Building big dream machines, and self

First up this week, a story on a builder of the biggest machines. Producer Kevin McLean talks with Staff Writer Adrian Cho about Adrian's dad and his other baby: an x-ray synchrotron.

Next up on this episode, a look at self-organizing landscapes. Host Sarah Crespi and Chi Xu, a professor of ecology at Nanjing University, talk about a Science Advances paper on how resilience in an ecosystem can come from the interaction of a plant and cracks in the soil.

Finally, in a sponsored segment from the Science/AAAS Custom Publishing Office, Jackie Oberst, assistant editor for custom publishing, discusses challenges early-career researchers face and how targeted funding for this group can enable their future success. She talks with Gary Michelson, founder and co-chair of Michelson Philanthropies and Aleksandar Obradovic, this year's grand prize winner of the annual Michelson Philanthropies and Science Prize for Immunology.

This week's episode was produced with help from Podigy.

About the Science Podcast

TRANSCRIPT

0:00:05.7 Sarah Crespi: This is the Science podcast for May 5th, 2023. I'm Sarah Crespi. First up this week, a story on a builder of the biggest machines. Producer Kevin McLean talks with news writer Adrian Cho about Adrian's dad and his other baby and X-ray synchrotron. Next up, we take a look at self-organizing landscapes. Chi Xu discusses how China's Red Beach is faring under increasingly dry conditions and how the resilience of this ecosystem is actually strengthened by cracks in the soil. Finally, in a sponsored segment from our custom publishing office, assistant editor of Custom Publishing, Jackie Oberst talks with Gary Michelson, founder and co-chair of Michelson Philanthropies. And Aleksandar Obradovic, this year's grand prize winner of the Michelson Philanthropies and Science Prize for Immunology.

0:01:00.0 Kevin McLean: In physics, data collection is a major endeavor. Researchers build giant machines like particle accelerators, often paving new paths and making things for the first time ever. Thousands of scientists use these facilities to make new discoveries, but over time, they grow outdated and need to be upgraded. Staff writer, Adrian Cho, is here today with a story that is both a report on the rebuild of the advanced photon source at Argonne National Laboratory, but also a personal essay about the work his late father did, designing and building this massive scientific machine in its original form. Adrian, welcome back to the Science podcast.

0:01:39.0 Adrian Cho: Thanks, Kevin. It's nice to be here.

0:01:41.2 KM: Great. Well, first let's talk about the Advanced Photon Source or APS, I guess as it's called. This is a particle accelerator at Argonne National Lab in Illinois. But what exactly does this machine do?

0:01:55.5 AC: The very short answer, the one sentence answer is that it's an X-ray source that produces very, very high intensity, very stable, very pure beams of X-rays for all science. So you can unlock the structures of proteins, you can look at the atomic structures of materials, cracks in building materials and engines, turbine blades, you name it. If it involves matter at the atomic scale, there's probably some way it can be studied with X-rays. They continue to be the premier way of looking at the atomic structure of matter. But in a little more depth, what this is, what the APS is, is a 1.1 kilometer long ring-shaped accelerator that's known technically as a storage ring. It's kind of synchrotron if people may have heard that word before. Essentially what happens is that it takes a beam of electrons, it accelerates them to high energy and sends them around this ring, and they go around the ring about 300,000 times per second 'cause they're traveling at essentially light speed.

0:03:05.1 AC: And it's a very basic piece of physics that if you have a charged particle like an electron and its path gets bent, it will radiate. So as these electrons go whizzing around the ring, they radiate X-rays, and you can make a very intense X-ray source this way. And a way to think about it, which is actually, not too bad, is, if you took a wet washcloth and you twirled it from one corner, it would flick off beads of water. And a similar thing happens as the electrons go around, they radiate these X-rays that come off tangentially from the ring and they go into these X-ray beam pipes and they're piped to, I think they have 68 experimental stations all around the ring. And so for the past 27 years, this ring has run to produce some of the very brightest X-ray beams in the world and they've done all things with it.

