Science Friday - Milky Way Gas, COVID Ventilation, Immunotherapy And The Microbiome. August 28, 2020, Part 2

Episode Date: August 28, 2020

Recently, a group of scientists studying the Milky Way through the world’s largest ground-based radio telescope identified something they had never seen—a cold, dense gas that had been ejected at high speed from the galaxy’s center. The mystery of this gas—what caused it, how it could move so fast, and where it will end up—prompted research by Enrico Di Teodoro, a scientist in the department of astrophysics at Johns Hopkins University. He joined Science Friday producer Katie Feather to talk about the new discovery, as well as answer some fundamental questions about what is happening at the center of our galaxy. Plus, this year, back-to-school season comes with some major challenges to keeping students and teachers safe. Recently, New York City Mayor Bill DeBlasio announced a plan to give K-12 classes the option to move outdoors; the idea is that an open space, with a fresh breeze, lessens the chance of spreading the coronavirus. We’ve been brain-storming, too: What if you could bring the benefits of the outdoors inside, by creating better ventilation in the classrooms, akin to outside winds? What would it take to re-design or modify a typical classroom—not to mention your office building or home? Most modern buildings ventilate space with 80% recycled indoor air, and 20% of fresh outdoor air, to save on energy costs. But Shelly Miller, professor of mechanical engineering at University of Colorado, Boulder says, “In a pandemic, we don’t care about energy efficiency.” Miller explains that to lower the risk of infection, ideally indoor spaces would be ventilated with 100% outdoor air—but most building HVAC systems aren’t strong enough to handle that. Miller joins Jose-Luis Jimenez, professor in the department of chemistry and biochemistry at University of Colorado, Boulder to discuss what we know about the coronavirus, and our indoor air space and how we could build safer, healthier indoor spaces for the future. And cancer immunotherapy, especially a type known as checkpoint inhibitors, has given new hope to many people with cancer. The treatment takes the brakes off the body’s own immune system, allowing it to attack tumor cells. But some people respond to the therapy, while others don’t—and it’s not entirely clear why. In recent years, researchers have been looking into the microbiome—the collection of microorganisms that live in and on your body—for clues. Studies have found that there’s a microbial difference between people who respond to immunotherapy, and those who don’t. Research recently published in the academic journal Science, suggests scientists may have finally unraveled how one of those bacteria has an effect. The researchers discovered that Bifidobacterium pseudolongum, a species of bacteria found in elevated levels in the tumors of mice who responded well to immunotherapy, produces a small molecule called inosine—and that under the right conditions, inosine can help to turn on the immune T cells needed to attack a cancerous tumor. Kathy McCoy, one of the authors of the study, and the director of the IMC Germ-Free Program at the University of Calgary, joins Ira to talk about the study, and the challenges of raising mice without any microbiome at all.     Subscribe to this podcast. Plus, to stay updated on all things science, sign up for Science Friday's newsletters.

This is Science Friday. I'm Ira Flato. Later in the hour, we'll hear how indoor ventilation is impacting the spread of COVID-19, and why hardly anyone is talking about it. And we'll talk to a researcher studying connections between the microbiome and cancer immunotherapy. But first, the Milky Way. It's a swirling galaxy of billions of stars, including our own. But what is going on far away from our little celestial neighborhood at the center of the galaxy? With help from the world's largest ground-based radio telescope,

scientists recently looked there and uncovered something strange. Science Friday producer Katie Feather has more. When I first heard the news, researchers had discovered mysterious clouds of dense gas at the center of our galaxy, I realized that I don't know where the center of our galaxy actually is. Do you? So we asked Dr. Enrico D. Teodoro, one of the scientists behind this discovery, to help us answer some fundamental questions about what is happening at the center of our own Milky Way. Dr. Enrico DiTiodoro is a researcher in astrophysics at Johns Hopkins University.

Dr. D. Teodoro, welcome to Science Friday. Thank you very much for every movie. So the first question I have is actually a deceptively simple one. Where is the center of our galaxy located? Yeah, that's actually a very good question. Because as you probably know, our son and ourselves, we love. live in a spiral galaxy that we call the Milky Way. And you can imagine our galaxy as a thin rotating disk,

hosting several hundred billions of stars and lots of gas, mostly hydrogen gas. And our sun is located quite far away from the center of this disk, because we are at a distance of about 27,000 light years from it, which means that light takes 27,000 years to travel from the galactic center to us. And this also implies that when we look at the center of our galaxy, we are looking at events that happened 27,000 years ago.

