S5E3: Can physics help combat COVID-19?

Numerous medical professionals, biologists and other experts have been combating COVID-19 and the havoc it has wrought since the pandemic began. Physicists have also joined the fray, including one from the University of Maine.

The invention of a new microscope allows Sam Hess, a professor of physics at UMaine, to obtain new insight into the structure of the virus that causes COVID-19 — SARS-COV-2 — and the influenza virus. These findings could help pave the way for effective treatments.

In this episode of “The Maine Question,” Hess discusses the development of this breakthrough in microscope technology and his decades-long quest to aid in the fight against these deadly diseases.


Ron Lisnet: Hello and welcome to The Maine Question podcast from the University of Maine. I’m Ron Lisnet.

So how long has it been since you sat in a physics class? What do you remember learning about physics?

For me it was junior year in high school and I remember a few things. Force equals mass times acceleration or F=MA. Also the force of gravity- things you drop accelerate at 27 feet per second per second. That’s about all that has stuck with me. I don’t remember anything about physics having the potential to help in the fight against infectious disease but that is exactly what Sam Hess, a professor of physics at UMaine is doing with his team and a breakthrough advance in microscopes he has developed.

Sam Hess: Part of what we do is use light microscopes to study viruses. And physics has allowed us to invent new kinds of microscopes that can do really amazing things.

Ron Lisnet: In this episode, Sam tells us about his high-resolution microscope and how it is being used in the battle against the Flu virus and COVID-19.

We won’t try to explain how this microscope works here. We’ll leave that to the expert in just a few minutes but with this new high-tech tool, Sam and his students can look at the actual structure of the FLU or COVID virus and they may be able to find some weaknesses that can be exploited and lead to new drugs and treatments for these devastating diseases.

Using physics to fight pandemic diseases. A promising new way to tackle one of the biggest challenges of our time.

Ron Lisnet:  Sam, thank you so much for joining us. We appreciate you taking the time.

Sam Hess:  Oh, it’s my pleasure.

Ron:  A lot of us, it’s been a long time since we sat in a physics class. I remember vaguely dealing with gravity and momentum and forces. Maybe you could tell me if I still remember anything here. I remember F equals ma.

Sam:  That’s absolutely still valid.

Ron:  It is?

Sam:  Good memory.

Ron:  P equals mv. Momentum equals mass times velocity. Is that right?

Sam:  Yes, absolutely.

Ron:  OK.

Sam:  Good. Also, very useful, still.

Ron:  That’s good. That’s what I remember from physics. You’re a physics professor, but you’re working with the flu and COVID. Can you help us understand how those fields collide?

Sam:  That’s a great question. Physics connects to so many things in the world, talks about how things move ‑‑ you were mentioning p equals mv ‑‑ about how things move around and have momentum and interact with each other and also, importantly, how things interact with light.

Part of what we do is to use light microscopes to study viruses. Physics has allowed us to invent some new kinds of microscopes that can do amazing things. I was working on influenza for about 20 years now. Then, when the coronavirus pandemic started, I realized we’d probably have to find some new ways to fight the new virus.

There were some similarities and differences that I noticed between the SARS coronavirus and the influenza virus. I thought of using our molecular microscopes to look at similarities and differences between those two. That’s how I got interested in it.

Ron:  To me, a microscope is, essentially, it’s a big old magnifying glass. It’s lenses and glass. You’ve built a high‑resolution microscope. How does the one you built work, and what can it do that maybe other more traditional microscopes can’t?

Sam:  Absolutely. A microscope is designed to make smaller objects look bigger. Light microscopes do this quite well up to a point, but for really small things, they’re limited by a process called diffraction. Diffraction comes from the wavelength nature of light.

Normally, diffraction prevents us from seeing things smaller than about 200 nanometers using a light microscope. To get around this limit, we invented a microscope method called FPALM, which breaks the diffraction limit, meaning it gets us around that limit and allows us to see much finer details with our microscopes, even in living systems.

It’s one of four techniques that were published in the mid‑2000s that were able to achieve this. This gets us the capability to image things as small as even a single molecule. In fact, we routinely image individual fluorescent molecules to make a map of how a biological structure looks.

Ron:  You have to remind us, what is a nanometer? How small is that?