0:04:02.3 KM: And so those X-rays that they're now using then, those X-rays are sort of doing what you think of, with... An X-ray would do, where it is imaging different types of things and finding out what things look like or what, how is that being used?

0:04:16.1 AC: That's more or less it, machine in a dentist's office or in a doctor's office, that works by simply slamming an electric charge, a bunch of electrons into a piece of metal. And when they stop, they radiate X-rays. And you can get a lot of X-rays that way, but you can't get anything... [laughter] The X-rays you get out of one of these machines, right, which come in these tiny, tiny little beams that are incredibly intense. Now, when you think of getting a medical X-ray, you're just getting an image, right? If you put your hand under the machine, essentially what you see, because the X-rays don't go through the bone so well, the image is just the shadow of the bones. But X-rays can do a whole lot more subtle and complicated things. If the X-ray wavelength is short enough as it is at the advanced photon source, what happens is that the X-rays will scatter off of different planes of atoms in a crystal.

0:05:09.2 AC: Crystal can be thought of as stacked planes of atoms. And the X-rays will scatter off those planes in a way that allows you to back out the crystal structure, and that's called diffraction. And that's an incredibly powerful tool. And surprisingly, what it's proved to be really great at is determining the structures of proteins and biomolecules. For example, the APS helped decipher the structure of COVID-19, the virus that causes COVID-19. It helped develop Paxlovid, it's been involved in determining 35,000 protein structures. So, yeah, so it's more than imaging, but yeah, these are whackingly intense X-ray beams.

0:05:51.6 KM: Okay. So now they're in the process of upgrading the system. What exactly is that gonna entail and and how long is that gonna take?

0:06:00.7 AC: It's going to entail a complete rebuild of the machine that was my dad's baby. This is the thing my dad worked on for a long time. Basically, what's gonna happen is that the entire accelerator, except for some key parts, the entire ring is gonna come out and is gonna be replaced by a new design, which will make this teeny-tiny little electron beam even smaller. And that will produce a 500 fold increase in the brightness of these X-rays, which will enable all kinds of new things. Right? So just to go back to the example we were talking about, the structure of proteins. You can already use really small crystals and get a structure out of a machine like the APS, but you'll be able to go even smaller because the X-rays are gonna be 500 times more intense. So that's what they're doing. They're basically taking this machine that my dad built, and they're gonna take it out. Lots of pieces are gonna get melted down, and they're gonna replace it with a whole new design, which they actually have in a warehouse, and it's ready to go, and the whole thing's gonna happen in a year.

0:07:05.6 KM: Oh my gosh. Okay. So you've... You brought it up, the upgrading of the machine and it's really this whole dismantling, but you wrote about this from also at a very personal angle because, as you put it, it was your father's baby. What really was his role in building of the original APS system?

0:07:28.1 AC: My dad, Yanglai Cho, was an accelerator physicist at Argonne. He spent his whole career there, and he led this small group that wrote the conceptual design report that eventually became the APS. So he was in on the ground floor. My dad, a fellow named Gopal Shenoy, who was a material scientist who looked at and developed the scientific case for what the machine might do. And about a dozen folks, starting in 1983, started pushing the lab to build this machine. And the thing that was interesting about it was there had been this report, sort of high level report that said that the United States should push for this machine. I think I was 18 when he got started in this in earnest. Argonne had sort of... Was sort of in a lull, because they had shut down their main particle accelerator in 1979 because all the action had moved up the road to Fermilab.

