Scientist Stories: Chad Mirkin, Nanotechnology where Small Things Matter

Good afternoon. I am Farnam Jahanian, Provost here at Carnegie Mellon, and on behalf of my colleagues here at CMU, it's my pleasure to warmly welcome all of you to CMU's Dickson Prize Award presentation and lecture this afternoon. Thank you very much for being with us today. I wanna first acknowledge and thank Professor Emeritus Guy Berry and his colleagues on the Dixon Prize Committee, university professors who are on the Dixon Prize Committee for making such an excellent choice in the selection of this year's honoree, Dr. Chad Merkin. I also want to take a moment to thank two faculty hosts this evening. Dr. Chris Matuszewski, who as you know is in our chemistry department, and also Professor Rongqiu Jin, also a professor of chemistry in the Mellon College of Science. Professors Matuszewski and Jin were the nominating professors who brought Dr. Merkin's candidacy to the table, and I want to thank them for their excellent recommendation. Let me say a few words, first of all, about the Dixon Prize. The Dixon Prize lecture is one of Carnegie Mellon's most important scientific events of the year, one that not only honors a leader in science for their contributions but also marks important trends and new directions of scientific thought. The Dixon Prize in Science at CMU and the Dixon Prize in Medicine at the University of Pittsburgh were established by Dr. Joseph Dixon, who was a prominent Pittsburgh surgeon, and his wife Agnes Fisher Dixon. With this prize, Dr. and Mrs. Dixon helped to bring as much prestige and honor as possible to, to two universities here in Pittsburgh. Carnegie Mellon has been bestowing these awards on leading scientists since 1970, for the past 45 years. And year after year, we have been able to bring some of the country's most forward-thinking scientists to our Pittsburgh campus. This procession of renowned scholars over the last 45 years has allowed us to chronicle and pay witness to incredible advances that we have seen in natural sciences, in engineering, in computer science, and of course in mathematics. At a time when we see significant challenges to our foundational values, it's even more important to reaffirm our commitment to the pursuit of knowledge and support for long-term scientific research. This belief in the power and potential of science is a fundamental part of our national identity, which is synonymous, of course, with innovation, with curiosity, with discovery and ingenuity. One of the nation's earliest advocates for investment in science research was Vannevar Bush. He was essentially our nation's first science advisor. He was the director of the Office of Scientific Research and Development shortly after World War II, and he said at that time, research is the pacemaker of technological progress. Bush also recognized that new products and new processes do not appear full-grown. They're founded on new principles and new conceptions, and in turn are painstakingly developed by research in the purest realm of science. Basic research is not only a key factor driving American competitiveness within the science and technology and education enterprise, it is also the foundation for long-term discovery our economic prosperity, and our societal well-being. This was true during the 1940s when Vannevar Bush wrote his 1945 report. I'm sure most of you are familiar with that, Science: The Endless Frontier, which spurred the creation of a system of public support for university research that endorsed this rate. Just think of National Science Foundation, NIH, DARPA, NASA, and so on. And that is even more relevant today. The Dickson Prize is one of the many ways that Carnegie Mellon demonstrates its respect and commitment to these ideals by recognizing leaders in diverse scientific fields of study who have significant and longstanding contributions. We especially consider the work of those investigators whose research relates to our, to our institution and active lines of inquiry at Carnegie Mellon. The 2016 recipient, Dr. Chad Mirkin, is a fitting addition to this illustrious group. He is the George B. Rotherman Professor of Chemistry and Director of International Institute for Nanotechnology at Northwestern University. Dr. Mirkin is widely acknowledged for his groundbreaking discoveries and nanoscience expertise that have changed the way scientists think about chemical systems. Like many previous Dickson Prize winners, his research has had far-reaching implications and applications across many fields of inquiry. To give us further insight into the many accomplishments and accolades of this year's Dickson Prize recipient, I now invite one of Carnegie Mellon's own highly acclaimed scholars and professors, Dr. Krzysztof Matuszewski, to join me at the podium to say a few words. Krzysztof, please join us.

