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Episode 18: Combatting COVID-19

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In this Episode

Illustration of the coronavirus outer surface Courtesy of CDC/ Alissa Eckert, MS; Dan Higgins, MAMS

This illustration, created at the Centers for Disease Control and Prevention (CDC), reveals the spikes that adorn the outer surface of the novel coronavirus, named Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2). It was identified as the cause of an outbreak of respiratory illness first detected in Wuhan, China in 2019. The illness caused by this virus has been named Coronavirus Disease 2019 (COVID-19).

The novel Coronavirus is raging through communities around the world. It’s a virus never before seen in humans, and therefore, not recognized by our immune systems. According to the Centers for Disease Control and Prevention (CDC), people over 65 and those with underlying health conditions are at the highest risk.  There is no vaccine or drug therapy to prevent or treat the illness caused by the virus, known as Coronavirus Disease 2019 (COVID-19). The heroes of this battle are the healthcare workers on the frontlines and the scientists and researchers in the labs developing a weapon to take down this persistent enemy.

On this episode, we talk to two scientists joining the fight against COVID-19. SwRI scientist Dr. Jonathan Bohmann is using the Rhodium™ Software (Structure-Based Virtual Screening) to analyze drug compounds that could successfully fight COVID-19. He’s working closely with Dr. Ricardo Carrion and his team from San Antonio-based R&D organization Texas Biomedical Research Institute. Dr. Carrion explains how scientists everywhere are joining forces to eradicate the virus.

Listen now as we discuss the global pandemic that has rapidly changed the way we live.

TRANSCRIPT

Below is a transcript of the episode, modified for clarity.

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Lisa Peña (LP): Scientists across the globe have joined the urgent fight against the COVID-19 pandemic. Coming up, hear from two researchers in the race to eradicate the virus and save lives.

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We live with technology, science, engineering, and the results of innovative research every day. Now, let's understand it better. You're listening to the Technology Today Podcast, presented by Southwest Research Institute.

Hello, and welcome to Technology Today. I'm Lisa Peña. Now, usually, we record in our studio but today we are working from home, practicing social distancing, and recording our interviews by phone. So this episode may sound a little different.

Of course, the coronavirus pandemic is changing how we do things and changing lives around the world. The illness caused by this virus is called coronavirus disease 2019, or COVID-19. The numbers of COVID-19 cases and deaths are rising every day. Our guests today have joined the race to stop the widespread coronavirus in its tracks. Dr. Ricardo Carrion is a scientist, Professor and Director of Contract Research at Texas Biomedical Research Institute, which is an independent, San-Antonio-based research and development organization. Texas Biomed's focus is infectious diseases.

Dr. Jonathan Bohmann is a Principal Scientist at Southwest Research Institute. They are combining their expertise to search for a coronavirus drug therapy. Thank you both for joining us today.

Let's start with Dr. Carrion, Ricardo, your team has answered the international call to tackle this virus. What is happening right now at Texas Biomed to mobilize against the coronavirus?

Dr. Ricardo Carrion (RC): Thank you. We've had a Texas-Biomed-wide effort to tackle coronavirus research. As you mentioned, our business is trying to eradicate infectious disease. So this is part of our mission.

And with being led by our President, we are focusing on developing animal models. Because once we identify candidate drugs, so drugs, some of which we're working with, SwRI with, we need to test them in a relevant animal system. So that will be the bottleneck in the future, is testing these drugs and these animal systems. So we're looking at three different species of non-human primates, marmosets, baboons, and rhesus macaques, to determine if coronavirus causes COVID-19 disease, and that's SARS-Coronavirus-2, when exposed to these animals, these animals can develop a disease similar to humans.

The idea would be that if these animals model human disease, we can use them to test these therapeutics. Aside from that, we have to develop the tools, which we had been doing and we have done, to assay samples from these animals. But also, look at compounds to see if these compounds that we're looking at can prevent replication of the virus. And if they can, they automatically become the candidates for using in these model systems.
 
3D model of the novel coronavirus Courtesy of SwRI/Protein Databank (www.rcsb.org), entry 6LU7

A 3D model of the novel coronavirus. SwRI’s Rhodium™ virtual screening software recently used the model to evaluate 2 million drug compounds to identify drugs that have high probability efficacy against COVID-19.


