Podcast: Models for Long-COVID

A conversation with Terina Martinez, a field application scientist at Taconic Biosciences.

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Long-COVID is a challenging diversity of symptoms that people experience after recovering from COVID-19. My story on ways to understand what underpins long-COVID is here.

In my reporting I speak with researchers around the world and also produce podcasts to share more of what I find out. This podcast episode is one of several I am producing on long-COVID.

Here is my podcast with Terina Martinez a field application scientist at Taconic Biosciences, a company that develops and sells mouse models for research use. A transcript of the podcast can be found below. You can find this episode on Apple podcasts, Google podcasts, Spotify and wherever you listen to podcasts. 

Note: These podcasts are produced to be heard. If you can, please tune in. Transcripts are generated using speech recognition software and there’s a human editor. But a transcript may contain errors. Please check the corresponding audio before quoting.

Transcript of podcast: A conversation with Terina Martinez

Vivien: Hi welcome to conversations with scientists, I’m Vivien Marx.

Terina Martinez: We are all on the brink, hopefully, of reaching some better population immunity because of the vaccine program. But the research doesn't stop because of the vaccines. I think that because we have this whole group of people who have long COVID, we need models that will help us understand what's going on there, because, you know, giving someone another vaccine, is not going to stop their long-COVID. This is a process that's now, you know, triggered by but now secondary and independent of. the actual virus.

So we need models that that are something other than a vaccine to continue to study this. And that's where I think a lot of the current research is going, because while we're not all vaccinated yet, we have the luxury of having many effective vaccines that eventually will get people very protected. But we still have a long way to go.

Terina Martinez (Taconic Biosciences)

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Vivien: That’s Dr. Terina Martinez talking about COVID-19. She is a field application scientist at Taconic Biosciences, which is a company that develops and sells mouse models for their research. You will hear more from her in this podcast. In my reporting I speak with scientists around the world and this podcast is a way to share more of what I find out.

This podcast takes you into the science and it’s about the people doing the science. You can find some of my work for example in Nature journals that are part of the Nature Portfolio. A lot of papers are published there. Those papers are written by working scientists and are about the latest aspects of their research. And a number of these journals offer science journalism. These pieces are done by science journalists, like me.

This podcast episode is one of several I am producing on long-COVID, which is this difficult diversity of symptoms that people experience after recovering from COVID-19. Scientists are working on what might be causing long-COVID. I am doing a story on long-COVID for Nature Methods. Figuring out what causes long-COVID is difficult. And some approaches involve modeling the disease in animals. Yes, that means experimenting on animals, which I know some people are opposed to. Indeed, animal experiments are uncomfortable to consider. But please give this podcast a listen. It might offer some aspects that you might not have heard yet about the value of doing ethically responsible research with animals that can potentially help people with long-COVID.

After recovering from COVID-19, people are, of course, grateful and relieved. They’ve survived a scary ordeal. But many people find that even months after their infection they struggle with symptoms. And those symptoms can include difficulty breathing, muscle or joint pain, fatigue, heart palpitations, they might have sustained damage to their lungs, heart, kidneys. And they might experience what is called brain fog. When the symptoms are severe, the lives of many, many people get completely derailed.

And it has upended the way work is done. Here’s Terina Martinez:

Terina Martinez 3.05: Obviously it's front of mind on a personal level because it's affecting all of our work patterns. But to your point, it has opened up new areas of research, but then also pressurized ongoing areas of research that also need to remain priorities, but difficult to compete when, you know, when you've got this big distraction going on.

Vivien: COVID-19 has changed a lot about research in academic labs, at non profit research institutions and at companies. It’s not the new normal it’s the new exceptional, she says.

Terina Martinez 3.35: Obviously, we can all understand in a say, in a clinical trial in oncology or heart disease, the patients have difficulty getting into the clinics or the at risk patients. But in the research space, even when you take it back to the preclinical step, as you mentioned, if the researchers are having to practice social distancing in the lab, it just really changes what's normally an extremely collaborative team approach. It requires a sharpening of prioritization, potentially a slowing down of progress

But I think that we're all working on, I like to think of it as instead of the new normal, the new exceptional, trying to take the lessons that we're learning and really see where things have been streamlined and how we can risk-mitigate and apply some of these things long term.