And if you want to see the center of our galaxy at night, you should look in the direction of the Sagittarius constellation. And if it is dark enough, you will notice a clear patch of diffuse light. And that's exactly the center of our Milky Way. Oh, wow. So you can actually see it from outside at night if it's dark enough. Exactly, yes. What does a clear patch of diffused light look like? Like what exactly am I looking for?

I mean, when you look at the night sky, you see all the single stars. But there is also what we call the Milky Way. I mean, and it's like a diffuse emission. So diffuse light that goes across the sky. And the most luminous part of this diffuse emission is the center of our galaxy. Okay, so that's what it looks like if we were standing outside at night looking up at the sky. But if we could travel to this spot, the center of our galaxy, what would you actually see there? Yeah, I mean, the galactic center is like the downtown of our galaxy.

So there are a lot of very interesting things happening there. So first of all, the galactic center is a very crowded place in terms of stars. So there are millions of stars all packed together in a very small volume. And the night sky for an empathetic in the galactic center would be absolutely spectacular, because there would be million stars very bright with brightness greater than the brightest stars in our sky, which is serious. And this also means that you could easily read a newspaper at midnight just relying on the starlight alone. So it's a very different environment from where we are. And beside the stars, the galactic center is just relying on the starlight alone.

The Galactic Center is also interesting because there is a super massive black hole, which is four million times more massive than our sun. However, it's also very dangerous because all these stars are very young and very massive, and they can easily explode as supernovae, and they can release a lot of energy. And the black hole as well can release a huge amount of energy when the matter falls onto it. So you recently used a ground waste telescope to look at the center of our galaxy and you noticed this weird type of gas emitting from it. What was strange about it? What caught your eye?

So basically all this energy, it's like a huge bomb that creates a shockwave that blast away everything and in particular gas, which is light and easy to move around. And this gas can be even pushed out the galaxy and escape if the shock wave is strong enough. So this is what we call a galactic wind, okay? And for analogy with winds here on Earth. But this wind, a particular wind, moves with velocities of a few million miles per hour, so it's very fast, and it extends for several 10,000 light years. So yes, as you said, for this particular study, we used a telescope in the mountains

of Chile in South America. This is called Apex, and this particular telescope can see microwave light. But this light is coming from the coldest place in the universe. In particular, we have observed carbon monoxide gas, which is very abundant in the universe. And this gas looks exactly like the clouds that we see here on Earth. So I'm mixed in with this hot galactic wind that we already knew about, you've now discovered these clouds of colder gas. What does that mean? What are you expecting is happening there? Yeah, exactly.

As you said, this galactic wind is very hot plasma gas. And I'm talking about temperatures of millions degrees. And this is what we call the Fermi bubbles, which are exactly that. There are two enormous bubbles filled with fast-moving hot gas. But now we have discovered that within these hot bubbles, there are a bunch of cloudlets of cold and dense gas with temperature of minus 400 Fahrenheit. And these clouds are floating around and moving with a hot flow. So this is what we call molecular gas, because it's the only gas cold enough to contain complex molecules.

And the existence of these cold gas islands within the hot gas ocean was very surprising and puzzling because it is like to see ice cubes floating in a volcano lava. You wouldn't expect them to last very long time without melting, you know. And also another very puzzling aspect is how those dense gas clouds go there. Because hot gas is light and very easy to push, but cold gas is not. It is very heavy. And it is like if you blow on a bowling ball and you try to make it move. So we think that the energy released by our galaxy is not enough to easily push this dense gas out.

Therefore, we do not know yet how this happened. This is a second mystery that we are still trying to actually investigate with new observation. Do we know how long this gas has been there? Well, we don't know exactly for how long this wind in the center of our galaxy has been active, but we think it's at least 10 million years, probably much more. And of course, the condition of the center of the galaxy can change with time. and the black coal can become more or less active, the star formation can be more or less intense.