0:08:24.5 AC: But my dad was a very determined guy, and he realized this opportunity and he got this group together and he started pushing the lab to try to build this machine to get DOE to give it to Argonne. And so he worked on the conceptual design, which was the original layout, specified the parameters, more or less, of the accelerator, the parameters of the building, all kinds of stuff. And he was definitely not the only person involved in this [laughter], but he was in on the ground level. So, my dad, he passed away in 2015. He'd been quite ill in the later years of his life. He'd had a couple of strokes. But I have to admit, after my dad died, I kind of thought of this machine as his legacy, and it was some comfort to think that the machine lived on, even if he was gone. And as happens with these things now, the machine itself will be gone. Right? And so the facility will still be there, but this accelerator that he thought so much about and occupied so much of his time, they're gonna take it apart, then they'll replace it.

0:09:30.7 KM: You've written a lot about physics throughout your career and you are familiar with this facility in different ways, both professionally and personally. It must have been an interesting experience to report this story, but what was sort of surprising to you? Anything you hadn't thought about before?

0:09:47.8 AC: I've been working as a science writer for more than 20 years now, and I've written about a lot of big projects because physics involves a lot of big projects. The thing I really hope that this little essay conveys is the very kind of peculiar nature of being a machine builder because it's very different than being a user of one of these facilities. Right? And the APS serves something like 5700 individual scientists every year, right? So there are literally thousands of people depending on this X-ray source to do all kinds of things. There's a much smaller group of people who go around designing and building these things. And it's really kind of... I mean, I've never built anything, so I can't say any of this from firsthand experience, but there's this kind of special skill set right? That's involved in conceiving of a big scientific machine and then executing it.

0:10:46.8 AC: And there are these skills that you have to have that are not exactly the same as the skills you have to have to be a user of one of these facilities. So, for example, one of the things that I've become aware of over the years is that if you want to build one of these facilities and you're the designer and you're gonna propose one of these things, which is at some level, the conceptual design report fleshes out a general idea and says, okay, here's something that we can build. Right? It's not a detailed engineering design, but it's enough to really judge the project. If you're gonna do this, you cannot obviously design something that's so fantastically ambitious that you have no hope of building it. Right? I mean, and you have to build it for a fixed amount of money on a fixed amount of time.

0:11:36.1 AC: So you can't... You can't just let your imagination run wild. But the flip side of that is that you can't be too conservative either. Because if you're too conservative, nobody will build it because you'll essentially be reproducing something that you already have. Right? I mean, if you know for a 100% certainty that it will work, when you're laying out the conceptual design, you're probably not pushing far enough because the only way to be a 100% certain is if you've already built something like that. So the people who build these machines are always working on this balance where they're trying to propose something that does something new, but it's not so outlandish that it can't be achieved on time and on budget.

0:12:17.6 KM: Yeah. It seems like this just incredible balance between like a ton of knowledge but also a lot of optimism as you wrote about... And just also practicality and realism as well. It really feels like such an amazing balance that a person has to have in order to have that role.

0:12:34.1 AC: I think it's a different sort of skillset than just being a scientist. I mean, no knock against being a user of one of these facilities, but to build something is this kind of different mindset. So it's really interesting 'cause my dad was an immigrant, came to the United States when he was 24 years old. My dad had a disability. He'd had polio when he was a kid. So he walked with a very bad limp and he couldn't run. He had a really fiery temper, [laughter]

0:13:05.3 AC: My dad was this guy who I think, in a lot of sort of the course of normal life, was a little bit of an outsider. Because there was cultural barrier, there was this issue with obvious disability. Most of the time, he seemed to be a little bit of a square peg in a round hole. But what was fascinating to me, as I've gotten older, I've learned about how people build these machines, and what's involved, is that looking back on it, it's really interesting that in this world where things have to be done just so and have to be done on time and on budget, a guy with my dad's imperious attitude not only could find a place but could actually thrive in part because of this kind of attitude. I mean, the people who build machines, as far as I can tell, there is a real kind of put-up or shut-up attitude, because these things have to get done, and they have to get done on time, and they have to get done on a budget. And so, if you got a bad idea, apparently, they're just going to tell you flat out. So it's a bit of a... As far as I can tell, a bit of a bare-knuckled profession, but somehow it was just perfect for him. He managed to really thrive in this kind of unusual parts of science, and then it's an incredibly important part of science. As this machine, as this rebuild starts, I've been thinking a lot about my dad, but also about what's involved in building these big machines.