Good afternoon. It's really a great honor and pleasure to introduce Chad Mirkin today. In fact, What Farnam said, that Chad is a professor of chemistry, is not exactly true because he's a professor at 5 different departments. So it is not only chemistry, but also material science and engineering, biochemical engineering, and medicine, and also biomedical engineering. So it's a really person of practically extremely broad expertise and extremely broad interactions at different departments. Chad got his BS not in Dixon but Dickinson College, and this was in fact in Pennsylvania as well. Then he got his PhD in Penn State and then moved to MIT and was a postdoctoral fellow with Mark Ryton, and '91 joined at Northwestern University. And Chad, in fact, is one of a few, less than 20 researchers and scientists who are members of 3 different academies: Academy of Sciences, and also Medicine and Engineering. And in fact, I must say that we are very lucky with the Dickson Prize because 3 of the former awardees also are in this elite category. So it was first Bob Langer from MIT, then was Dave Tyrell from Caltech, who was also faculty at Carnegie Mellon. And 2 years ago was Joe DiSimone. And I must add that our president, Subra Suresh, is also among these elite people. Chet, in fact, was recognized by many awards. And you can see the list here. And probably the last very significant award was Dan David Prize from 2016. And Chad's prolific activity in publishing papers can be evidenced here by 670 publications which are cited more than 100,000 times. And I checked today on Google Scholar, his H-index is 152, which means that he published at least 152 papers which are cited more than 152 times. And in fact, there are 20 papers cited more than 1,000 times, which is amazing. But in addition, he's unusually involved in the developing intellectual property and patenting. There is a list of more than 1,000 patent applications and 290 issued patents. And this is unbelievable that 90% of them are licensed. Chad started 3 companies. You could see here Nanosphere and Aurasense and Terraprint and Exicure. And these companies produce more than 2,000 commercial products, which is really amazing accomplishment. He's a member, or was a member in fact, of Obama's PCAST team for 8 years. And we had that during lunch today. Discussion what will be during next president, PCAST team, if this team will exist, but extremely good service to not only government but also to publications. He's for many years associate editor of Journal of American Chemical Society, a flagship journal in chemistry in U.S., and also founding editor of Small. Concerning his research, very broad but essentially focused at nanotechnology. And one of the most interesting is really development of these spherical nucleic acids and also idea that the nanoparticle can be treated sometimes as an atom, giant atom, and DNA as a linker essentially enabling connectivity between these large atoms. Concerning nanotechnology, one of the most important really discoveries was the deep panditography and also on wire lithography. And National Geographic a couple years ago considered this one of the top 100 discoveries which can change our world. And I think equally important is area of the nanoparticles, and this would be, I presume, covered a little bit today. It started, in fact, with Professor Hong Chao Chin, who was one of the most famous now PhD students. And the topic of today's talk will be related to nanotechnology and how small things may matter. So before inviting Chad here, I would like to really pass a few words to—

Sure. Well, thank you very much, Chris, for that introduction. Before we're treated to Dr. Murkin's lecture this afternoon, We want to officially confer this year's Dickson Prize to Dr. Merkin. Would you please join me on the stage? Dr. Merkin, on behalf of Carnegie Mellon University, I'm pleased to present you with the 2016 Dickson Prize in recognition of many distinguished contributions you've made to science. With this comes a medal and a check. Congratulations.