Sam:  A nanometer is a billionth of a meter. A common scale for microscope things is that a human hair is about a hundred micrometers. A nanometer would be 100 thousand times smaller than that. It’s more or less the size of a carbon‑carbon bond or a small piece of a protein that’s on that scale of a single molecule or even part of a single molecule.

Ron:  Does your microscope…Can you look into it and see what you’re examining, or does it put it together in some other way that is not visual, I guess?

Sam:  It’s amazing that you can look through the microscope eyepieces, and you can see the single molecules blinking in front of your eyes, with your own eyes, which is, it’s cool. What we acquire with the microscope is a movie of those flashes of light that occur from different parts of the sample.

Then we use a computer algorithm to look at those images and find where each flash came from. That’s called localization. When we found all those locations of the molecules, then we plot them all together and make a final image out of it. There’s some of each. You can look through and see what you’re getting, but you can also have to do some analysis to get the final image.

Ron:  You get many images to create a composite. Is that how it works as well?

Sam:  Exactly. We’re taking many, many frames, 10,000 frames, 20,000 frames, from a movie of a single cell or a single area of something. Then we’re making a composite out of all of the locations of the molecules within that big stack of frames.

Now, we can even do this where we move the area that we’re looking at over and tile it to do multiple regions to make an image of something that’s too big to image all at once.

Ron:  It goes without saying, you’re crunching a lot of data, a lot of numbers.

Sam:  Yes. Many hard drives have been filled. [laughs]

Ron:  I bet. You’re looking at certainly two of the major issues that we’re dealing with in our world these days, flu and COVID. Talk to me about how you decided to dig into this work. Why is this important to you? Why spend your time on this as opposed to something else, other than the obvious that we need all hands on deck to deal with some of these issues?

Sam:  Obviously, the urgency is there. We have these two viruses that are causing a lot of trouble. The coronavirus right now is causing the most trouble. There’s great vaccines available to protect us, but the viruses also mutate with time. We’re hoping we can have some kind of a backup.

If you’re susceptible to a breakthrough infection ‑‑ breakthrough infections occur sometimes ‑‑ or if you’re not vaccinated, there’s a chance you could get sick. We want to have something to protect us even if infections happen. We’ve been looking at two of the most important proteins involved in the infection process, the spike proteins.

The spike protein from the influenza virus is called hemagglutinin, or HA, and the spike protein from the coronavirus is called S. Those spike proteins basically stick out from the surface of the virus, and they are allowing the virus to stick inside of our respiratory tract. That’s called binding. They also allow the virus to enter through a process called membrane fusion.

I have been working on the influenza spike protein for quite some time. The microscopes we have were helpful for that. Again, when the pandemic started, it seemed like maybe we could use this technology that was working against flu to also fight the coronavirus.

Ron:  When a virus mutates, obviously, that definition of that is, it’s changing. It’s turning into something else that it wasn’t. Are you basically looking at the parts of the virus that don’t change, which are some of these spike proteins that stay constant, essentially?

Sam:  Good question. Parts of those spike proteins do change. They mutate over time fairly rapidly. That’s one reason we have to revise the influenza vaccine each year. The ectodomain, the part that sticks out from the virus, is mutating.

Then that can interfere with the function of the immune system to recognize that structure as dangerous and attack it. However, there’s a portion of the spike proteins that does not change very quickly. That is what we’re going after. The tail is what it’s called. It sticks inside a virus rather than outside.

Since the immune system recognizes the outside part, the virus is gaining benefit from changing its outside parts of the spike protein. There’s no benefit to it changing the tail, which sticks inside and isn’t accessible to the immune system. That part seems to be quite invariant.

We also noticed, when we express one of these spike proteins in a cell, not the full virus but just the spike, that there were some interactions between the tail and some of the host cell components. Then we started thinking about, how could we disrupt that interaction?

That could interfere with the function of the spike protein, and that could then block the ability of the virus to bind and enter. Looking at that interaction and trying to figure out are there drugs that could break that up, that’s been a thrust of our research for a few years.

Ron:  We love analogies around these parts. Essentially, the spike protein is the key that unlocks the door to let the virus in and do its damage, right?

Sam:  Yes. It’s got two important jobs as far as starting an infection, the binding where the spike protein recognizes something on the surface of the target cell binds to that target. Then, through a series of events, the host’s cell is fooled into bringing that virus in.