0:14:37.4 KM: Do you have a sense of what your dad would think about this upgrade and what's happening next and everything?

0:14:45.2 AC: He would be the first to say, "Okay the machine has been around for 27 years and technology has moved on. So we got to change." He was not a sentimental guy. If a machine had served its purpose and it was time for an upgrade, he would be all over it. I mean, these machine builder types, they are not a sentimental lot. I mean, they will look at a machine and they'll say, yeah, that machine did this great, but it didn't do this thing very well. And they should have done better on that.

0:15:11.0 KM: So it sounds like he would also say it's time.

0:15:13.9 AC: Oh, yeah, absolutely. He did not look backward. He was not a guy who was... Especially when it came to his work, he was not gonna get sentimental about the machine. He'd be right there wanting to make it as good as it could possibly be so.

0:15:27.3 KM: Great. Well, thank you so much, Adrian.

0:15:29.4 AC: Oh, it's my pleasure, Kevin. Thanks for taking the time.

0:15:31.8 KM: Absolutely. Adrian Cho is a staff news writer at Science, you can find a link to the story we discussed at science.org/podcast.

0:15:40.1 SC: Stay tuned for my chat with Chi Xu about the plan that paints China's Red Beaches red, and how these tiny succulents keep a toehold during a time of increasing droughts.

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0:16:00.4 SC: Many patterns can be found in nature, from stripes on a cat to spirals in the head of a growing fern. And these patterns can often be described using modeling and math. At a larger level, we can see patterns in the landscape, like fairy circles and grassland or cracks in the tree cover in a forest as the tree crowns resist touching. This manipulation of space by the interaction of biological things, and the land itself is called spatial self-organization. It can also be described through modeling, and it can help us detect changes in ecosystems over time. This week in Science Advances, Chi Xu and colleagues wrote about spatial self-organization in a coastal salt marsh in northern China called Red Beach. Welcome to the Science podcast, Chi Xu.

0:16:46.9 Chi Xu: Thank you for having me.

0:16:48.5 SC: Why don't you start with just a description of this landscape of this place?

0:16:53.8 CX: We studied coastal salt marsh landscape in the Yellow River Delta in northern China. This is typical a salt marsh ecosystem in northern China and you can find it in a lot of place all over the world.

0:17:08.7 SC: What does it look like, what makes it special?

0:17:11.2 CX: This landscape it dominate by a plant called suaeda salsa. Let's just call it suaeda or seepweed. It is a salt-tolerant succulent species in many coastal regions across the world. This kind of succulent can dominate massive salt marsh landscapes. In Autumn to winter, they turn red like maple leafs. So you can imagine during that time the entire coastal landscapes become reddish, which in China, we call them red beach. It is not only a touring attraction but also a biodiversity hotspot. Every year tens of thousands of migratory birds traveling between Siberia and Australia use red beaches as an important stopover for their rest or food supply. It's a pretty important ecosystem.

0:18:05.7 SC: So the Red Beach is actually a salt marsh and the seepweed, I'm saying seepweed, not seepweed, seepweed is this succulent land plant that turns the whole ecosystem, this gorgeous brilliant red during certain times of the year. What you focus on here is the interaction between the seepweed, these red plants, and the soil during dry times. As we mentioned, this is a salt marsh, so usually there's lots of salty briny water around, but when it dries up, the landscape looks very different.