LP: OK. So walk us through the process a little bit. In order to study the disease the disease and the virus, well, you need to have a sample there in the lab. How and when did you attain access to the virus?

RC: The sample we received was through a resource that the government has called BEI Resources. The objective is to make available to scientists samples that can be used to look at therapeutic compounds and other things. So we received a shipment of a small quantity of the virus back at the beginning of March.

Since then, that material needs to be grown up, amplified, so that we can use it for other experiments. We've done that part of it, where we expanded the virus in a tissue culture system. We've analyzed the genome to make sure that it didn't undergo any changes while we grew it. It's authentic to the original isolate. And the original isolate was one of the first cases in Washington State. So it's from the person that was ill with the disease. At this point now, we've developed assays to be able to test therapeutics.

But we need to make sure we have confidence of the assays. Otherwise, when we perform tests, we won't know if it's a real effect of stopping replication of the virus. Or if this is a artifact of our testing system. So we've been through this entire process, trying to get to the point now where we could test compounds.

LP: So for our non-research-minded audience members. Can you define what assays are?

RC: So assays are in vitro experiments in which we take the virus. And we will mix it with, in this case, a candidate drug. Then we'll try to determine if that drug kills the virus, or it prevents it from replicating.

Viruses, they depend on mammalian cells to grow. So if you have a virus on a surface, it's not going to magnify itself. It's not going to amplify in that space. Because it needs another cell to grow. Viruses require some machinery. We take invaded cells, take it over, produce more of itself. So that's how we determine if the virus replicates, is we use that virus to infect a cell in a tissue culture plate. And determine, after a set amount of time, if the virus has expanded, if it's grown. Or has it stopped replicating or stopped growing?

So a drug that's efficacious, a drug that works, would prevent that virus from actually making more virus. And we can determine what amount of that drug causes the virus to stop replicating. So we do dose chart analysis, where we look at if we have 100 times the amount of this drug then we start reducing it, do we see an effect on virus replication?

 
Headshot of Dr. Ricardo Carrion inside a lab Texas Biomedical Research Institute

Texas Biomedical Research Institute Professor and Director of Contract Research Dr. Ricardo Carrion.


LP: What is a realistic timeline to develop this drug therapy or a vaccine?

RC: Outside of a pandemic like we're experiencing right now, it can take 5 to 10 years for something to be developed. We've had a head start. There is a level of collaboration among the scientific community that has not been seen before. We had SARS-1 outbreak occurring back in early 2003.

There was MERS outbreak back in 2012. Those were very similar outbreaks. But the current 2019-2020 outbreak, we have scientists from all over the world exchanging data in real time.

Technology has a lot to do with this. We have worked in group meetings. We Zoom information between each laboratory. Every time a scientist uncovers a piece of the puzzle with this coronavirus issue, everyone's known about it.

So it helps in two ways.

One, it has determined the speed at which we have discoveries. If we do an experiment and we uncover something about the virus, another lab doesn't have to discover that same issue. We're able to share information. So it works quickly. So in this case, I think we're going to see a compressed timeline.

Also, many of the companies have already learned from previous outbreaks and are able to adapt their technology to make vaccines using existing vaccine platforms, and drugs using existing drug platforms that we know work in other types of viruses that could be applied to this one. In addition to that, because of the Ebola outbreaks, and some of these other diseases, we've been able to use animals as surrogates for humans. In the case of very deadly diseases, it's unethical at times, and impossible to do traditional human trials, where you look at efficacy in humans.

So being able to substitute animals that replicate the disease in a way that humans do will help compress the timeline as well. We're not going to skip safety. So that's not going to be an issue. Everything has to go to appropriate safety testing.

But with regards to efficacy testing, on the ability to use animals helps us to reach our goal much more quickly. So there are some estimates that within a year from now we'll be able to have a drug compound or a vaccine out that would be approved for human use.

LP: From 5 to 10 years is in a normal situation. But because of the collaboration worldwide, you're looking at fast-tracking this and maybe getting a good drug therapy out in about a year.
 
Jonathan Bohmann leading a presentation on the Rhodium

SwRI Principal Scientist Jonathan Bohmann led a presentation on the Rhodium™ virtual screening software at the Institute’s 2017 Annual Meeting.