Vivien: And it means a lot of time on Zoom.

Terina Martinez: I have my warm tea here so that at the end of the day, if I start to get a little laryngitis, I can, you know, soothe my vocal cords.

Vivien: The first focus for the world was seeing how fast it spread and then addressing the many, many fatal cases in overwhelmed hospitals where there was little physicians could do to help patients. According to the data dashboard run by the Johns Hopkins University Coronavirus Resource Center, as this podcast production , there have been over 3 million deaths world wide attributed to COVID-19. The US leads this sad tally with over 560,000 deaths.

Terina Martinez 5.35: This is a nascent field. I mean, the coronavirus, we feel like we've been living through it forever. But realistically, it's a it's a short time span horizon. What I think is key to long COVID is that it took some several months of us experiencing COVID on a population basis to understand what it was. Because what was grabbing the most attention was the fatal cases and the really acute organ failure, ventilator-dependent cases. And it wasn't until people began to really appreciate that even mild cases, months later, people recovering from mild cases, that didn't require hospitalization, had long-term symptoms. Considering that they would get their COVID-diagnosis, recover and still abide by social distancing, and all of the other rules of our shutdown economy and society, it wasn't likely that these symptoms were coming from other areas.

Vivien: They weren't in a tropical area or someplace traveling or got Lyme disease or something like that?

Terina Martinez: Absent any exotic sort of case studies you'd see on House M.D., the TV show, it was, I think that's what had allowed clinical clinicians to begin to realize that there was a subpopulation of patients who recovered and the uncanny observations that it could be anywhere from 10 to 30 percent of patients who recovered from COVID. Now, of course, there's some handwaving there, because many people are asymptomatic carriers. People may have had a mild case and have not had access to a test.

So they don't have confirmation of it. But we do know from other viruses that viruses can trigger auto-immune components and we're beginning to appreciate potential auto-immune contribution to long COVID condition. It's still very early days, but this is based and predicated on some observations that people who have long COVID symptoms exhibit auto-antibodies to things like interferon. And interferon is an important cytokine release factor. So cytokines are basically, if you think of neurotransmitters as the chemical messengers of neurons, cytokines are the chemical messengers of inflammation cells. That interferon is a very popular it's one of the first antiviral responses you'll have whether you're having an antibody response to influenza, COVID or West Nile virus, any number of viruses, interferon will be involved.

So the idea is that even in patients who have a mild case, they will have this raised interferon level long enough and the immune system is just out of whack. It's never seen this pathogen before. It's not really coordinating a really specific response. It's really just throwing anything and everything at the virus, which maybe in certain cases of subpopulation predisposes people to develop auto antibodies against the interferon. And any time the immune system has an auto antibody approach, that means that it's recognizing self as foreign.

And we can think of things like rheumatoid arthritis, type one diabetes as examples of autoimmune disease. And what seems to be happening, again, we need to put some resolution and sharpness to this picture, but it seems that for some reason, individuals with long COVID will have this inappropriate auto-immune response long term. That is what's causing these symptoms of fatigue and joint pain or arthralgia, difficulty concentrating. These are actually symptoms that coalesce in other autoimmune diseases as well, which is another sort of dot that's being connected to link this potentially to auto-immune mechanisms.

Vivien: Part of studying what long-COVID is and isn’t involves looking deeply at what the virus does to the body. Once inside the body, for example when it is inhaled,  SARS-COV-2 the virus that causes COVID-19 uses a doorknob to get into cells. It locks onto a protein that is found on many human cells, it’s called ACE-2.

Terina Martinez 10.00: When someone's exposed to SARS-CoV-2 the virus that causes COVID-19 it'll usually, of course, it's going to enter through respiratory, through mouth or nose because it enters through aerosolization and then it gets into the respiratory tract

There are receptors that the SARS-CoV-2 virus latches on to our cells and it just uses that as a Trojan horse way to get into the cell. So only certain cells have those receptors, called ACE-2 receptor. Those are really high density in the lungs, the intestines and on endothelial tissue, which is the tissue that lines blood vessels. And that's why the heart is also a target organ.