Therefore, we expect that the strength of this galactic queen also can change with that. So why do we think this gas is there? I mean, what's it doing there? What's it used for? Okay, this gas is outflow from our galaxy, so it's just being pushed out. But what is very important about this discovery is that this gas may have a strong, impact on the future of our galaxy. That's because the cold and dense gas that we

have observed out flowing from the Milky Way Center is the same kind of material that galaxies use to form stars. And if a significant amount of this gas is lost because it's driven out with this wind, like our data suggests, you can imagine that at some point our galaxy will run out of the fuel that it needs to assemble new stars. And it is like, when gas is leaking from the fuel tank and there is no replenishment of gas, at some point we finish it and we stop it. And if the Milky Way stops its star formation, well, this could have very important consequences for the future of our galaxy because the life of a galaxy that actively forms stars is very

different from the life of a galaxy that doesn't form stars anymore. But anyway, this is not going to be a problem for us human beings because this transformation of the nitty way will not happen earlier than several tens million years. Wow. So this is, so the center of our galaxy is like a fuel tank leaking this star-forming gas that it needs to form more stars. When it's leaking this gas, where is that gas actually going? Is it getting blown away out into the galaxy? Or is it affecting other things in our galaxy? Yeah, the fate of the gas in this wind depends on how strong the wind actually is. So if this wind is strong enough, all these gas will be just pushed out of our galaxy and just escape,

and it will go in the space in between galaxies, just hanging out there. But if the wind is not strong enough, then at some point the outflowing gas will lose its momentum, and because of the gravity of our galaxy, it will fall back onto the galactic disk, and it will be recycled again to form new stars. So it's kind of a cycle. And we think that in the Milky Way, the current wind may be strong enough to blow away this gas, but we are not 100%. Are there other galaxies we know about that have stopped making stars that we can kind of study

to see where we're headed in about 10 million years or so? Yes, there are many galaxies in the universe, actually, that do not form stars anymore. And astronomers broadly classify galaxies in two categories. So on the one side, we have galaxies like Milky Way, which have active star formation, a lot of gas, young blue stars, and these galaxies look like flat rotating disks. But on the other side, there are galaxies that have stopped the star formation a long time ago, and these galaxies are more spherical, they do not rotate, they do not have gas, and they are just made up of old red-looking stars. So these galaxies are kind of dead, and we think that they represent a late stage in the evolution of a galaxy. So the Milky Way may actually be in a transitional phase between these two stages, because it is still a disk forming stars, but its star formation is declining with time. Well, I'm sort of glad that we don't have to worry about this for another 10 million years, but I hope that you are able to solve these mysteries of the dense, cold.

gas at the center of our galaxy soon. Thank you so much for joining us to talk about this. Thank you very much to you for having me. Dr. Enrico D. Teodorro is a researcher in astrophysics at Johns Hopkins University. Science Friday producer Katie Feather. We're going to take a break and when we come back, thousands of kids across the country are headed back to school and back indoors. How can we make indoors more like the outdoors to help keep the virus from spreading? Some answers after the break. Stay with us. This is Science Friday. I'm Ira Flato. It's back to school season, and of course this year, that comes with some major challenges

to keeping students and teachers safe. This week, Mayor Bill de Blasio of New York announced a plan to let K-12 classes be held outdoors, the idea being that an open space with a fresh breeze lessens the chance of spreading the coronavirus. We've been thinking, what if you could bring the benefits of the outdoors inside by creating ventilation in the classrooms akin to the wind outside? What would it take to design or modify a typical classroom, not to mention your office building or your home? Here to tell us what we need to know about the coronavirus and our indoor airspace

is Dr. Shelley Miller, Professor of Mechanical Engineering at the University of Colorado and Boulder, and Dr. Jose Luis Jimenez, professor in the Department of Chemistry and biochemistry at the University of Colorado in Boulder. Welcome both of you to Science Friday. Thanks for having me. Let me begin with you, Dr. Jimenez. What have we learned over the last five or six months

about how the virus is spreading throughout the air? Well, as you probably know, it's a controversial issue. We have been told by the CDC and the WHO that the virus primarily is transferred through touching contaminated surfaces or touching other people and then touching our eyes or our nose, or by these large droplets that come out of people when they talk or the cough or sneeze and then they may impact us on the eyes, the nostrils or the mouth. And then there's this other way which we call through the air or through aerosols

in which smaller particles that come out at the same time when we talk, but they stay floating on the air and then we may inhale them when we breathe and that can make people sick. The importance of this third route has been controversial, but we think that the evidence is increasing and increasing that it is important. Dr. Billa, what are we talking about when we say ventilation? Is there an exact term for that phrase? It generally means bringing outside air indoors to dilute the air that's inside, that's been occupied and possibly contaminated by indoor releases, including an infectious virus. And so it's done

in very different ways, depending on the type of space that you're considering homes versus commercial buildings versus healthcare facilities, for example, are all ventilated very differently. How are most modern indoor spaces ventilated? I've always, because I'm an engineering geek myself, I like to look at rooms, I like to look at the ventilation, and I notice there are gratings on the ceiling, there are gratings on the floor. How does the air get ventilated in a room? Yes, so most commercial spaces have an air handling unit and a very complex in many cases or sometimes a little bit simpler, HVAC system, which is heating, ventilating, and or air conditioning system. Many spaces need to be either air conditioned and heated to make sure that the indoor space is comfortable. And so what is typically done is some outside air is brought directly indoors to dilute the indoor air.