RC: Right. Also, it costs money to do this. There's a ton of money being invested into these programs by the government. But also, locally, we're fortunate in that San Antonians have donated to Texas Biomed to do these critical monkey experiments, that we're fortunate that San Antonians understand the value of science.

And they understand the value of these types of experiments. And they're really willing to give monies to do this. Because we're a private nonprofit institute. So we can't do this without support from our local community.

In addition to that, the government, with BARDA, NIH, DoD, are also providing monies to help supplement this research. Again, availability of money and also, the sharing of resources to right chain of information is helping to expedite these discoveries.

LP: I wanted to ask, I feel like this is an important question. But how is this virus different from other infectious diseases you've studied? What have you learned about it?

RC: This virus is much different than what I normally study. I normally study filoviruses, ebolavirus, marburgvirus. And in those cases, you have up to a 90% fatality rate. 9 out of 10 people die. With the current coronavirus outbreak, the SARS-Coronavirus-2, you're seeing if you have underlying conditions and you're very old, there's maybe 10% fatality rate. Otherwise, it's 1%.

So with difference in mortality, it's something different. But the other thing is, with ebolavirus, essentially, a patient has to be very sick, throwing up on you, in order for you to get infected. So it's infectious and deadly. But it's not as transmissible as Coronavirus. Where you're able to infect other individuals, even though you don't have these outward signs of disease.

Now, you do get sick. You do get a fever. And when you have a fever, you can transmit the disease.

But unlike Ebola, if the person is not actively excreting some sort of bodily fluid on you, you're going to be OK. Whereas with coronavirus, that's why we have the six-foot rule. If you're near somebody who's coughing, there's a potential you can get infected. Now, I haven't looked at the reproductive number lately.

The next thing, the number of people that get infected from an individual, so I think when it first came out they thought it would be three people. So three. So three people for every one person infected, if there were no barriers. So no six-foot rule. No protection, three people get infected.

Whereas, the Ebola virus is essentially a one. So 1:1. So if somebody's next to you an throws up on you, you get infected. So again, the difference in transmissibllity to what I've worked with in the past is a big difference. However, having said that, this is not the most transmissible virus, coronavirus, in the world. So it could have been a lot worse, had it been more transmissible.

LP: All right. So what you're finding is it is, indeed, highly contagious. Perhaps not the most-contagious virus in the world, but definitely up there. I do want to go to Dr. Bohmann now. Jonathan, you are collaborating with Ricardo's team and contributing to this effort with a powerful software, Rhodium. So Jonathan, if you could tell us, what is Rhodium? And how does it work?
 
Kendra Alfsont dressed in white personal protective equipment Texas Biomedical Research Institute

Kendra Alfson, Ph.D. is a scientific support manager in Dr. Carrion’s lab. She’s turning on her powered air-purifying respirator (PAPR) before entering a BSL-3 lab to study SARS-CoV-2. The PAPR is required personal protective equipment (PPE) needed to study the virus.


Dr. Jonathan Bohmann (JB): Sure. Rhodium is a software program that is designed to search for new candidate therapeutics, given information about the biological structure of proteins that the virus expresses. So in its replication, some of the, if you will, machinery, is an enzyme called a protease.

The main protease is the target that I've selected first, and other people have too. But this main protease in the replication cycle chops part of a longer protein up into functional units, and those are used by the virus. And the target I have is that main protease. And the idea is to find, with Rhodium, compounds that might bind and compete with its normal function.

So what Rhodium does is it's able to take not only the main protease, but any other proteins for infectious diseases, and look over the entire surface. It can perform a virtual screen.

A virtual screen means that we can take a virtual library, represented in a computer as digital objects, I guess. The library would be composed of maybe millions of compounds that are potential inhibitors. So Rhodium checks all those combinations and determines what compounds might fit best to be inhibitors or blockers of those proteins.

What I have is computer processing power here in San Antonio to do that virtual screening. I'm also now cooperating with Walter Reed Army Institute of Research. We have a cooperative research and development agreement with them. And I've been able to access some of their computer resources to do this virtual screening. That's basically what Rhodium does. And it harnesses the processing power that's available here on our campus and also at other locations.

LP: So how long does it normally take for Rhodium to screen these millions of compounds? What is the time frame you're looking at?

JB: Oh, not very long at all. We've had some really amazing fairly recent developments in the processing speed. We do have our computer scientists on campus that have been involved in the Rhodium development for several years.