Okay. Let me begin, first of all, by saying thank you for this incredible honor. Just got to know Farnam today, and Chris, of course, I've known for quite some time. And Rongqiao, one of my most spectacular students, helped, I guess, put all this together, and I very much appreciate it. I have to say that the visit— I've been to CMU before— the visit was spectacular. I grew up in Pennsylvania, so I've always been impressed by CMU and its incredible reputation. But every time I come here, I see amazing advances, and today was no exception. I've also been really impacted by the students that CMU has produced. I've really had the good fortune of having many wonderful students, in fact 5, come from CMU and really impact my research program. Most notably recently, Matt Jones, but also Jill Millstone, came, or Mark Langel. Alyssa Chinnan came. And then this is kind of the give-back type of thing. I've sent Rong Chao here, and he's already producing great students that are now coming back to Northwestern, and the cycle continues. And he sent me Anadita Das, who's also done quite well. And I actually, when I recruit CMU students, I say, look, I've never been burned. I've had an incredible pipeline of wonderful students and I expect that to continue. So the pressure's on, and they always rise to the occasion and do quite well. So that's been wonderful. And then, of course, just the— I want to thank the Dixon family and the folks that have made this possible. This is really quite an honor. I've been aware of this prize. I've actually nominated people in the past for this prize, and to be up here to accept it is very humbling and also a great honor. What I thought I'd do over the next 45 to 50 minutes is tell you a little bit about my field of nanotechnology. And this is supposed to be a general talk, so I've tried to lay it out in a way that at least I can appeal to the interests of many different groups of people regardless of what your background is. And hopefully give you a feel for why I have such passion for the development of this field. And to do that, I think I have to give you an introduction and talk a little bit about the history of nanotechnology. And it has a kind of an unusual history. And there's both an old, very far-reaching history and a more recent one. Talk a little bit about scale and why scale is so important. Why is there a field of nanotechnology? Is it just about making things smaller so that we can pack more structures per unit volume, or is there something more to it than that? And there is, it turns out. When you have a new field, and by new, this is the modern field I would say has been around for about seriously for the last 15 years or so. So that's still relatively new by scientific terms. And there's a lot of excitement, a lot of projection of opportunity, and I think that's reasonable. Some people would call that hype, but I think it's important to think about possibilities. And this field, of course, experienced a lot of that. Some of them— some of the hope was diminished after scientists started tinkering around, and other types of things were discovered that really drove the development of it from that point forward. And then I think it's fair to ask a little bit about opportunity realized. You know, where was potential truly realized? Where are we seeing major advances? And I'll try to answer aspects of that in today's presentation. So historically, some people give this man credit for starting the field. This is Richard Feynman, a Nobel Prize winner. Back in the late '50s, he gave a speech called Plenty of Room at the Bottom at Caltech. You have to keep in mind that he was a Nobel Prize winner, so he was given the— I once met Richard Smalley and I saw him present to the NSF and he proposed that the NSF spend their entire budget on his research program. And I got up afterwards and I said, you know, a lot of people were irritated, there were other scientists in the room, they were ticked off, I said, you know, Rick, I go, where do you get the nerve to first of all say that, but to say that to an entire crowd of other scientists that are hoping NSF will fund their research programs. You know, Chad, he goes, the great thing about the Nobel Prize is once you get it, you pretty much can get up and say anything and a good fraction of the audience will believe you. And so, again, taken with a grain of salt, I mean, it's pretty impressive. This guy was giving a very visionary speech. And I encourage you to go back and read it. Because it's remarkable. And you have to think about it in the context of time. This is before the age of miniaturization, the microelectronic revolution. Before the fact that we knew we were gonna have tools that allowed us to visualize atoms and manipulate them one at a time, a scanning tunneling microscope, for for example. And in that speech, he says, "I'm not afraid to consider the final question as to whether ultimately in the great future we can arrange the atoms the way we want, the very atoms all the way down." And you'll see he actually predicts— and I'll come back to this a little bit later on— a timeline of when this is gonna happen, which is, I think, pretty shocking. And a lot of what he said was actually wrong, but some of what he said— a lot of what he said was actually right. And not only right in terms of what was gonna happen, but also the timeline over which it would occur. Occur. Others point to money as a driver of innovation and the excitement that the Clinton administration had, for