did in spine, the numbers are so much larger and I’m doing so many different varied procedures. Whereas had I gone the human route, medicine is now so specialized that you don’t really have a possibility to get into many different types. 

Ken:  The last podcast we did was with Vince Mendenhall. He goes over the fact that he’s learned he does everything from orthopedics to heart transplants, and you’d never get that in human medicine. 

Michael:  Exactly. That was one of the things when I transitioned from academics to industry, that was the one thing I missed. I like where I’m at now better in some respects because I’ve gotten back to the variety. When I was working in academia, the breadth I worked on, I started as a biochemist in a biochemistry department, then I moved to a pathology department where I worked on immunology. Because of all the diseases we tested, there were so many subsystems you had to learn and go into, like all the metabolism, all the activation of cells, and all the genetics that you need to know for diseases that are hereditary. Or all the just making your tools to do your studies. It’s such a huge scope and such a wide variety.

When I went into industry and was doing like I’m developing this molecule, I ended up working on four separate projects, all of which we moved forward. But it was just four molecules and four systems. Three were targeted for immuno-oncology, and one was an autoimmune field. While it felt very fulfilling in that I was finally moving something forward, at the same time, it felt very restricted because I had to focus on just those things. When I moved back into working with Pioneer, now I’m working with a breadth of clients like, “I’m trying to develop an autoimmune drug,” or “I’m trying to develop a tumor oncology drug.” I’m getting that, “Okay, I’m going to research this one here.” Because they’re like, “Can we measure this molecule here, or can we order this disease-inducing agent here?” I have to go and do research like, “Yeah, we can do that. Yeah, we can do that. We can make that work. We need to do a pilot study. I’ve never done it. I’m sure we could do it, but we just need to show you that we can before you drop a huge amount of money and not be able to move forward.”

Ken:  I think this has been a great podcast. 

Michael:  Thank you. I appreciate the invite. This has been a lot of fun. Hopefully my light flickering, like the camera auto-dimming. I was trying to keep my rotating down so that it wouldn’t auto-dim on you too much. 

Ken:  No, it looks good. I can tell it’s nice and sunny out there in California. 

Michael:  Yeah, well, we got lucky today or this afternoon. It was pouring this morning. It rained, so I was there, what, two weeks ago? I think it rained the entire week. Yeah, yeah. That was the day I was out for my son. He had a camp out for school, so I was chaperoning, otherwise I’d have been with that same session with everybody else. Sure. Yeah, we had a good time. Teaching liver biopsies to Russell, and, uh, yeah, we did some IT stuff in rats. I think our next training, the last I heard, they were planning on sending Anthony and Fabian, one of the two of them back east to you guys for some more training on some other things. 

Ken:  Yeah, that’d be great. 

Michael:  That was the last I heard. 

Ken:  Yeah, that’ll be fun. It was good though.

Michael:  Anthony and Fabian. Yeah. He is one of the RVT’s. He works for Russell’s group. And Anthony Noe is our resident, like experts in actually doing all the procedures. Because they both have very good hands, and Noe’s been doing it forever. And but you know, whether he’s officially signed off on things is always one of those. Our paperwork side of stuff. But you know, Anthony’s also very similar, like Rashan. 

Ken:  He was great. I taught Anthony CSF collection, and he picked it up like he’d done it for years. He’s really talented. 

Michael:  Yeah, it’s almost a shame that when Bo promoted him to a project manager, he’s got to spend all of his time regulating stuff and less time doing stuff. I can see him kind of like, he’s not getting to do things as much anymore. He’s got to have other people do it, so he’s got to stand there and watch them and hope that they get it. But he needs to know how to do it so he can teach everyone, so. 

Ken:  Sure. Great. Well, all right, Mike, again, this has been a great podcast. It’s been great talking with you. 

Michael:  Well, thank you for the invite.

Ken:  I had a great time. 

Michael:  Yeah, of course. Me too.