So right now, on a ordinary-sized computer that I have in my lab, we're talking about 250,000 compounds a day. So during the, well, I'll tell a little bit more of the story. The structure, the three-dimensional structure of the main protease of this virus was solved, or it was determined and published to the scientific community back in February, the first week. So by the end of February, I had five million compounds screened. And that was using resources here on campus and then off of campus.

Now, after that, we were able to take those ranked results. So Rhodium will rank the way that these compounds will fit and could be inhibitors. And then we took those, and we did, Ricardo did talk about the importance of safety. Everyone understands that.

We did take the, we'll call them hits. And we did additional screening of those hits with machine-learning algorithms that we have, to remove compounds that would represent a safety risk. So there's about 20 different toxicology endpoints that are predicted by this software. It's separate from Rhodium, but nevertheless.

What we can look at is would this be metabolic liability? Would it be a carcinogen? Would it be any number of things that would be a safety risk? So from that list of five million, we selected 60, after we screened not only by what we predicted to be their activity against the virus. But then these other safety screens that we applied after.

So, to answer your question, we had those compounds selected at the end of February. The compounds that we've selected are now in and they're undergoing preliminary safety assays. So in the lab, over in our area, on our campus.

As we complete that work, then Riccardo will be able to start analyzing those compounds. So from start to finish, that was the beginning of February. We've screened five million compounds. We're down to 60 candidates by our computer screening. Now it is just the beginning of April. So that's two months to get to where we are from the first information that was available.

LP: So when you say 60 candidates, you're saying that those are 60 drug compounds that could effectively and safely treat COVID-19. However, they do need to go through further testing?

JB: Oh, of course. Yeah, that's exactly right. We have 60 candidates. We actually had to accelerate that, like Ricardo was saying. The Walter Reed Institute for Research is starting to cooperate with us too, on another front, where as Ricardo's group advances those compounds, they've also agreed to do in vitro, so in laboratory, safety screening with other assays.

We've predicted these compounds to be safe and effective. Ricardo's lab will be able to test the efficacy. Then Walter Reed has agreed to already start assessing the safety in the laboratory. These would be cell-based assays. So we're not talking about animals yet.

But everyone's so interested in accelerating this program, that they've agreed to do those tests without having any of Ricardo's data. Normally it would be that you would evaluate the efficacy and then the safety to reduce the number of tests. But now for the sake of time, Walter Reed is providing the bandwidth to simply test the compounds for their safety so that we'll get the results at the same time with them, concurrently.

LP: You're identifying these compounds and then relaying that information to scientists in labs like Texas Biomed, like Walter Reed.

JB: Right.

LP: Then they are taking it to the next step.

JB: That's right.

LP: Are you able to communicate? Ricardo mentioned a scientific collaboration at a level never seen before. Are you able to communicate with scientists around the world? Are you keeping this on the national level, the local level? Or are you really dispersing this information globally?

JB: We're dispersing this information, right now, nationally. And it's true that as we work through, you know, the way forward with our project, that Walter Reed has reached out to provide most of the support. But there are certainly more than those 60 compounds. That was just an initial cut. There's probably several thousand more that would be interesting candidates out of that. There's certainly opportunities to share that pretty far and wide.

LP: I did want to ask you the same question that I asked Ricardo. How is this virus different from other infectious diseases that you've studied and maybe passed through Rhodium?

JB: What I can speak from is from the standpoint of searching for drugs for this virus. Actually, one of the bigger challenges, I think, from the modeling side, the predictive side, it was harder to come up with a good structural model for making predictions for drugs that target Ebola. That was quite a challenge.

The knowledge about this main protease is much more complete than it was at the time I started doing work on the Ebola inhibitors. Where not as much was known about what kinds of structural proteins would be good molecular targets for that. So from where I sit, from the work that I do, this is actually, in a sense, a little bit easier to get started. It's a little bit easier to make a hypothesis, yeah.

LP: Yeah. So the information is really flowing about this virus. And you are able to get a hold of that 3D model. That was not created at SwRI, correct?

JB: No, no, no. Ricardo, this alludes to what he was saying. The rate at which these compounds were made available, not compounds, I'm sorry. The structural information was made available so rapidly to the scientific community that it was just amazing, the rate. For that to be able to have been made public was just absolutely amazing. So we were able to utilize that information very early, like I said, in our efforts.