example, in terms of investing in nanotechnology. Also at Caltech, it turns out, President Clinton announced the National Nanotechnology Initiative in 2000, where he basically talked about the incredible opportunities this new field was going to bring. To science, engineering, and medicine. But also the fact that the federal government would invest initially $500 million and then every year thereafter over $1 billion, and that continues today. And so resources are required to develop any scientific field, and this got a lot of people really excited. And he was clearly excited. He says, soon researchers will bring us devices that can translate foreign languages as fast as you can talk, materials 10 times stronger than steel at a fraction of the weight, And this is unbelievable to me, molecular computers the size of a teardrop with the power of today's fastest supercomputers. Now that's coming from a guy who would never tell a lie. That's a joke stolen from Mark Hurston, but it works. It turns out in every country, every time, red state, blue state, doesn't matter. Clearly had a lot of enthusiasm. Scientists were pumping him up, and I don't think there's a whole lot wrong with that as long as we get to credibility and we begin to pick pick apart a field. But it's important to think about what ultimately might be possible. And this was happening in the early stages of what I call the modern field of nanotechnology. Now historically, of course, this is as much evolutionary as it is revolutionary. People have been developing structures and devices based upon nanomaterials for a long time. You can go back to Roman era times. There's something called the Lycurgus Cup that's coated with a glaze that has metal nanoparticles. And those particles, it was known, scatter light in unusual ways so that depending upon how you look at it, it appears very different in color. So you could use it for cosmetic purposes and to create interesting structures like this beautiful chalice. And of course, stained glass windows, the red colors in stained glass windows come from metals. For example, gold nanoparticles in particular. Ancients didn't know that they were nanoparticles. They had no way of really imaging them. But they knew that if they processed glass in a certain way that was contaminated with these types of materials. They would create these structures that were beautiful in color and would stand the test of time because unlike the dyes in your clothing, these didn't photo bleach. So this was a real technology that came out of, again, the processing of materials on the nanoscale. It wasn't until the mid-1800s that Michael Faraday actually proved that these types of structures were in fact little nano nuggets of gold particles, what we call a colloid. There are dispersions in the Royal British Museum that you can go today and see that Faraday had produced. These are stable structures and can be used for all sorts of different purposes. Then there was the age of miniaturization. That was the microelectronics revolution. We start with a big transistor and then we realize that, hey, if we can make things smaller and smaller, we can begin to create powerful devices where we can pack more and more devices per unit volume. And that allows us to create computers like the one I'm using today to give this presentation with more and more power with as we begin to learn how to make things even smaller and smaller. And that's arguably the most important nanotechnology industry today. And then, of course, what we realize is that this is a very important area where we have to learn how to do two things. One is to manipulate atoms, like Feynman said. So instrumentation drives this development, but also chemistry does as well, being able to use chemical reactions to begin to build structures, that are on a scale that matters. And of course the question is, what is the scale that matters? Um, I had, uh, the good fortune of working with NOVA for a while, and they were trying to communicate some of this. There's an episode called "Making Stuff Smaller." It's still played today. It's kind of exciting. This guy David Pogue came to, uh, Northwestern. He was really sick. This is actually in a green room, and you have to stay very close together, and I kept worrying about him passing his pathogen to me, which he, of course, did, it turns out. But we got through this interview, and none of the stuff in the background is actually there. It's actually produced after the fact. But he was asking me about scale, and I thought rather than going through my analysis here, I'd just play it for you so you can get a feel for it. They have better software than I do, and it'll put things in context.

[Speaker] I don't even know what a nanometer is. So this is a meter, this is a centimeter, this is a millimeter. Is this a nanometer? What's a nanometer?

[Speaker] Let me try to illustrate it for you. If we shrink you by a factor of 2, You're about the size of a small child. We continue to shrink you by a factor of 2 4 more times, you're about the size of a golf ball. We go to 10, you're now the size of an ant. We keep going another 7 times, and now you're about the diameter of a human hair. That's roughly what we can see with the naked eye.

Even after so much shrinking, I'm not even close to the nanoscale. Cut me in half 5 more times, and I'm the size of a red blood cell. 5 more times, I'm a virus. 7 more times, and I'm finally 1 nanometer in size. 1 billionth of a meter. That's less than half the width of DNA.