0:18:39.7 CX: We have been working on these sites for years for decades. What we study boils down to the question or phenomenon so-called spatial self-organization. In nature, we can often find other spatial patterns, they could be spots, they could be stripes, circles, labyrinths, or other irregular shapes. For example, in African and Australian dry lands, people have found tiger bush, which is shrub vegetation presenting special patterns resembling stripes on tigers. And while these patterns are fascinating, but a natural question is how does regular patterns come into being. Well, they are not made by humans or aliens. [laughter]

0:19:23.0 CX: Instead, they can arise spontaneously when particular conditions are met. We call this spontaneous process spatial self-organization. Sometimes, spatial self-organization patterns are so unique that they can carry important signals. So we can compare the observed patterns with the counterpart derived from computer models to understand how the ecosystem develop, or how they function, or how they respond to climate change. Now, scientists have reviewed the mechanism underlying many, many spatial self-organized systems. In many cases, spatial self-organization is triggered by biological processes such as the competition and the facilitation between plants. But sometimes it seems that self organization patterns can also emerge without the involvement of organisms. Examples that are familiar to most people would be like sand ripples, dunes or mudcracks. Mudcracks is what we are studying now. [chuckle]

0:20:33.3 SC: Yeah.

0:20:34.6 CX: So we call them physical self-organization.

0:20:38.5 SC: So there's not this interplay where something happens with the plant, it affects the land, the land responds, the plant pushes it forward.

0:20:47.1 CX: Exactly.

0:20:47.8 SC: Versus more the physical thing happens first.

0:20:51.4 CX: So this kind of physical self-organization, they're usually studied by geologists or geographers, but now we ecologists are also interested in them. We want to understand how physical self-organization is linked with ecosystems. Will these kind of processes affect ecosystem structure, dynamics and functioning, especially when it comes to the big questions like climate change? So these are still open questions, these are new questions and this is the essential motivation of this work.

0:21:28.9 SC: When you look at an aerial view of this region, it's just amazing. You see these red banks of plants cut through with estuaries, small streams, it's ocean and march and red. It just looks amazing and very lush. So what exactly brings about the cracking mud that we're talking about here on the Red Beach.

0:21:50.2 CX: Intensive drought in spring or in summer. Especially when in the recent years we know that the heat waves strikes the whole northern hemisphere frequently, these mudcracks are more and more frequent.

0:22:06.5 SC: How do they relate to the seepweed, and the red plants?

0:22:10.7 CX: Oh yeah. This is...

[laughter]

0:22:13.3 CX: This is an interesting question. Basically, we have seen that after drought, cracks appear all over the mudflat, and the present regular polygonal shapes, which is a typical sign of spatial self-organization. While this drought can... In the meantime, they can kill most plants across the whole landscapes. But after a couple of weeks when the mudcracks come into being, the plants come back. They are growing out of the cracks, and following that, the salt marsh vegetation can recover very quickly across the entire landscapes. So at the first stage of this process, we can see that the seepweed plants, they're growing out of the cracks, and they are almost associated with the cracks completely. So it's quite an interesting question. We start pondering, well, maybe this self-organized mud cracking can play an important role in sustaining the ecosystem.

0:23:19.1 SC: I saw in the paper there's like a series of images and you see the mudcracks and then you see these like little... The little starts of the plants coming up and then you kind of see the pattern getting hidden. But that was very important early on for the colonization by the plants. What did you try to kind of tease apart with your research?

0:23:37.5 CX: We designed a couple of field experiments. The general idea is that the manipulative field experiment allowed us to look into the interaction between plants and the cracks. I can give a couple of examples if you don't mind. [chuckle]

0:23:52.9 SC: That'd be great. Yep.

0:23:54.0 CX: Okay. For example, we transplanted the seepweed into areas with or without cracks to look at how cracks affect plant survival and the growth. And you can imagine if the areas with cracks, the transplanted seepweed can grow better, it means that the cracks is good to the plant. [chuckle] Also, we took the soils within and outside the cracks back to lab. And after a couple of weeks, we counted how many seedlings can generate from them. Basically, in this way, we checked if the cracks can capture more seeds. They are acting like traps. And when the cracks are there, it traps a lot of seeds and allows the seeds to germinate. But in the field we cannot tell. We need to take the soil back to the lab and wait. [chuckle]

0:24:46.9 SC: What was different about the soil in the cracks, is it richer in some nutrients? Is it wetter?