LP: We will have a picture of that 3D coronavirus model up on our episode page for this episode, Episode 18.

JB: Right.

LP: I want to go back to Dr. Carrion. Is this the most urgent project of your career?

RC: Most urgent, we were working, up until recently. There was an outbreak of ebolavirus. And I think all these viruses, the diseases that affect human life is urgent.

However, this seemed to be, how can I put it? This virus, because of the restrictions on movement, the closing of restaurants, makes it seem more real. In that when we work on ebolavirus it's in Africa, primarily, right?

We had a few cases during the last outbreak, of people importing it. So this one is around us, in our United States. So it just seems more real. But essentially, all the work we do, we consider it urgent. And we're working hard to come up with advanced science so that we can combat it.

But this is just in a situation where we're not able to go across the street and eat at Chili's. We're having to bring boxed lunches. And much of the Institute is empty. Only the people working on COVID-19 or these other infectious diseases are here. Again, I think it makes it more real to us.

LP: What is the tone or the feeling in your labs right now with your team?

RC: I think everybody's excited, but we're tired. To get the virus amplified so quickly, we had to do the deep sequencing, to analyze it. Essentially, individuals are working every day of the week. And now that we've started animal studies, we're used to working around the clock, so in the evenings and at 1:00 AM, to check on the animals. That's going now too.

In addition to coronavirus, we have other obligations with regard to other science that we're doing as well. So I think we're excited to be fortunate to be part of this. And we all have a role with this.

Those that aren't doing science support us, our life in other ways. Individuals listening now, by staying home when they're sick and adhering to some of the city recommendations, are helping. So I think we are the world.

But people that work at SwRI, and here at Texas Biomed, our hands are a little more involved because we're actually able to touch the virus and work with it. But without the community support, the social distancing, being able to isolate yourself if you're sick, it'd be a lot worse. So these things are helping. And we all have a role to play in combating this disease.

LP: What kind of safety precautions do you take since you are handling the virus?

RC: We use a Biosafety Level 3 precautions. So what this means is that there is a specialized lab that has airflow that's negative through the entire building. Individuals in the lab wear a respirator, which includes a face mask where their entire head is covered up. Their body's in a Tyvek suit which is a semi-porous material.

So when you look at these HAZMAT teams, those white suits they use, that's what we use. Double gloves and booties. So essentially, when they're working with the virus, none of their clothing or their body is exposed to it. So that's the type of precautions that we use.

Actually, working with the virus is very safe because we have these precautions. It's that people in hospitals, the first responders, those are the ones that are more at risk. So we have the easy part, when you talk about dealing with the disease. Individuals that work with patients that are sick, they're the ones that have it tough.

LP: When you step out of the lab, do you have a different decontamination process for going home?

RC: That is correct. All that material I mentioned to you gets discarded. So before we exit the lab, we have the surface decon of that material, the suits, the toppers, the purified air respirators that we use. Then that gets bagged up and autoclaved.

And when we work with these animals, people also, whenever they leave a space, take a physical shower. So the idea is if there is anything that is on individuals, somehow, gets washed off. What I didn't mention is that all this work is occurring under a biosafety cabinet.

So this is a work area, workspace, in which there is flow of air that prevents any type of inadvertent aerosols that are being formed when you manipulate the agent from passing out of that space. So everything's worked with what we call primary containment. So even if there was a spill, if there was, if somebody were to drop a tube and it were to splash, it's contained within this safe zone.

So the BSL-3 suits are actually our back up, our last line of defense. The precautions we use in the lab, by using this biosafety cabinet. Also when we centrifuge the samples we use what we call airtight canisters. A tube is placed within a canister. That's screwed tightly so that when you spin it, it the tube breaks, it's still contained deep within the canister. So there's all these other precautions that we're taking in addition to this suit. So it's a very safe environment to work with this agent. So it's more safe than being, again like I mentioned, in a hospital setting, where you have patients that have this disease, or that you're treating for it.

LP: All right. Highly safe environment over at Texas Biomed. Jonathan, I did want to ask you the same question. Is there a different tone or a feeling? What is the tone, the feeling in your labs right now?