Vivien: The virus can target these cells with the ACE-2 receptor, get inside, take over the cell and use it to further its own, viral needs.

Terina Martinez 10.50 So then the virus will use that receptor to get into the cells, hijack the cells nucleus-DNA machinery to make many, many copies of the virus. While the virus is inside the cell, the immune system has no idea what's going on. The virus has to replicate many hundreds, millions, thousands of times, and then it ruptures the cell and dumps all that new virus into the tissue or the bloodstream, whatever is in the area. And then that process just continues to magnify.

So the immune response will initially maybe see some of those unique lipid signatures or unique factors of the virus, just that says 'you are a virus' and the immune system can trigger that initial innate response with certain cytokines involved. If you have a robust, early, innate response, but one that's not over exuberant and wild, then that will trigger. Those cytokines will do two things. They will do things that are bad for the virus.

And they'll also be a homing signal for your adaptive immune system to get in gear. It's basically says there's something going on here. It gets that innate immune cells to migrate to the area. That way it can look at the pieces of the virus and get specific with its recognition of it.

Vivien: And then followed by, I guess, destruction, which would be the good outcome. Right. Which hasn't happened in so many cases.

Terina Martinez 12.20: Right. But then so the idea would be that in people who have a really quick and efficient, innate immune response, those are the people who are likely the asymptomatic carriers, the ones with very mild cases, they get it and resolve. I n some people, though, because we've never really seen this virus in its unique iteration. If it escapes that initial, if it evades that initial innate immune system and gets enough copies of itself generated, then the immune system kicks into overdrive.

And that's where we get what we've you've probably heard of cytokine storm. That is when someone is very ill and their immune system has basically been duped initially and now it's overcompensating by generating too high of levels of cytokines so that that actually causes like cell death, you get blood clots and organ damage and organ failure. So really, what happens in this virus, which is just so obnoxious, is that some people have it so mild you don't even know. Some people have a mild case that the immune system does what it's supposed to and they resolve it.

Some of those who do that end up with long COVID later because there are little mechanisms of this autoimmunity that that kicked in in the meantime. And then other people don't get that initial immune response and just immediately go into that overdrive with cytokine storm.

Vivien: Cytokine storm is bad news and difficult to treat.   COVID-19 in general has been very difficult to treat. And long-COVID is hard to treat too.

Terina Martinez 13.50: When you think about the symptoms. So the CDC lists the common symptoms. And this is again taking this subset of people who've recovered and have the long symptoms. There is no one magic test that someone can take and say you have long COVID, what they have is the information of someone who previously had the infection, has cleared it and now they have the sequela and clustering of symptoms. The common ones are fatigue, cough, shortness of breath, chest pain and joint pain. But then many people will also report muscle pain, heart palpitations, occasional fever, difficulty concentrating.

But when you take that list of symptoms, which is many and they are diverse, that could be many things. I mean, those same symptoms could also be, you know, Chronic fatigue syndrome, Epstein Barr virus. It could be all kinds of other diseases that that are auto-immune. What I think is really important is that now we're as you mentioned, it's hard to diagnose and hard to treat autoimmune diseases. But we do have some tools.

We have ways of suppressing the immune system. So we need to figure out what the right approach is for this, which of the immunosuppressants that have been used for anything from lupus to rheumatoid arthritis, which one would be better? Because what you want to do is stop the inappropriate auto-immune response, but not shut down immunity in the time of a pandemic and when you need to fight other diseases. So that's where I think the clinical research really needs to concentrate.

But coming back to preclinical research, that would enable some of those mechanisms and sharpen the focus of the targets. This is where I think we need to really change some of our focus, similar to how I mentioned with the human clinical population, the attention early days was, in a fair way, the very sick, ill, severe patients.

Vivien To study long-COVID labs need models to do so. The current models are ones that have been used to study the acute course of disease. Here’s Terina Martinez.