That step isn’t enough to cause an infection by itself. The cell brings it into a compartment, a vesicle, that’s surrounded by membranes protecting the cell from the virus. The second step, which is called membrane fusion, is where that spike protein opens a hole between its own membrane and the host cell.

That’s what allows the genetic material of the virus to enter the cell. That leads to an infection. That membrane fusion process depends very much on getting clusters of the spike protein. For influenza, you’ve got to have a certain number of them close together to work together in order to get that hole in the membrane to open up.

We’ve been studying that process of how the clusters form, looking at how the host cell might play a role in generating those clusters, and how to disrupt that. That’s one of our interests.

Ron:  If you find what you’re looking for, a spike protein that doesn’t change much in that you can attack this problem, how does that get developed and become a potential solution or a potential way to battle this virus?

Sam:  If we’re able to find some type of a drug that disrupts the interaction, obviously, you can’t just start taking that immediately. One of my collaborators works on toxicology. Let’s suppose we find a new class of drugs that blocks this interaction between the spike protein and the host cell, disrupts those clusters of the spike proteins, and stops the virus from entering.

This could be discovered in a dish with cells. We might test in similar compounds to see if they also work. The steps toward making this available for people would then involve getting that work published, showing that this is able to work in a wide variety of situations, that it’s not too toxic to the cells.

One of the ways we can test toxicity is with an animal that people use at the university called the zebrafish. It’s a small fish that has some ability to model human disease and is also a great way to test whether drugs work in a living organism. We’re able to see inside of these zebrafish with our microscopes while the zebrafish is alive. That’s a very useful way to test this stuff.

Then, we would publish that work showing this class of drugs seems to be effective and it’s working in animals. The hope would be then that further work would test whether it’s safe for people to use, how effective it is, and I could have mentioned, to be on the shelf as an option to tech people to get a say.

Ron:  This would be a drug to treat the disease as opposed to a vaccine which boosts the immune system and lets the person fight it off?

Sam:  Exactly. The way viruses are mutating and the way sometimes you get breakthrough infections, having a backup to help when an infection does occur, as far as we to try to stop them from occurring, having something to help just in case, is a real urgent need right now.

Ron:  It seems like a lot of different disciplines are coming together here. Your background is physics. There’s biology. There’s chemistry. There’s medicine. All of those disciplines involved here, is this something we’re going to see more of, this merging of different disciplines to attack these complex problems?

Sam:  Absolutely. Multidisciplinary research is crucial for tackling this very complex mechanisms of infection. These viruses are quite sneaky. They have redundant mechanisms. You figure out a way to break something and stop it in one way, it adapts to sneak around and infect in a different way. They’re constantly changing.

We’ve got to pull from physics, chemistry, biology, computer science, engineering, including virology, to make progress in this project. I have to say I’m very lucky to have a great team of people that I can work with at UMaine in virology, in chemistry, in engineering, and NIH as well as, computer science, biophysics, and virology.

It’s crucial because we don’t all think in the same ways. I might, as a physicist, think about attacking a problem in a certain way. On the other hand, a virologist would say, “We need to try this and control for this possibility.” We’ve also started doing modeling of molecules using computers. That’s something that’s happened since the start of the pandemic for us.

We have a collaborator who I’ve never met in person. We’ve been working with him successfully for over a year on a totally new direction. That’s now giving us insights at even smaller lens scales in our microscope image. Having this great team has been incredibly helpful.

Ron:  We’ve spoken with Melissa McGinnis before, who I know you know. She’s a virologist. One thing she told us about viruses, maybe this is a misconception that’s out there in the public, a virus is not a living thing. It’s basically a vessel for its DNA to replicate. It’s not like a bacteria, right?

Sam:  That’s correct. It’s basically some genetic material and wrapped in either proteins, membranes, or both in this little package. It’s just unlocking all the capabilities, hijacking all the capabilities of the host cell to make more copies of itself. It’s amazing how much trouble a 100‑nanometer sphere with a little genetic material in it can cause on this whole planet.

Ron:  How many students do you have involved? I imagine a lot of students in this field are drawn to this work because it is so crucial. So much work needs to be done to battle this.