JB: Oh. We are, right now, it's essential personnel working on this project are there. In terms of from where I sit, I am actually trying to stay home to be out of their way. So we have as few people that are actually in that lab. Just so they can keep working as long as possible.

Everyone is focused on processing the samples right now. I think there's a real sense of urgency about getting this work done. So it's a good thing that I'm not there, is what I'm trying to say.

LP: Yeah.

JB: It's that, we're taking it that seriously, that only essential people are working in that laboratory. And we're talking maybe two or three times a day on the status and things that we have to do to keep the project going. So yeah, everyone is very motivated to make that work happen. And obviously, our external collaborators, Ricardo and his lab, it's really amazing.

And that's what we're seeing, is all of our collaborators, people are working together and taking this very seriously. And things are moving pretty quickly. I think that the other thing is people are looking for ways to work together.

People are reaching out, to ask hey, what are you doing? And I'm able to reach out and ask people, hey, what are you guys doing in general, to various labs? Yeah, the level of collaboration, it just blows me away. It's really amazing.

LP: That collaboration.

JB: Yeah. The sense is very urgent.

LP: To close out, I do have a question for both of you. I'll start with Jonathan. Jonathan, as a scientist on the inside of this fight, you have a unique perspective. Any words of advice, encouragement, for our listeners? We are just overwhelmed by the news we are hearing every day. Our lives have completely changed almost overnight. Is there a light at the end of this tunnel?

JB: I would only say I've never seen scientists working harder and faster to solve a problem in my career. That's a reassurance there, them working together.

LP: I think that that definitely gives us all hope. And Ricardo, same question for you. Any words of advice or encouragement for our listeners in this unprecedented time?

 

A Deeper Dive

Southwest Research Institute is addressing the COVID-19 pandemic through several engineering and scientific disciplines. We are implementing measures to help mitigate the spread of COVID-19 such as directing staff to work remotely and implementing guidelines to ensure social distancing for those working at our physical locations. Our response ranges from researching emerging infectious diseases to offering solutions to mobilize manufacturing of biomedical devices and adjusting our community outreach initiatives.

Visit SwRI COVID-19 Response & Resources to learn more.

RC: I think there is hope. So as Jonathan mentioned, working together, scientists are coming up with ways to help defeat the virus, preventing it or helping those that are sick get better. And I think the other thing is that we all have a role to play.

So it's very important to stay home. Not to go out when you're sick, to isolate yourself when you do become sick, even if it's not coronavirus. It's only by doing this, do we by time, and also, help minimize the impact to those that can be really severely affected by the disease.

Many people are young and healthy, and if they get sick it would be a terrible thing. But they're likely to survive. Whereas the elderly, those with underlying diseases, co-morbidities, diabetes is one of the risks factors for a bad outcome. And we're in a city in which there are many diabetics. Hispanics are affected greatly by this complex disease.

So again, I think we ought to do our part. If you're not actually in the lab, you have other roles in supplying food for us at the grocery stores, but doing so safely that we're not transmitting the disease. Because we know that isolation, quarantine, these help to slow it. And that buys us time to hopefully minimize the total number of people that are affected by it.

LP: Yeah. Such an important message. If you are not in the lab, if you are not a health care provider, if you are not one of those essential workers our grocery workers, our truck drivers, then what you can do is stay home. What all of us can do is stay home. It's a really important message to just keep saying over and over.

Hopefully everyone abides by it and we can get through this together, and quickly. I want to thank you both for being here today. And truly, thank you isn't enough for the vital work you are both doing to save lives around the world. Your collaboration is inspiring and really gives us all hope that there is an end in sight to this pandemic. So thank you, again, to our health care workers and other essential employees taking care of us during this time of great uncertainty. And thank you both again, for joining us today.

JB: Thank you. Happy to do it.

RC: Thank you, stay safe.

All right, thank you both. And just a quick note about Texas Biomed and SwRI. We have the same founder, Tom Slick, Jr. Both organizations were established in the '40s.

While we are two separate organizations, our scientists often work together. So we wanted to focus on the coronavirus for this episode. Our segments Breakthroughs and Ask Us Anything are on hold for now. To our listeners, we appreciate you. And no matter where and how we are working, we will continue to be innovative and find ways to bring you new episodes each month.

Then we'll be back in our studio as soon as we can. Well, that wraps up this episode of Technology Today.

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Stay safe and thanks for listening.

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