So those are some good benchmarks. So a red blood cell, 5 microns in diameter, or 5,000 nanometers. DNA, the diameter of it, roughly 2 nanometers. Chemists would like to say that this is the chemistry length scale, but in reality, I think it's truly the biological length scale. We need chemistry to begin to build structures that are important on this length scale, but it's ultimately a length scale where these types of structures are on par with a lot of the systems that Mother Nature has learned how to synthesize and build. And that's gonna become important a little bit later on because it allows you to begin to build structures that can manipulate living systems in unusual ways as well. It also kind of emphasizes an important point of this field. This is not just about going below a micron. Turns out that most of the action in this field is in the 1 to 100 nanometer length scale when you build structures on that length scale. Why is that? That's not rigorously true. That's a general range. Because materials begin to behave differently. One of the fundamental premises of nanotechnology is that everything macroscopic when miniaturized to this length scale will have different properties. And part of that's if you think of just taking a bulk, let's say, sample of gold and shrinking it down. When you have a bulk material, the contribution to properties from the surface atoms is relatively small. It's a drop of water in the ocean, or a small number of them compared to the bulk atoms. You shrink the structure down to a very tiny length scale, now they significantly contribute to the overall properties of the resulting material. And that's going to be true regardless of whether you're talking about gold or some other type of material. And that allows you to tune properties in an unusual way. Now, to be able to do this, you have to be able to see them. And so another part of this field was the development of tools that allow you to image and to manipulate structures. In this length scale. So having access to powerful instrumentation, I tell my provost and president that, you know, the smaller we go, the more expensive it's gonna get, and that turns out to be the case. Scanning electron microscopes, transmission electron microscopes, and the invention of the scanning tunneling microscope, that might have been one of the most important things, 'cause the first time, for the first time, you could begin to visualize atoms, not with light, but with physical probes that would allow you to measure their presence under a sharp conducting tip., and then move them around to build tiny structures. So how do we think about this? I can tell you how I think about it. You can get different definitions depending upon who you talk to. But what is the opportunity in nanotechnology? To me, it boils down to 3 different things. The first is, and this is why chemistry plays a big role, developing tools for making, characterizing, and manipulating materials on this sub-100-nanometer length scale. We have to get really good at that to be able to really develop this field.. So that's both surface analytical tools, but also chemistry tools that allow you to take atoms and assemble them and stop them in terms of their growth into structures that are relevant on this length scale. The second is, and this is where a lot of the science is, what's different? So creating ground rules and understanding of why miniaturization makes a difference, the chemical and physical consequences of miniaturization. And to give you a feel for that, here's an example. These are particles. Silver and gold, composition is the same. There are, what, 6 different examples here. Silver spheres on the right, you can see 40, 80, and 100 nanometers. You can see them. We can use electron microscopes to image those particles and see their little nano nuggets of silver. And you can see the way they scatter light is very different depending upon size. They're all spheres of silver, but very different in terms of optical properties. If I go to gold, 50-nanometer structures, I get a green hue.. And if I go to 100 nanometer particles, I get orange. And now if I change the shape of the gold, or the silver in this case, they're silver nano prisms, I get red. So that's kind of neat. With one material, I can manipulate properties systematically simply by adjusting size and shape. And that's a new and very powerful concept and very important if you're thinking about ultimately discovering new materials and developing new technologies.. So the third part of this is in fact doing that. Once you recognize the differences, asking what can I do with those differences and how do I use them to create technology that solves a problem that's important to me. And you're gonna see that theme in the examples that I provide today. This is one of the best examples of what we call convergent science because nanotechnology doesn't discriminate in terms of field. It takes and impacts all fields by taking concepts and putting them together. And if you look at what we do at Northwestern, we put teams together that come from chemistry, biology, material science, physics, all different aspects of engineering and medicine to begin to look at these new types of materials and ask how we can solve major problems in the subfields of interest. We've built up a very large operation at Northwestern. It now has over $1 billion worth of infrastructure centered on both the Evanston and Chicago campuses, the medical schools and the Chicago campus. And then we've got alliances, strong alliances with Argonne National Laboratories and now more recently University of Chicago.. And what this creates is an incredible hub of intellectual capabilities, great instrumentation as you're going to see, but also it attracts phenomenal students that want to come here regardless