air, and then the indoor air is recirculated so that it can be either heated or cool, depending on what is needed in the indoor space. A typical building is ventilated with only 20% outside air and 80% recirculated air commonly, and here in this pandemic, we're really recommending 100% outside air, which is very difficult for most building systems to achieve. Would it be just a question of putting a better filter in the system? We do recommend putting a better filter in the system, but we haven't really designed our building systems, our air handling units to have this kind of capacity.

Partly the system is not, it doesn't have the right size. You know, it might need a bigger fan. It might need also different heating and cooling components. It's, you know, to bring in all that outside air and then heat it and cool it at the same time expends a ton of energy. And so there is this push-pull issue going on where we usually try to spend as little energy as we can to heat and cool air in a building but still make it comfortable.

And now in a pandemic, we need a lot of outside air. And we're saying, oh, well, let's use the energy that we need to do this, right? And then let's back off when we don't need so much outside air to save energy. Dr. Jimenez, is there a good way to visualize how the, virus moves through the air in a room? Yeah, so you have these two ways. You know, the droplets will go in front of the person emitting them and they will fall to the floor in a couple of meters or six feet. And then these other aerosols, the better analogy is smoke, like cigarette smoke or vaping smoke. It comes out of the person, but it doesn't fall to the ground. It, you know, stays in the

air and gets diluted. And it really depends on how the air is moving in the room, you know, If it's a room that has an air current, the windows are open, then it may move very quickly. If it's a room in which the air is not moving still, then it may accumulate and accumulate over time, and then that room will be more dangerous. We'll have more smoke, which in this case is just an analogy for the virus. I know that in some well water systems, people have drinking water and they have well water systems to make sure that there are no bacteria in the water, they install a simple ultraviolet light inside the system. And it kills on contact. It just kills all the bacteria in the water.

Why could we not do that with the air, put an UV system up in the duct somewhere and just kill the bacteria? Oh, yes, we can definitely do that. It is a really effective technology for disinfecting air. You have to make sure it's designed, just like you would for a water system, so that it provides enough contact time with the air and provides enough energy to inactivate the airborne virus. But that is a really useful technology that I think a lot of buildings have been using and are using, especially in this pandemic, to better treat the recirculated air as opposed to increasing a filter. Have we just solved the whole problem right here, right now? Well, we haven't because UV is a technology that's applicable on certain settings. It's not, it's not applicable in all

settings, just like every engineering technology doesn't work in every setting. And so, you know, trying to understand where it will work and where it won't is a challenge. Dr. Jimenez, let's talk a little bit about the theory here. When did we discover that poor ventilation would cause a problem for public health? And why haven't we tackled this problem earlier? Well, I mean, I think this has been known for a long time. And I was actually reading some writings yesterday of Benjamin Franklin, where he was saying that people who, you know, being in couches around the city and one of them was sick and then other people would get sick. So generally, this has been known for a long time.

But as Professor Miller said, there are these tensions. And I think in the last few decades, the tension towards saving energy and the push from climate change and for economic reasons, you know, to ventilate less and recirculate more has won over the disease transmission, which brings you in the other direction. So if you were to design the perfect ventilation system, let's say you were building a new classroom or a new home or someplace a mall where people are going to gather, what would that look like? Would that look like bringing in 100% air? So we are moving in new builds to bring in supply air, but we're applying technology

called heat recovery ventilators or energy recovery ventilators as an example of a technology where you can bring in more outside air, but then you can recover some of the energy that you're losing by expelling out-in-door air and exchange it with the outside air. It's a heat exchanger type technology, and that will allow you to bring in more outside air, actually even filter the air without expending too much energy. But as far as the air circulating in the room, I'm looking at the room with ductworked in it, from soup to nuts from the beginning. You have a blank slate of how you would do it.

So, you know, right now we mostly supply air at the ceiling and exhaust air at the ceiling, but there are really important considerations for the airflow patterns that you might have in a room. and that does drive how air is handled. And so, you know, one suggestion and it's studied quite often and applied in many situations is to bring in clean supply outside air at the floor. It rises past the people, which are the main source of contaminants in an environment, and then it is exhausted out the ceiling. So that is a common recommendation.