Sam:  I currently have four graduate students. I’ve had three former students graduate quite recently. Many of them have taken this fight against the virus to heart. They’ve had family members be affected. They’ve had loss. They’ve had their own lives disrupted.

I’ve been very impressed with how my own students, coming from physics background, have adapted to learn all this biology they need to learn to be able to do the work we do, how hard they’ve worked through all the changes and disruptions. I’m very lucky to have the students that I have.

Ron:  This microscope, is this something that you created from scratch, or is this building on some other concepts that are out there? Is this a new breakthrough in microscope technology, basically?

Sam:  This invention was a breakthrough in 2005, published in 2006. It’s a funny story. I was trying to sleep one night. There was a raging party next door to me. I had my ear plugs in and my pillows over my ears and the air conditioner turned up. I could not sleep.

While I was lying there, it occurred to me that there might be a way to use almost like programming of the molecules to get around this diffraction limit. I’ve been talking with colleagues about how we could break it and how we could use it to look at influenza.

Then this idea came into my head for a way to do it, which I thought, “It’s the middle of night. Maybe it’s one of these things that you’re going to laugh at in the morning.” I went downstairs and wrote it down and went back, finally did get to sleep. Came down in the morning and looked at it and I couldn’t find any problem with it.

Then I thought, “Surely, this has been done.” It’s taking a normal fluorescence microscope, but it’s changing the kinds of labels that we use, the kinds of molecules we use to visualize what’s there. I thought, “Surely, somebody has done this before, or there’s some mistake.”

Then I went in to campus and talked to some colleagues. I said, “Please save me the embarrassment. Tell me what’s wrong with or tell me who’s done it.” Nobody could do that. I started to think, “Maybe I better get a move on and try this out.” I started ordering things and got the pieces together.

What’s different is the markers you’re using, the labels that you’re using to attach to the molecules. They are not all visible at the same time. They’re only visible in small numbers at a time. You’re using lasers to control how many are visible until you look at the ones that are visible.

You’re using a very sensitive camera to map those very faint flashes of light. It’s using a conventional microscope. In a way, it’s amazing that this didn’t get invented 20 years ago. The technology to do it was there. It’s just a matter of thinking in this weird way of approaching it. That allowed us to start doing new things.

Ron:  Maybe you should move back into that apartment. It might spark some other idea.

Sam:  [laughs]

Ron:  Using this approach, using this microscope, this tool, what other kinds of issues do you want to explore? Do you think it’ll be a key to battling other diseases or other problems?

Sam:  That’s a great question. We are working on some other health problems. I have a collaborator who’s looking at muscular dystrophy together with us. We’ve also been looking at toxicology of compounds that are used in everyday products. Those sometimes affect the mitochondria, which are the energy producers of the cells.

As far as the whole field goes, there are probably thousands of different biological applications happening now. A Nobel Prize was awarded in 2014 relating to this invention. There are other groups that invented similar methods. That’s led to an explosion of activity in this area.

It’s a great thing to see new insights and progress on health problems happening because of this technology.

Ron:  What’s next? What do you think we’ll see in 5 to 10 years? Is a bigger, a more power microscope on the horizon or breakthroughs, potential to come up with, you can’t predict the future obviously, but some drug might be the result to this that is effective against COVID or other diseases?

Sam:  You’re right, Ron. It is hard to predict the future. There’s many reasons to be hopeful. The number of people working in this area…It’s giving us, maybe a factor of 20, better detail than we could have seen before. There have been discoveries already as a result.

I see this going towards smaller and smaller lens scales, better and better resolution. With all these people working in the area, things have been improving. It’s possible we’ll get to a place where we can look inside molecules, not just where they are located, but actually how the different parts are moving. That could lead to some great insights.

I mentioned the idea of using a computer to simulate the structure of a molecule. There’s great potential for those two things to tie together where the simulation can look at certain details that we might not be able to reach directly with a microscope, but that we can test with a microscope.

Those are growing together like trees that were planted separately, but their branches are getting more intertwined. I think that’s going to continue in the future. I’ve had this philosophy of going after a biological question and trying to invent the technology that I need to answer that question.

Sometimes, that works out when we get an answer. That answer leads to new biological questions which then leads to new needs. I’ve been trying to keep the technology and the biology walking together and helping each other. That’s something I may continue to do. I think other labs are doing that too.