0:24:52.5 CX: The first thing is that it's softer, it contain more water, and it's less salty. It's more suitable for the plants to grow. The seepweed is salt-tolerant, as well, less salt is... It's better.

0:25:05.1 SC: It's preferred. Yeah. You also did some modeling in this study. What were some of the variables that you were looking at there?

0:25:12.4 CX: So we have the intuition of these underlying mechanisms that the plants and the cracks can have a positive feedback. The plant like cracks and the cracks also likes the plants.

[chuckle]

0:25:26.2 CX: So basically that's it. And we put these interaction mechanisms in our model so we can get the parameters of the models from the field observations or from the field experiment I mentioned earlier. We want to see if this model can reinvent, so to speak, reinvent the whole spatial patterning. And what surprised us is that, well, this is a very simple model, but it does a very good job reflecting the spatial patterning, it re-invented the regular spatial patten soft mudcracks and the vegetation almost perfectly. So we're thinking, well, it's possible that we are... Maybe we are close to the truth.

0:26:14.9 SC: Yeah. So the plants like the cracks because they have better soil or lower salinity, more moisture. They help the plants grow, and the cracks [chuckle] like the plants because they reinforce the cracks and keep them in place. How does that system that you kind of described here, how is that going to react with climate change? I'm assuming that we're gonna see more variable climate in the region, so maybe more droughts or stronger droughts, just big changes to come.

0:26:44.0 CX: Yeah, it's a difficult question. Especially what we are looking at is large scale system and also the dynamics, the response of the system to climate change happens at longer time scale, so to say. So it's not like the field experiment we did, but the good thing that we have this model tool and we are using this model to study how this physically self-organized mudcrack can affect ecosystem resistance to drought. Basically, in the model, we can increase the droughts step by step. And we found that when a certain critical threshold reach, the whole ecosystem collapse.

0:27:33.3 SC: Yeah.

0:27:34.7 CX: But the presence of mudcracks can help the ecosystem withstand drought. In other words, when drought is intensified, this ecosystem go to collapse, but the mudcracks can make the collapse only occurs at higher level of drought, at stronger droughts.

0:27:51.0 SC: So the mudcracks provide this buffer. So the cracks gets more severe, the plants have a little bit more of a toehold.

0:27:58.4 CX: Exactly.

0:28:00.4 SC: And that kind of helps the landscape at least until a certain critical point, and then it's too far and too bad. It's a complex story. It's a big space. There's very many layers of interactions. It's really interesting.

0:28:13.1 CX: Exactly. That's what we ecologists do. [chuckle]

0:28:19.6 SC: Yeah. [laughter] So true. Thank you so much, Chi.

0:28:23.4 CX: Yeah, thank you.

0:28:23.9 SC: Chi Xu is a professor of ecology at Nanjing University. You can find our link to the Science Advances paper we discussed at science.org/podcast. Next up is a sponsored segment from our Custom Publishing office, brought to you by the Michelson Philanthropies & Science Prize for Immunology.

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0:28:48.4 Jackie Oberst: Hello to our podcast listeners, and welcome to this custom-sponsored interview from the Science AAAS Custom Publishing Office, and brought to you by Michelson Philanthropies. My name is Jackie Oberst and I'm assistant editor for Custom Publishing and Science. Today we'll be talking about immunology, disease, and how funding for early career researchers can make a difference. The immune system is what stands in the bound between good and poor health. It is part of the body's defense mechanism in which it identifies and eliminates harmful and foreign stimuli, such as trauma, microbial invasion, or noxious compounds, and begins the healing process. However, when chronologically activated and sustained, it can lead to progressive tissue injury and reduce survival. Chronic inflammation can have a deleterious effect on the body and is a key factor causing almost all chronic degenerative diseases. The World Health Organization ranks chronic inflammatory disease as the greatest threat to human health worldwide. Three out of five people die due to chronic inflammatory diseases such as stroke, chronic respiratory diseases, heart disorders, cancer, obesity, diabetes and arthritis, and joint diseases. Improving these outcomes depends on transformative research in human immunology. In 2021, the Michelson Philanthropies partnered with Science to create an annual award to encourage and support early career researchers in immunology.