Dr. Jimenez, some people are worried now that HVACs are spreading the virus indoors, or is not getting rid of it, is there any truth to that? We don't know, to my knowledge of any case where that has been shown for this virus, and we don't think it is very likely. So there are other viruses like missiles, for example, that are very highly contagious. And you see that kind of pattern, what they call long-range transmission. This virus, at least most of the time, is less contagious. And when people get sick, get infected, is because,

because they have been talking to someone else closely, you know, who has the virus or when they have been in the same room for a long time. So Professor Miller and I have studied this case of the choir in Washington. A lot of people got infected, but that was after spending two and a half hours in a room with low ventilation and singing together. And many other outbreaks are when people were, you know,

singing in karaoke or spending a long time in a bar where the music may be loud. So, I mean, we think this virus is not very consistent. And we have to help it, in fact, a little bit. You know, we have to spend a lot of time indoors, talking loudly without masks and with a lot of other people. And that's how a lot of people get infected. What about a fan blowing in a room, Dr. Miller?

Is that mixing of the air helping or hurting? And if I'm concerned, do I want to be by the fan in a restaurant, let's say? Yeah, I'm a little bit hesitant to promote that kind of. of approach because we have seen that strong air currents have transported the virus from an asymptomatic infected individual to other individuals in the space and they have been infected. And so generally speaking, you know, strong air currents that whip things around and could even suspend virus and then blow it into people is not a good idea. We do recommend if you need a little bit more outside air in your space and you're not getting it to open a window and put a fan in the window

and if the space is occupied, blow air out. Because if you're blowing air out, then air will come in to replace it. But do not blow air around in a room. Dr. Jimenez, why haven't we heard any guidance from the WHO or the CDC regarding ventilation the way we have with masks and handwashing? Well, you have, or you should have, so the WHO has an ad hoc advisory panel in ventilation to which we belong, and we have helped them draft some recommendations for ventilation, which includes some of the things that we have discussed today. But the problem is nobody is paying attention to them because they basically say that transmission of the virus through the air is very difficult.

They still take that position. So then, you know, as Dr. Miller was describing, all these issues with ventilation, and adjusting these systems, they are costly. They require effort. They require money. They require work. And, you know, unless it is a high priority because people are getting sick that way, just people are not going to pay attention to their recommendations.

I'm Ira Flato. This is Science Friday from WNYC Studios. In case you're just joining us, we're talking about air circulation in buildings and how to make them as safe as possible with Dr. Shelley Miller, Professor of Mechanical Engineering at the University of Colorado and Boulder, Dr. Jose Luis Jimenez, professor in the Department of Chemistry and Biochemistry at CU Boulder. So I guess the simplest thing to do is have your classroom outside, if possible. That will be the best thing, and that actually does not depend on any of these debate

about whether the virus is going one way and the other. That's an empirical fact. There is, for example, a contact tracing study in Japan, where they showed that it was 19 times more likely if you talk to someone that you get infected if you are indoors and if you are outdoors. And there are databases of super spreading events that have more than a thousand events

and I think there is two outdoors and more than a thousand indoors. So it's very, very clear that being outdoors greatly reduces the chance of infection. And that's what we are recommending that as many activities as possible should be moved outdoors. And in terms of a silver bullet

to prevent infection. I think they, of course, you know, you can do a lockdown and then the virus won't reach you through aerosols or any other way. But if you want to be a little smarter, if you meet outdoors with the six feet distance and with masks, you know, I would bet that is really, really difficult to get infected that way, that that's very safe. And then indoors, there is always more risk. You know, we should use these layers of protection, but you are always, you're always having more risk. Dr. Miller, you agree? Yeah, if I could add an important point is that the highest risk is when you're talking loudly, generating virus containing particles if you're infected, and close to each other because it's this close contact that drives this transmission. And so if you're outdoors talking close to each other and talking loudly or talking for a long time, then the risk is higher in those situations, even though you're outside.

And so I do want to be, you know, I do want people to understand that the close contact for a long time talking loudly, even outdoors could possibly put you at higher risk. I mean, it's much safer outdoors, but move apart and maybe walk as you're talking and face into the wind. And, you know, then then you might be feeling more comfortable. But at the same time, if you're going to talk all that much, you might as well wear your mask. I can see people jostling for the upwind position in a conversation. Have you seen that? I've seen that already. Oh, I fight for the upwind position on the trail when I'm hiking here in Boulder all the time.