Finally, I would say, as we build on the technology we have, automating that technology has become more and more important. That’s something we’ve been working very actively on, to make it so that our microscope can drive itself and recognize from images whether this is something interesting or not and take more data.

That allows us to do things that are even more complex, but still using the same‑sized team. In the long run, I am quite hopeful that we’re going to be able to find some drugs, find some treatments, and maybe even find some cures for these infectious diseases that are causing us trouble right now.

Ron:  I know I speak for many when I say we wish you much success in the future. We thank you so much for sharing the story with us.

Sam:  Thank you very much. It’s been my pleasure. I hope we can talk again soon.

Ron:  Great. I will turn it over to Margaret who I’m sure has some questions as well. You’re muted.

Margaret Nagle:  Of course, I am. I just wanted to check your lipreading skills, both of you. Ron got it. He’s seen that from me too many times. Sam, game for a couple more questions? I like your office. That’s the background. That’s the look you should have gone for. Is that your office or home?

Sam:  This is my home office.

Margaret:  I like it. On that note, we need a photo of you either in your home office, in your lab, or whatever. We’ve got your students’. Let me know if that’s possible. If you’d rather do it outside, not indoors, I’m OK with that too.

I’m going to move through some things quickly. I’m not going to take too much of your time. I’m going to take the content that Ron’s interview yielded and then a couple more answers here. I’m going to draft and send to you. We may have to talk one more time quickly. You should be able to answer anything that I’ve missed in the draft of the story.

I want to go to your students really quick. Tell me about the kinds of questions they’re pursuing in your lab. How are your students dovetailed into your research?

Sam:  My students are an absolutely crucial part of this work. They spend the vast majority of the time doing experiments. They are typically coming from a physics background. Sometimes, they’re coming from the GSBSE. They would start learning about viruses and membranes. Also, start learning about microscopes and fluorescence.

If they’re more on the physics side, they would maybe choose things that have some methods development, trying a new tweak to the microscope, or adding a new component to get a new kind of information.

Then, they would also apply that to test a question about how the viruses work. Students with a more biological background to begin with might jump purely into biological questions and learn to use the microscopes. Then, go after the things that are most interesting biologically.

Margaret:  Give me a couple of examples, not necessarily corporate names, but students who’ve gone on from a lab to do what, or pursue what, or where they’re in industry, they’re in medical labs, just in general.

Sam:  There’s a fair variety. There are a few that have gone into postdoc positions such as Cornell medical school, National Institutes of Health. I’ve had some go on to work with companies. We’ve made some patents around this technology. A company has licensed those patents and is making super‑resolution microscopes. One of my former postdocs worked as a scientist there.

Margaret:  That’s good. That gives me a sense of the breadth. That works. I want to take you back a little bit. Tell me why physics. Tell me how your dad influenced you, dad and your mom, actually. I think…Anyway, go ahead.

Sam:  That’s a good question. I kept an open mind about what I wanted to do. When I was in high school, when we were taking some standardized tests that predicted I would do a certain thing, I wasn’t sure I agreed with that. I wanted to choose a discipline that would leave doors open in the future so that once I had grown up, I could finally figure out what I wanted to do.

I just have had the philosophy of sticking with the things that were fun. Then, telling myself I would switch to something different if it wasn’t fun anymore. Physics ended up being very flexible and a lot of fun. I stayed with it. I did do an undergraduate major in physics.

Again, during that time, I thought maybe I’d like to do engineering, maybe I’d go into bio‑related things at the end, maybe something aeronautical, maybe something astrophysics. I made some of my decisions based on the people I met. Certainly, my dad being a physicist had a big influence. I loved, I got to play with electronics, oscilloscopes, and things as a kid.

That certainly opened my mind to those things. I also saw that my dad as a physicist loved his job, but was still able to be a good parent. That to me was a good data point about that kind of a career, especially at UMaine.

As I met people in college and graduate school, I decided in some cases that I was going to do work in a particular area because I felt I had a connection with the people that I [inaudible 32:04] finding out with these people for a few years.

Having a good relationship is also important. It’s a balance between interest in the things I could do and also in the people that I met. Maybe I’ve been lucky to meet lots of good people.

Margaret:  Going on quickly, your mom has an interest in science fiction?

Sam:  She’s written a science fiction novel.