Terina Martinez 16.00: The models that we have, the preclinical models and we can speak more about the mouse model Taconic has, is a model that is replicative of severe COVID. So the animals get sick very quickly. They get extremely ill very quickly and have a very severe outcome. I think we need to focus on more mild immune, so more mild infection in order to get better information about what may be happening at the organism level for long COVID.

So it's going to be hard to study long COVID in a preclinical setting where you really can turn up and turn down certain things to investigate mechanisms and really get specific in a reductionist way. Reductionist being good, to answer a question with clarity. So I think we really do need to focus on finding model systems, whether it's changing the model system or c hanging the way we expose them to the coronavirus to get a sublethal infections, to then study these effects with the auto-immune mechanisms. And then we can use the toolbox that we have used before to look at auto-immune mechanisms.

Vivien: In order to shift focus to the more mild infection and to find out what underpins the symptoms in long COVID and to see what might be keeping the immune system in overdrive. Labs need the right types of models. Their needs and choice will vary depending on the research question they want to get at a lab might try to understand individual symptoms such as joint pain or chronic fatigue. Or they might want to assess the immune system at different time points. But a typical lab mouse will not do for studying these questions because mice do not get COVID and do not get long COVID.

Terina Martinez 17.50: This is the key. The reason why normal mice like your normal field mouse or your normal research mouse won't get sick from SARS-CoV-2 is because they have a different version of the ACE-2 receptor. So all mammals have to have this ACE-2 receptor. It's actually very important in regulating blood pressure, just as its normal, normal job, its day job. But there is enough difference between the mouse version of ACE-2 and the human version of ACE-2 that mice, even if they inhale, if they inhale coronavirus, SARS-CoV-2 because their receptor won't recognize it and bind it and allow it to get into the cells and replicate, they don't get infected.

Vivien: The current models, and there are different types, were mainly before SARS-COV-2.

Terina Martinez 18.50: So the current models usually, I'd say the vast majority of them, use that mechanism and that's the current model we have at Taconic in this particular case. It has ubiquitous expression. So it's expressed in widely in many tissues. But we have in our pipeline. And there are one or two reports of models across the globe. But again, it's very difficult to access them, where you use a targeted genetic approach and you knock out the mouse version and you pop in the human version in its place

Vivien There are different types of mouse models also models in the making . In Taconic's current mouse model for COVID, the mouse has the mouse and human ACE-2 receptor on its cells, but it is otherwise a mouse with the murine the mouse's immune system.

Terina Martinez 19.45: It doesn't have the human immune system. Really, the reason why the mouse is getting ill is because it has the human ACE-2 receptor and then its immune system kicks in.

Vivien: This mouse model is not quite responding the way people do. It has the human ACE-2 gene and its own immune system. For cancer research, there are mouse models that have some aspects of the human immune system.

Terina Martinez 20.05: We start first by basically using a bunch of different genetic tools to knock out the mouse immune system, and then that lets us replace parts of that mouse immune system with a human immune system. But for that model to be sensitive to COVID, you would have to have that mouse that has no mouse immune system and the human ACE-2 gene and then come back with hematopoietic stem cells from a human so that the human immune system reconstitutes. I think that that's another direction the research is going because that's where we need to be.

So what we've now made and when I say iterative, I don't mean tiny baby steps. You can have iteration, that's a moonshot. We have made iterative progress in putting the human ACE-2 receptor into the mouse. Now we need to start understanding more the human immune system. So what we're trying to do now is take some of the dots that we're seeing clinically in humans. Take the human receptor that's now in the mouse, now it's sensitive to the human virus, but eventually if we can integrate the human immune system in the mouse, we can really open up the opportunity for research.

Vivien: So the current mouse model for COVID is not going to quite work for studying the intricacies of long COVID. But labs and companies like Taconic are working on ways to change the model. The new model might, for example, have fewer ACE-2 receptors. Mainly COVID-19 needs to not take a deadly course, as it does in people who have a severe case of COVID-19.

Terina Martinez 21.40: Right now, though, the current model is that it could come down to the density of the receptor that it's so sensitive. It's a very short course
It's a very acute, almost lethal course. So right now we're working on models that have a different version of the same human receptor, but less of it, or basically create models that are sub-lethal so that we can study long COVID.