of field and begin to explore how nanomaterials and concepts from nanoscience and technology can impact their subfields of interest. So what I thought I'd do is just give you a couple of examples of some of the things that we've been working on and talk a little bit about why I think they're impactful and kind of illustrate what I've been introducing you to here. And so here are areas of impact that we focus on: electronics, security and defense, clean water and the environment, energy, and medicine. These are technological drivers, right? So that's the neat thing about this. If you think about this as the world's greatest materials play, new materials will almost always lead to advances in these areas and in certain cases allow you to solve major problems in those areas. The name of the game is figuring out what material to use for a particular area of interest. So let's look at electronics and materials in general. Photolithography, a technique I think most people are familiar with to some extent. This is the way computer chips are made, microfabrication and nanofabrication is done. The basic idea is you can create a mask, you can shine light through that mask over a substrate that's coated with some sort of polymer that's photosensitive, and that allows you to transfer a very intricate pattern to the underlying substrate. And then you can change the materials of— or the properties of the— for example, the polymer coating that substrate. So you might make it insoluble. And therefore, if you rinse away the unexposed area, leave the exposed area, you've transferred the pattern from the mask to the underlying substrate. Then you can chemically etch the underlying substrate, and that transfers then the pattern into that. You lift the polymer off, and now you're left with a device architecture that you've preconceived and now made. Using light, directing where things happen with light. Now, that's the good news. The bad news is that these types of systems have a limit in terms of how far you can go. Turns out that limit was not as bad as we thought it was. Physicists, engineers have gotten very good at playing tricks with light to make smaller and smaller structures. But as they do that, two things happen. One is they're limited in terms of the materials that they can process.. And they're ultimately limited in terms of how small they can go and how they can actually fabricate these. The expense of producing these goes way, way up. So at Northwestern, we had a great— have a great researcher, a guy named Mark Ratner, who put forward the idea with one of his postdocs at the time that we could think about preparing electronics and computational devices in a different way. Instead of relying on silicon, which is the basis for much of the semiconductor industry, we could begin to think about building device components out of individual molecules. It's a chemist's dream, right, where a molecule would be the basis for a transistor or a different type of functional architecture. So conceptually, that's really neat because I can, for example, I can look at a cube of sugar and if I think of each molecule as a device, I have 900 billion transistors in one cube. Obviously an incredible trivialization because those aren't wired up molecules. And there's a major issue here in terms of how you think about connecting these. And then they may or may not have the properties you want. But at least it gives you a feel for what the dream was and the hope was that we could begin to move towards a much more tailorable class of materials. And in the process go even smaller and get more powerful in terms of capabilities. But it also highlighted some of the limitations of what we had developed as a world in terms of capabilities with respect to silicon technology. We do very expensive fabs and fabs where they don't want other types of materials in there. It's a very streamlined process. It's a process where contamination can be a major problem. And so working with new types of materials is not something that's very exciting to somebody who's just spent billions of dollars on producing one of these fabs. So we began to think about this and ask the question, could we begin to develop new types of tools, lithographic tools, that would allow you to pick and place molecules where they needed to be and to wire them up so that you could begin to make measurements on both conventional chemical structures but also biological structures? And this was referenced in the introduction. Actually, I thought it was a gross exaggeration. It was picked as one of the— not— it was actually not 100 potential, it was actually 100 most impactful discoveries that changed the world. This is not a discovery that has changed the world, at least in terms of technology. It's a discovery that changes the way you think about manipulating matter on the nanometer length scale. I think, ironically, it's going to have impact that goes beyond what they were talking about here with respect to electronics. In fact, I think that's the minor play here, as you're going to see in a little bit. But that's the neat thing about science. You are not constricted. At a university, you make discoveries, and then you kind of follow them and figure out where you can use them to make advances. But at the time, we were thinking about using these types of tools to pattern molecules on surfaces and hopefully begin to address this issue of how do we make structures where we can begin to define the properties of molecular-based systems, at least with respect to electronics and optics. Now, we wanted more than that, We don't want to go to a fab to do this. We want to be able to do this at the point of use. And there was a blueprint for doing this, right? If we look at the modern printing industry, it's incredible. Not so long ago, we