Margaret:  She talked to me about it once.

Sam:  She’s a neuropsychologist. There was some biological influence there, I suppose.

Margaret:  Agree. On that same note, tell me about the value of invention and always thinking about what’s possible. You and Ron just talked about and I’ve heard that scenario in which you described your breakthrough thought, I’m constantly reminded in my interviews with you through the years, always thinking about what’s possible.

Again, I know your dad. He’s one of those thinkers too. Tell me about the value of thinking about invention or knowing that something else is possible all the time.

Sam:  I feel so lucky to have been able to see examples of people who invented things. My grad school adviser, Watt Webb, at Cornell was a big influence in that kind of thinking. He invented more than 10 different microscope methods and spectroscopy methods. It’s unbelievable if you look at his publication record.

There was this culture in his group of inventing new ways of doing things. I got to see other people in the middle of that creative process hashing out, “Could we do it this way? What about this way?” Somebody sitting in the corner of the room, not even part of the discussion, chiming in, “You guys should try this,” or, “You guys should use this system to test it.”

That then leading to something that worked out, was a new thing, and was published was eyeopening to me. It’s not magic, even though, infact I think of it sometimes as magic. Looking back, this was something that was totally unconceivable 20 years ago.

Breaking that glass case around the idea of inventing something being inaccessible or too hard, you have to be some kind of a person to do that, and seeing people doing it, and it was successful, gave me inspiration.

Then, having this microscope invention, when I first thought of the idea, and I started telling colleagues about it, and they, a lot of times, were quite encouraging, but students couldn’t believe it. I would tell the students about it, it was too amazing to be true. It was like, “How can this really work?”

A lot of that early stuff was done…Mike Mason and I, both professors, and Mike, I think, had seen that kind of thing happen. He’s definitely an inventor. Us building this thing together and getting some of the data, and with the data, we could convince other people even more effectively.

In a way, I wasn’t convinced either about it. It took a while to start to believe it. Other people believed it. Other groups published it about the same time.

Then, it started to sink in, “You know what? This is really worse.” It’s like, “Wow. How lucky that I could see that process.” It changed how I think about invention.

Now, I tell my students, “Be careful. Take good notes. Write things in pen in your notebook with dates because we’ve invented things here. You’re going to see how this works. You’re going to come up with good ideas. You can do it too.” Seeing it once made all the difference.

Margaret:  Very cool.

Sam:  Is that what you were asking? I’m not sure if I answered your question.

Margaret:  Perfect. I know I’m taking up too much of your time. Why the flu 20 years ago? It could have been anything. Why the flu?

Sam:  Great question. Interest in infectious disease was not on my mind when I looking for what to do next. It was when I was making the transition from grad student, very physicsy PhD work to the next step. I knew I wanted to do something biological.

I met this guy, Joshua Zimmerberg, who was a group leader at NIH. We just hit it off. He invited me to his lab at NIH. It was at his lab where I awoke to the idea. They were working on HIV, they were working on dengue, they were working on malaria, and they’re working on influenza. It was during a visit and in his lab where I did my postdoc that I realized we have not defeated infectious disease.

It seems like it. We took antibiotics. They seem to be super powerful. We say, “Yeah, these viruses…” We’re dismissive of it or I was anyway. Seeing all this work, it was like, “You know what? This is something we need to figure out. We’re not done with this.”

Even more reinforcing that idea was the first SARS pandemic which happened while I was a postdoc in Dr. Zimmerberg’s lab. I remember the scientist from Hong Kong flying, having gotten off a flight, coming directly at NIH, and coming in to this boardroom ‑‑ it was packed, small boardroom with like 120 people in it ‑‑ telling us what was going on.

It was before it had hit the mainstream media. That briefing made a big impression on me that these things are not something we just read about in textbooks from 1918. This is going on now. These viruses are evolving now. We need to be prepared.

Dr. Zimmerberg had a great team working on influenza. I actually did work on malaria also, but influenza work was well‑suited to my physics background because the idea of clustering was central to the virus life cycle.

The clustering is something that physicists can think about with mathematics, measuring clusters in different ways and how they’re changing. That was a natural affinity, I guess. Not to mention, the health effects of it worldwide.

Margaret:  Hold on. Are you still working, collaborating in his lab? Who are you working with at NIH now?