But I do have my bandana on. I'm guilty of that also. Since you're both at the University of Colorado in Boulder, do you anticipate any problems this semester? Sure. What we have done is an extensive analysis and overhaul of, of our building systems. And so we are providing the best ventilation and air cleaning that any university in the country can.

And we have incredible social distancing rules and masks. And on campus, the adherence to our guidance is great. And I cannot imagine that we're gonna have an outbreak on campus. We do have situations where we might have parties off campus with students who are unmask and close talking loudly. I haven't observed one, but it's common here. So we're working closely with the landlords and the cities to help us make sure that no transmission off campus also occurs due to our returning students. Dr. Jimenez, you agree? Yes, I mean, I think the campus has been made very safe

and CU has listened to Dr. Miller and myself and other experts exceptionally well. And in fact, I always joke that I wish my family listened to what they tell them about preventing contagion as much as my university does. I'd like to thank our guests. Dr. Shelley Miller, Professor of Mechanical Engineering at the University of Colorado in Boulder, Dr. Jose Luis Jimenez, professor in the Department of Chemistry and Biochemistry, also at the University of Colorado in Boulder. Thank you both for taking time to be with us today.

Thank you for having me. Science Pride is one of my favorite shows. Same here. Actually, I listen to Science Friday all the time, so I'm proud to be here. Well, thank you very much. We're wishing you a safe school year. Thank you. We're going to take a break, and when we come back, the connection between the gut microbiome and combating cancer. Stay with us. This is Science Friday. I'm Iraflato. Cancer immunotherapy, spurring the body's immune system to fight cancer, has given new hope to many people. with cancer. It takes the breaks off the body's own immune system, allowing it to attack tumor cells. But there's a flaw. In some people, the therapy works very well. In others, not at all.

And it's not entirely clear why, or what the differences are between people who respond to the therapy and those who don't. In recent years, researchers have been looking into the microbiome, the collection of trillions of microbes that live in and on our bodies. looking to the microbiome for clues. Is there a bacterial difference between people who respond to immunotherapy and those who don't? Writing in the journal Science, researchers say they may have found one reason why, in mice at least. Dr. Kathy McCoy is one of the authors of that study, a professor in the coming School of Medicine at University of Calgary in Alberta, and the director of the IMC germ-free program there.

Welcome to Science Friday. Hi, Ira. Thank you for having me. Let's talk about your study. You took bacteria from gut tumors in mice that both respond to and didn't respond to immunotherapy and looked at what was different than the bacteria that lived there? That's correct. We, first of all, we looked to see if there was a difference in the fecal microbiome, because that's what we tend to study in humans. And then we decided to also look at if there was any difference in the of bacteria that were associated with the tumors themselves. And we found that there seemed to be a sort of an enrichment of different types of bacteria

in those tumors that were responding to this type of aminatotherapy. When you say there was an enrichment, do you mean there was a larger population of the bacteria there? They were present at a higher proportion in the tumors that were responding to aminotherapy compared to those tumors that were not responding. And do you have any idea what the bacteria were doing in those cancer tumors that were responding? Yeah, because we found this enrichment, we wondered if that really had any important role. So we were able to purify and isolate each of these different bacterial species.

And then what we did is we put these bacterial species individually into germ-free mice so that these mice were monocolonized with each of these individual bacterial species. species. And then we try to see if having the presence of only one bacteria would allow the immunotherapy to work in germ-free mice. We know that the immunotherapy doesn't work at all in germ-free mice. So if you have no microbes at all, immunotherapy has no effect whatsoever. And then what we found is that we could identify three of these bacteria that allowed the menoptherapy to work, even when only one bacteria was there. And what we identified was that these bacteria make a small molecule or a metabolite called inocene. And innocene was the key molecule that was helping to turn

on the immune cells to enable them to be anti-tumor. Is it possible to replace in the mice that had cancer to give them this inocene and then watch what happens to the tumors? Yes, indeed. And that's exactly what we did. So we know that giving them just the bacteria in their gut was able to render immunotherapy that wasn't working and allowed it to work, not just in those tumors that were in the colon, but we also identified that it worked in other tumors that were not in the gut. And we also gave in a scene this small molecule by itself to germ-free mice. So they have no bacteria, we gave it to them either orally, so it just was in the gut, or we gave it to them systemically through an injection. And we found that both of those scenarios worked. So Innsin by

itself was able to turn on the immunotherapy and allow it to work to reduce the tumors. Wow. So this could work for many different kinds of tumors then? That's correct. And we looked at four different types of tumors in our animal models and found that it worked in all of those types. It did not work in one subtype of colorectal cancer that we tested in animals. So it looks like it works in many different types, but not all different types of tumors. Now is the idea then, at least in the mice and perhaps later in people, to give them the bacteria or the inosine? We're going to try both scenarios. The bacteria we are hoping to give maybe as a consortia of three or four different kinds of bacteria, and we would give that as an adjuvant therapy together with the immunotherapy.