0:30:06.0 JO: Grand Prize winner is awarded $30,000 US and two finalists are each awarded $10,000 US based on an essay describing work they have done in the past three years. In addition to the prize money, the grand prize winner's essay is published online and in print in Science Magazine. I'm very pleased to have with me Dr. Gary Michelson, founder and co-chair of Michelson Philanthropies, and Dr. Aleksandar Obradovic, this year's grand Prize winner of the Michelson Philanthropies & Science Prize for Immunology. Gary and Aleksandar, thank you so much for taking the time to talk with me today. Let's begin with Dr. Obradovic. What are some of the challenges early career researchers face?

0:30:44.3 Dr. Aleksandar Obradovic: Establishing a lab is not easy. Recruiting postdocs, recruiting graduate students, undergrads, kind of building up an infrastructure, all of that is a lot of time and a lot of work and a lot of effort. Getting grants is always harder to do until you've gotten your first couple. And so, I'm grateful and very lucky that I've had a lot of institutional support from my department, from my mentors, and also a lot of shared infrastructure, which has kind of helped me to face those specific challenges. Other challenges kind of relate to more specifically to me in that I wear many hats. I'm not only a young physician scientist, and so I'm in the midst of my medical training at the same time that I'm setting up this lab. Later in the career is when you tend to get more flexibility around building your own schedule. Having to work around a clinical schedule that's largely out of my hands has been a challenge, but it's been one that I've been able to meet.

0:31:46.0 JO: Let's now turn to Dr. Michelson. Dr. Michelson?

0:31:49.3 Dr. Gary Michelson: So in an an essay that was written by Francis Collins back in 2010, he pointed out that the average age of a researcher getting a RO1 grant for the first time in the 1980s was 34 years of age. Today, it's 44 years of age, and what's happening? Where are those 10 years going? You can't get an R01 unless you have underlying research to support it. It's a catch-22. If you're working at somebody else's lab, you don't get the opportunity to do that. If you can't do that, then you're working at somebody else's lab. What we're doing is this delayed puberty thing. It really has a tremendous cost, because prior to this modern age of research, if you look at the people who won the Nobel prizes in the hard sciences, the great, great majority of them were under the age of 35 when they did their seminal work. Our prizes were trying to take corrective action in several ways. So we know NIH only funds incremental research. And there's a great saying that you cannot leap a chasm in several small steps. So what they're not doing is they're not funding research that leaps, that would be breakthrough research. And that is by nature high-risk, high return, high failure rate. But what we try to do is to, first of all, give opportunities to young researchers under the age of 35. And we deliberately look for high risk, high return types of research.

0:33:21.8 JO: Have any of these high-risk, high return types of research succeeded?

0:33:26.4 DM: Every one of them has succeeded. Not in the way that we originally anticipated, but in the fact that it watered the courses, the trajectories of these people's careers. Every single one of them was able to get independently funded subsequent to the grants that we gave them.

0:33:43.7 JO: Gary, what sorts of young researchers are you looking for?

0:33:47.0 DM: We would like to get people who are not immunologists to apply for these prizes. I wanna get people in computational science. And this year, we did. I'd like to get somebody who's in protein engineering, synthetic biology. I'd like to get somebody who's in microbiome. We'd really like to get people who don't consider themselves to be immunologists to say to us, here's what I'm doing, but I think it relates to what you're interested in. That's our approach.

0:34:13.0 JO: Aleksandar, could you please walk me through the essay you submitted about your research that resulted in the grand prize?