Sam:  I still have a friendship with him. I still have a collaboration with him for almost 20 years now. He’s led me. He loves building relationships between scientists. He’s introduced me to many other scientists. This molecular dynamics with computer simulation direction was directly as a result of Josh’s desire to put me together with another expert there. It’s Dr. Alex Sodt, who’s in the same part of NIH but has his own lab.

Margaret:  Here, you’re working with virologists, chemists, engineers. Tell me who your top leads are. Are you still working with Mike?

Sam:  Yes. I still work with Mike a bit. I would say Melissa McGinnis is a amazing collaborator, a great pleasure to work with. They are very complementary expertise, I would say and Dr. Julie Gosse is a collaborator on the toxicology aspects of the work. I’ve been talking with Dr. Karissa Tilbury a bit. Clarissa Henry is my collaborator in muscular dystrophy.

Margaret:  You saw the first SARS pandemic, which answers my question about COVID now that led you to pivot. You saw one pandemic. That obviously was foundation for coming into this and pivoting from or using your foundation in flu research to look at COVID now, right?

Sam:  Yeah, to some extent. I have to admit I didn’t jump into COVID research at that time when I saw the first the pandemic. I was already working on flu. I continued in flu. I didn’t start on coronaviruses until I saw this pandemic coming. I wish I were further ahead. The connections, there are some parallels between flu and COVID.

Margaret:  That’s where I was going to take you now. Then, I’m going to let you go. Your research in flu molecules, the spike seeding with flu, describe how far you’ve come in that research and how it was a springboard for studying COVID now.

20 years of flu research, if I got you to talk about not so much breakthroughs, but benchmarks in that flu research, how did that a springboard for how you pivoted that last year?

Sam:  It took me quite a while to get familiar with the language of the new field when it was new to me, let’s say about a year of studying, reading, trying to understand the questions, and understand the terminology. Then, doing some electron microscopy of flu‑related, like the spike protein from flu or other, components.

That showed me that we needed to be able to look at fine details. We couldn’t do it in live cells at that point. Then, I started trying some of the methods I learned as a grad student with fluorescence. Those could look at living things, but they didn’t have the resolution we needed.

That, when I came to UMaine, motivated the need for a better resolution microscope. Being able to do that allowed us to have it both ways of getting the resolution and looking at living systems. Which then made us wonder, we could see the clusters, why are those clusters there?

Unbelievably to me, these clusters are crucial for the infection process. Yet, nobody knows why they arise. There were some theories at that time when I first came to UMaine about why clusters of viral proteins occur. Our data showed those theories to be wrong, which didn’t make me very popular. It did lead us to ask new kinds of questions rather than being what the old gapers were saying. Could it be something to do with actin cytoskeleton?

That was a new direction for me. The actin cytoskeleton is a structural framework that supports the motion and the changes of shape of cells, but is also connected very closely with membranes where the viral proteins go. That became a new area that I had to learn. We started to see these connections with a microscope.

Again, looking at why that would happen, there was no direct link. There was no way that we could understand for those two to be connected directly, only indirectly. Then, we started looking, what could be the indirect link? That’s when we started going to this area of phosphoinositides, which is something totally different that I hadn’t studied. I had to learn it.

That’s what we’re on right now. We’ve confirmed that served as an intermediate. It’s needed us to develop a multicolor version of a microscope and the ability to do better types of imaging to test these questions. That feature that the phosphoinositide can interact with is the tail I was mentioning, the tail of the flu spike protein.

Does coronavirus have something similar? Yes. It has a tail. A tail has some of the same features that the flu spike tail has that a coronavirus tail has and even more strongly. It’s like, “Let’s take a look. Nobody’s looking at the tail.”

[background conversations]

Margaret:  I’ll be right with you. Sorry, Sam. Go ahead.

Sam:  No problem. People overlook this tail. It’s small. It’s inside the cell. It doesn’t seem to have any role in the lock and key mechanism of entry, but it’s always there. In 17,000 different sequences of flu virus, they all had this theme.

Viruses mutate. If something is unimportant, it’s not going to last like that through every single sequence. I thought there might be something important about that. The same features are there in the SARS coronavirus spike. That’s to me very interesting.

Margaret:  How close are you publishing on that?