We would also like to investigate further the possibilities of giving this metabolite, Inocene, by itself. There's one caveat about giving inocene, and what we found in our paper is that inocene itself seems to have a dual function. on these immune cells that it acts on T cells. And whether it turns those T cells into anti-tumor, which would be a pro-inflammatory type of response that you want in a tumor setting,

it also can turn those T cells to be inhibitory, to turn the T cells off. And it seems that it requires a costimitory signal at the same time. At the moment, we don't know exactly what that co-stimitory signal is, So we are wary right now of just giving in a scene by itself until we can further identify what other signal is needed to ensure that we turn on those, that antitumor effect of the T cells. So what you're saying is that the bacteria are supplying something else that turns the effectiveness on? We believe so.

We believe it's a second signal coming from the bacteria, but it's also possible it could be a host-derived secondary signal that we're not sure what it is yet. This is amazing because I know a lot of people are going to say, well, if it's working in mice, why can't we give it to people? Well, we really hope to be able to translate this to humans, but it's easier to control all of the variables when we're working with animal models. And we really need to test the safety and efficacy of this in humans.

And if we want to give the bacteria by itself, we want to be sure that this bacteria is going to get into the host, into the humans, because they're already populated or colonized with a variety of different bacterial species. So we have to figure out the best way to administer this bacteria and to make sure that it's safe. When you say they're already colonized with bacteria, we know they have a microbiome. Is the bacterium that you're talking about, is it part of that colony that just needs to be tweaked up higher than separated? Is it something that's already in their bodies, I guess is what I'm asking? So we know that these bacteria are present in humans.

We don't know if they're present in every human. And it may be that they have to be at a certain level to be able to provide the efficacy that we need to enhance immunotherapy. But they are known. They are commensal, normal, non-pathogenic bacteria that are found in humans. it's possible that when people are sick, you know, if they have cancer, that we know that their microbiome changes and they start to lose diversity. Anytime somebody is undergoing a chronic inflammatory disease, their microbiome changes. And maybe that during those changes, they start to lose the presence of these beneficial microbes. So maybe what we can do is add them back.

What microbes, you said you had three and you were working with one, if I heard you correctly. What bacterium is that? So the one that we've been looking at most closely is called bifidobacterium pseudolongum. It's usually present in the normal human microbiome at low levels, but maybe many of the listeners might recognize the name bifidobacterium. Because bifidobacterium actually has been different species, not the one that we found, not this one called pseudolongum, but other bacteria have been identified and used in probiotics for many years. Yeah, I was about to say that I've looked at a lot of probiotics, and I see the bifidobacterium as on the label there,

what you're saying is not just the genus, but the species is important. It's very targeted. That's correct. So, yeah, not just the genus, but the species, even more so maybe even the strain. So even maybe different members of the pseudolongum species, at different strain levels, they may also have a difference.

You know, people listening to this are going to say, you know, I take bifidobacteria, why can I get that strain? Can I get that strain in a pill somewhere online? Right now, no, you cannot. We have to do further research to see how widespread different bifidobacteria are that make in a scene. But the one that we've identified so far, we have to do further research to find out how widespread it is and if it's safe. So it's not available on the shelf at the moment. You were talking about the microbiome being such a big mix of so many different bacterium.

How do you even study them one at a time in the mice? So there that's where you really need to have a facility like we have here at the University of Calgary, which is a germ-free facility. So we are able to breed and house mice that live really in bubbles. And they are born and raised without any microbiome at all. So that means no bacteria, no viruses, no fungi. And then we can isolate the bacteria that we're interested in studying and give them back to those germ-free animals.

How do you keep them germ-free? You know, I'm thinking you go into the lab every day. They're trying to study germ-free mice. How do you keep them from catching whatever bacteria are in the lab techs or in your gloves or clothing? Yeah, it's always a daily challenge, but we have implemented some very strict protocols and infrastructure to allow us to keep these animals germ-free.