Vivien: Developing that kind of model takes time and it will involve collaboration with academic labs. That was the case with Taconic’s current mouse model used to study COVID.

Terina Martinez 22.15: The particular model that we have currently available commercially is actually in licensed from a group at University of Texas Medical Branch in Galveston. They developed this model back in the early 2000s against SARS CoV-1, the first coronavirus. It just is a trick of biology that both the SARS-CoV-1 one and SARS-CoV-2 use the same ACE-2 receptor. So that's actually why we were able to first get the vaccines out so quickly, because they had we had all of the five, six, seven years of preclinical research from the first SARS and we were able to start ahead in the process.

So that's the model we have. But we are aware that that there's so much more that needs to be asked. And some of those specific questions we've talked about now, the long covid other mechanisms, those need more specific models and we're working on making those de novo in-house. We have several in our pipeline. We won't know until we get them developed and tested which ones will be relevant, for which purposes and what specific questions.

Vivien: All mouse models, including those new ones that have a less deadly course of cCOVID--19 need to be tested just as the ones currently in use have been. Of course, a mouse is not a person, and in order to understand long COVID labs have to assess if the mouse with the human ACE-2 receptor on its cells has drastically changed in any way.

Terina Martinez 23.40: From everything that we can tell, there is no change to the animal until you give it sars-cov-2 and then it's sensitive. But it doesn't change its blood pressure, it doesn't change its growth and reproduction. It seems healthy and normal in every other grossly observable way. But now it's sensitive to the SARS-CoV-2 that has been affecting humans, but previously would not affected mice. And it depends because there are times when you want to have when it's been advantageous to just have the human version.

There are times when it's benign. It doesn't matter if it has both. There may be times where you might want to have both and there may be times where you just want to have mouse. So, for example, we've heard a lot about the variants and the mutations that this virus continues to undergo. There could be times where the mutations in the virus actually occur at such a rate or such a level of specificity that it can now infect a mouse.

Because it all comes down to this lock and key approach of the piece on the spike protein of the SARS-CoV-2 that is recognized by the ACE-2 receptor, and if you change, if the virus mutates enough, that lock and key might fit the mouse version. So we are, we the collective we in the research community, are really attentive to what's happening at the structural level for the virus, the variants, and as the virus continues to mutate. And then what models would be the best to study the different versions.

Vivien: The virus doesn't exactly sit still and wait for labs to study it. The virus mutates and evolves
New variants pop up. The variants might, for example, make the virus more transmissible between people and it might begin to infect mice. When an earlier variant was not infectious in mice.

Terina Martinez 25.20: Those studies are still very, very early days. People are still focusing their studies on the mice that have the human ACE-2 receptor because we know that that's a more tried and true mechanism. But I think that that we do need to be attentive to the idea that as these the so-called South African or UK variants, when we talk about those variants, it doesn't mean it has one mutation. It has probably five, six or eight different mutations that have justt kind of been isolated into that variant.

So then we have to use another reductionist system to try to understand which of those particular mutations is causing a structural change or a communicability change or a stability of the virus change or an ability to recognize mouse ACE-2. I mean, the variables begin to get mind boggling. But but we people are the bright minds are paying attention to it. And I think we will we'll continue to learn so much more in the in the coming weeks and months.

Vivien: Terina Martinez and her colleagues are regularly approached by labs that have developed a mouse models on their own. They would then like to hand off the work to a company that will tend to developing mouse models more fully. And then, when it comes to testing, they would need help anyway because most labs do not have access to high security facilities needed for work with SARS CoV-2.

Terina Martinez 26.40: They want to focus on the research, but they would rather let us focus on the logistics of large scale production and shipping distribution. They don't have the luxury of a global shipment footprint like we do. So it's a partnership. And yes, Taconic has exclusivity for this particular model and then for the ones we're making, of course, we would also have exclusivity there, but we would. What's great about this partnership is that we don't have in our own labs that biosafety level three capacity. We can't do those tests ourselves. We need to work with partners, too. And that's where something like this type of partnership is very mutually beneficial, because they can bring the infectious disease expertise and we can bring the most expertise and meet in the middle.