Sam:  I wish we were closer. We have work on flu that’s quite close. We have a possible paper that’s talking about a possible drug, not confirming that people should take this drug, but confirming that it does help animals survive flu and why.

The why was not known. There have been some studies of this drug, which is called CPC or cetylpyridinium chloride, that showed CPC help mice survive an influenza infection. We have data that shows that it helps zebrafish survive an influenza infection.

We have molecular details about why it helps. It’s because it’s disrupting these clusters of the spike protein. That’s about to be submitted. That’s together with Julie Gosse, Ben King, and a bunch of great graduate students, a big team, and also NIH.

Margaret:  Are you first author?

Sam:  I’m last author.

Margaret:  Grad student first author?

Sam:  Grad students and undergrads are first.

Margaret:  Good. That means it’s their story. I love it. This is so terrific. I’m not going to speak for Ron. I’m going to speak for Ron. We’re both huge fans. I can’t thank you enough for your time always through the years. This continues to be a great story. I appreciate your time and sharing it with us.

Ron is going to do his magical podcast. I’m going to draft a piece. I know I need to write for the engineering magazine first. Then, I may go a little beyond that. I’ll keep you posted on every draft that I do. I’ll get a first draft to you of that story. OK?

Sam:  Wonderful.

Margaret:  Ron, anything else? Ron, thank you for your patience in hanging on and recording the last part of this. I appreciate it.

Ron:  This helps me too. I have one question. Is it called a super‑resolution microscope? Is that what it’s called?

Sam:  Yes. That’s because it’s going beyond what the resolution would have normally been.

Margaret:  Was it to infinity and beyond though? I just have to ask.

Sam:  [laughs] I don’t think it goes to infinity. We’re currently at maybe 10 or 20 nanometers. The lower, the better. Hopefully, we’ll get down to one.

Ron:  The next one will be the super‑duper‑resolution microscope.

Sam:  That’s right. We’ll have to figure out the right acronym, right adjectives.

Ron:  The one‑sentence description of what it is versus a regular magnifying microscope is what?

Sam:  Say that again.

Ron:  How would you describe in one sentence how it does what it does? It looks are really small things with cameras?

Sam:  It’s a great question, Ron.

Ron:  Can’t answer in one sentence?

Sam:  It’s hard to figure out how to summarize this in a short way. You could say that it looks at individual molecules. It maps individual molecules in order to create an image, instead of looking at a sample where all the molecules are there at once.

Margaret:  Does it take various sides of it? I know you were talking about the molecules lighting up. Does the illumination give you access or a view of different sides, parts of the molecule?

Sam:  In the standard version, no. The light is actually steady. The molecules are doing random transitions, random blinking on and off. It’s that either light‑controlled or random blinking that allows us to look at just a few at a time. They come on randomly. They light up. We look at them. They disappear, another few come on.

They are all doing their own thing independently. Because they’re not all visible at the same time, we’re able to see the individual molecules.

Margaret:  Listeners and readers will say…

Sam:  No. Go ahead.

Margaret:  Listeners and readers will say molecules light up?

Sam:  These particular molecules are fluorescent. They’re even customized for our use in that they respond to different colors of light in different ways. That’s the programming part. We use one color to turn them on. We only use a little bit of that light so only a few turn on.

You use a second color to highlight the ones that are on until they burn out. Then, you use the first color again to turn on just a few and use the second color again. It goes around and around like that.

Ron:  That happens naturally or you’re doing something to it to make them light up?

Sam:  Based on another Nobel Prize discovery of the green fluorescent protein, which is a protein from a jellyfish, which turns out responds to light and is a wonderful optical highlighter for proteins, you can tack it on to almost any protein. You can then see where that protein is. Otherwise, proteins themselves are invisible to a light microscope.

It’s that special highlighter protein. Then, customizing it so that it only turns on with one color and is very bright when illuminated with this other color. That’s something that other researchers have done and published. We’re using that specialized version of this jellyfish protein.

Ron:  Got it, I think. If I get confused, I’m just going to ask Margaret to explain it to me.

Margaret:  I’m going to try to write that. Then, Sam’s going to correct it and make it beautiful. Thank you. I really appreciate your time, Sam, Ron too.

Sam:  My pleasure.

Ron:  All right.

Margaret:  We’ll talk again. I’ll go after you, Sam.