So the animals are held inside basically a bubble, like a plastic bubble that is fed with filtered air, and they're fed with autoclap, sterilized food, and water and bedding, so everything that goes in where those animals are, has been sterilized. And those bubbles are kept in a secondary bubble and then another bubble. So we really have to do a lot of protocols and cleaning to be sure that no bacteria is introduced to these animals unless we specifically want to introduce that bacteria. We hear how important the microbiome is to so many body processes.

I'm wondering, are the mice with no microbiome acting normal? Can you tell? Are they doing something weird? Can you tell they don't have one? Well, if you just look at them by eye, you wouldn't be able to tell the difference. They look very normal. But if you start to study them in more detail, we know that if mice are bred without a macrobioom, their immune system is very immature and also shows signs of dysregulation.

So they make more IgE antibodies, for example, and IGE is the antibody that helps to mediate allergic responses. So they're more prone to an allergic phenotype. So there are many things involved with the immune system where it is somewhat dysregulated and immature. The microbiome is absolutely required to develop a mature and regular, regulated immune system. They also have some changes in their behavior. And you don't really see it just when you look at the animals, but if you put them through a battery of tests that would study

their behavior in response to stress or different things, they will have different behavioral outcomes as well. I'm Ira Flato, and this is Science Friday from WNYC Studios. Tell me what other things beyond cancer you are using these germ-free mice to look at. we are really using gerfrey animals to try to understand the cross talk between the microbiome and the immune system. And how it's very important that you get signals from your microbiome early in life in a critical window of development so that we make sure that the immune system is developed in a regulated way. And how if you're missing some of these critical signals in this developmental window, that has an impact. on susceptibly to diseases later in life. So we're looking specifically at diseases like allergy and asthma, but also diseases like

autoimmunity, things where we know that the immune system is very important for being regulated to make sure you don't get autoimmunity or allergies. So those are two aspects that we're looking at. But we're also looking at how the brain undergoes development and how how we're, how we're it receives signals from the microbiome in terms of neurodevelopment, but also later in life in terms of neurodegenerative diseases. I'm trying to tease apart how the microbiome may be involved in that. You know, we hear a lot of hype around the microbiome studies, and can you point to any true success stories in the real world where it's really made a difference?

Probably the biggest success story right now is looking at fecal microbial transplant. And that's in the scenario of people that are infected with a pathogen called Clustridium difficile. And Clustrium difficile is a bacteria that colonizes your gut and makes toxins that can make people very, very sick. And so the gut almost becomes overrun with this presence of this bacteria. And if you take the microbiome, so basically a fecal slurry from a healthy person, and you give that to somebody who is infected with glastodium difficile. It's the only situation that is curative. So more than 90% of people can be cured of their infection by fecal microbial transplantation.

So the success of that has really excited researchers to see if we can use that type of therapy in multiple conditions where we know that the microbiome complexity or, composition has been altered. So FMTES, as it's called, is being now used for inflammatory bowel disease studies and many other diseases. In the greater scheme of things, the number of people on Earth is so microscopic compared to the amount of bacteria and viruses there are on the planet. Could we be just looked at, we as humans looked at as just a vessel for these bacteria to carry themselves around? Yeah, that's actually that's a good analogy. And I like to say that we're not actually, we're not merely humans. We should be looking at ourselves as a super

organism because we are never without our microbial partners. From the moment we are born, the newborn baby enters a microbial world. And that baby starts to get colonized. And it's a very dynamic process. And so we live with these microbial partners in very close association with our bodies throughout our life. So we're never without them. And we would be naive to think that we are not influenced by them in any way. So we should thank them. I mean, we're a super organism and they make us healthier. I love that. I love to talk about it in that sense. I want to thank you for taking time to be with us today. You're very welcome. Thank you for having me. You're welcome. Dr. Kathy McCoy, professor in the coming School of Medicine, University of Calgary in Alberta, and director of the

IMC germ-free program there. Thanks again for being with us. One last thing before we go. Some news from our book club. We've picked the book and we want you to read it. It's called New Sons. It's a collection of short speculative fiction edited by Nisi Shawl. The club launches later this fall, so stay tuned for more announcements, and check out our website, sciencefriday.com slash book club. And of course, if you missed any part of this program or you would like to hear it again, subscribe to our podcasts.

And you can also ask your smart speaker to play Science Friday. Have a great and safe weekend. I'm Ira Flato.