0:34:17.5 DO: The central focus of my essay is precision immunotherapy and the idea of being able to provide that, coming up with a paradigm for how to provide that. The overall goal of my research work has been to leverage and develop new tools for better understanding and better profiling of the immune microenvironment of tumors and specifically understand what the mechanisms of resistance to checkpoint immunotherapy are. The main tools that I've been developing and working on are tools to transform gene expression data to an inference of which regulatory proteins are active on an individual cell level. So that gives me better resolution of what are the types of cells that are there. That gives me also potential targets for therapy. So once I understand the mechanisms and the cells that are responsible for treatment resistance in different tumor types and in different patients, the next step that I've already been working on and that I continue to work on is pairing those resistance mechanisms with combination treatments to help overcome that resistance. And that combination immunotherapy, that personalized combination immunotherapy is really an exciting concept. It's a concept that I'm very excited about, that I think has the potential to really have a significant therapeutic impact. Because a lot of these combinations aren't necessarily obvious, even the ones that have been clinically successful.

0:35:49.3 JO: This question is always a favorite of mine to ask awardees because you never know what they're going to say. Aleksandar, how did you go about writing this essay?

0:35:57.4 DO: I have a son who's a year and a half. And so he was just around a year old when I was writing this essay. And so I would come home from clinic to take care of him, do dinner, bath time, bed time routine. And then after all of that, 8:00 PM and onward was when I would really be working on my research work. And so I gotta write this essay. I gotta start writing this at least a week ahead of time 'cause it's gonna be an hour a night maybe. That's how it all came together.

0:36:23.6 JO: Oh, my gosh. As you said before, you wear many hats. Aleksandar, could you tell me how you were notified of winning this prize?

0:36:30.9 DO: I got an email telling me, hey shhh, highly confidential, but congratulations, you've won. I was thrilled. I didn't believe it at first. I was like, wow, that's... I better wait till it's no longer confidential. What if they change their minds? So I was very, very excited. It was truly an honor to get that email. I kept looking at it for a couple of days afterward to make sure it was still in my inbox, and it hadn't been unsent. Somehow. [chuckle]

0:36:55.3 JO: What advice would you give to those thinking of applying for next year's prize?

0:37:00.3 DO: I would say whatever phase of your career you're in, even if you're very early, as I myself was and am, it's worth applying. If you have a story to tell with your research, if you have exciting work to show, and I'm sure there are many, many who do, I would say it's always worth applying. It's always worth a shot because you never know what's going to get recognized.

0:37:18.6 JO: For those early career researchers thinking about applying for Michelson Philanthropies and Science Prize for Immunology, we'll give Dr. Michelson the last word on what young scientists have to gain from the award.

0:37:28.9 DM: Well, first of all, it's freedom. Even if you were a senior investigator, that you would go do something that is non-incremental, you wouldn't get funded. We're letting you take your great idea and do whatever you want and do it your way. And you know what? At the end of the day, if it does not succeed, nobody's unhappy.

0:37:46.8 JO: Gary and Aleksandar, it's been a real pleasure talking with you. I wish you the best of luck in your endeavors. Thank you for joining us. Our thanks to Michelson Philanthropies for sponsoring this interview. To learn more about the Early Research Prize and specifically how to apply, go to science.org/michelsonprize. Applications for the 2024 prize are now open and will be accepted through October 1st. This podcast has been edited and condensed for length by Erica Burke, Director and Senior Editor of Custom Publishing, and me, Jackie Oberst. Thank you for listening.

0:38:20.9 SC: And that concludes this edition of the Science Podcast. If you have any comments or suggestions, write to us at sciencepodcast at aaas.org. You can listen to the show on our website at science.org/podcast or search for Science Magazine on any podcasting app. This show was edited by me, Sarah Crespi, and Kevin McLean with production help from Podigy. Jeffrey Cook composed the music. On behalf of Science and its publisher, AAAS, thanks for joining us.