Vivien: In addition to the many scientific and technical aspects, there are also administrative ones. A material transfer agreement or MTA is often needed when academic labs want to share reagents or models. And that can take a long time to set up, especially with COVID. But in science, more generally, too. And labs don't want any time lost.

Terina Martinez 27.45: The ecosystem of animal model generation and distribution is is a broad spectrum. So I would say, if we took the Taconic commercial catalog, which is several thousand different types of models, some of those were made in-house with Taconic, some of those were made in partnership with maybe a disease foundation that had interest in a certain disease or model.

And other times it's what version we're talking about here, where an academic group made it on their own and then they said, OK, this is valuable. But my setup is like Gepetto's workshop. I need something more along the lines of a Nike factory. So how can we work together? So we we have models in our catalog that bridge the entire spectrum.

And that continues to be our strategy for developing novel models, because we're completely aware that that our internal R&D program is probably not going to capture all of the need. We want to be able to make sure that that landscape is widely assessed and that the gaps are identified by the research community, by the end users and by the brightest minds in the world. So that requires a more bottom-up mechanism.

The availability question is key because someone could have the best model in the world. But if it's not available to the research community for replication and for easy access, if it takes you 10 months to sign an MTA, then that really slows down the rate of science by getting it into the public domain quickly. It allows the research to happen much faster.

Vivien: Taconic works with a number of different labs. Terina Martinez has seen COVD-19 shift priorities in labs because scientists want to contribute what they can to studying COVID.

Terina Martinez 29.25: I think it's changed people's philosophies in two ways. One is: research groups who previously were studying mechanisms, so going back to cytokines and what they do and the diversity of the immune system and we've talked about its role in infectious disease, we've talked about its role in autoimmunity, those cytokines, there are so many of them, dozens of them, and the relative level and neighborhood of where they are is what changes everything with the outcomes.  

People have pivoted their research programs. They might have been studying a specific cytokine like TNF-alpha or IL-6 and its role in chemotherapy-resistant tumors because it has a role there, and now they're taking their early stage drug and pivoting that to COVID. So we've seen a lot of pivots. We have seen a lot of academic researchers, to your point, realize that there's a funding opportunity here and the timelines have been accelerated. They've not been dumbed down, but they've just been accelerated for grant review and for getting money out the door.

So we have engaged with academic researchers for that. One of the rate limiting steps, though, is the ability to do those those dangerous and tricky infection paradigms that requires a biosafety level three facility. So a lot of universities don't have access to that. So they come to us to try to, you know, do some matchmaking, do some, you know, do some help with some collaborations and help with finding research organizations, contract research organizations or other groups who can collaboratively work on their drug asset
But they have everything they need except the lab and the moon suits to get it done.

Vivien: As of right now in the spring of 2021, vaccines are being rolled out. And it could change the transmission dynamics. And will mean hopefully that many many fewer people become dramatically ill with COVID-19.

Terina Martinez 31.20: We are all on the brink, hopefully, of reaching some better population immunity because of the vaccine program. But the research doesn't stop because of the vaccines. I think that because we have this whole group of people who have long COVID we need models that will help us understand what's going on there, because, you know, giving someone another vaccine, is it going to stop their long COVID? This is a process that's now triggered by but now secondary and independent of the actual virus.

So we need models that that are something other than a vaccine to continue to study this. And that's where I think a lot of the current research is going, because while we're not all vaccinated yet, we have the luxury of having many effective vaccines that eventually will get people very protected. But we still have a long way to go.

Vivien: That was Conversations with Scientists. Today's episode was with Dr. Terina Martinez, field application scientist at Taconic Biosciences. And I'd like to say thank you to Ginny Somers, who set up this conversation. And I also just wanted to say, because there's confusion about these things, sometimes Taconic did not pay to be in this podcast. This is independent journalism produced by me in my living room on Vivien Marx. Thanks for listening.

(G. Altman Pixabay)

Vivien Marx

Journalist , Nature Portfolio

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