were using printing presses to print structures, newspapers, for example. And now we take for granted that we can have a desktop printer. We expect to have that. They almost give them away when you buy a computer now because they make most of their money on the inks that are sold. Remarkable, right? I published my thesis in graduate school using a plotter. Most kids in the audience don't even know what a plotter— Jill probably doesn't even know what a plotter is. Because you expect to have a laser printer that prints these really sophisticated structures and documents that you used to have to go to a very professional print shop to print. Well, the question here is, can we do the same? Would it be possible to see the same type of revolution if we could but in science and in technology, if we could begin to take what defines a fab and begin to create the equivalent of a desktop nano printer. But we want to be able to do this in a way where we don't just have fab capabilities, but where we can begin to print with almost any sort of matter, including biological structures. Well, we said if we're going to do this, it's likely not going to be done with light. They keep hammering down what you can do with light, but as I said, it becomes more restrictive in terms of what you work with as you do that. And so we began to turn to some of these tools, the scanning tunneling microscope. The important thing there was back in the '90s, a guy named Don Eigler showed that you could take and manipulate and spell structures out, in this case IBM. But that's done at 20 Kelvin. That's very, very chilly, right? And under vacuum, horribly impractical. So these are not structures that you can make and use for any sort of technological purpose, but at least kind of tweaked curiosity and said, hey, wouldn't it be neat if we could actually do this and do this routinely at room temperature with lots of different types of materials and to be able to create structures that are not so tiny? This is so small that it has to be magnified 100,000 times so you can see it, but where we could pattern over large areas. And that was the birth of something we called dip-pen analog lithography. And with dip-pen analog lithography, we used a variant of the scanning tunneling microscope, which was an instrument that uses a tip to basically feel a surface. And it was designed to be a reader. So that you could get a topological map of the surface as you move the tip around on the surface and got a contour map of the surface. Very powerful from a surface science standpoint. We looked at it and said, why couldn't we turn that into a writer? Why couldn't we think of that as a dip pen, like a quill pen, coat it with molecules of interest, and transfer those molecules to an underlying substrate? And it turns out you can, but you have to know some tricks. So one of the tricks is when you do an AFM experiment in air, and you bring the tip down in contact with the surface, what naturally happens is water collects at the point of contact. That's viewed as a major problem in the field. And we looked at that and said, hey, wait, we could use that as a carrier solvent. And if we designed molecules that chemically reacted with the surface, when we brought the tip down and moved it across the surface, they would react in a self-limiting way with the surface and generate a structure one molecule high. And you're going to see that in cartoon fashion here. Now, you got to keep in mind, The size of this tip is 1/100,000th the size of a quill pen. So it comes in contact, water condenses. And now as you move across, the molecules react with the substrate. The substrate could be anything. It's not paper in this case. It could be silicon. It could be a gold-coated silicon substrate. It can be a variety of things, anything where we have the proper ink and substrate combination to generate that. So this was kind of an innovation, and one that was quite powerful. So let's go back to Feynman's speech. We wanted to prove that we could have the control that was necessary to truly turn this into a lithography. So I told the students, let's go back to Feynman's speech and print it with molecules. So what you're looking at is not a print on paper, it's a print on gold. The white letters are one molecule high, and the image here is a false color map. The tip comes along and we measure the friction in the molecules that cover the gold substrate in this case, create a high-friction area, and the tip sticks, giving you this type of contour map— or I'm sorry, this frictional force map that you're observing here. And it's kind of neat. If you read this paragraph, it says, "As soon as I mention this, people tell me about miniaturization and how far it has progressed today. They tell me about electric motors that are the size of the nail on your small finger. And there's a device on the market, they tell me, by which you can write the Lord's Prayer on the head of a pin. But that's nothing. That's the most primitive halting step in the direction I intend to discuss." It is a staggeringly small world that is below. And this is incredible. In the year 2000, when they look back at this age, they will wonder why it was not until the year 1960 that anybody began seriously to move in this direction. So this guy is saying this, and he's predicting this. This was published in Science at the turn of the millennium, in the year 2000. Okay? So it's kind of an incredible thing that not only are these projections happening, but the pace at which the time they were happening was in sync with at least what he was thinking about. Now, that's good, but that's printing a structure. Those tips are really, really sharp. We're printing a structure that's 100 micrometers by 100 micrometers. You can't even see that, right? 0.1 millimeters by 0.1 millimeters. To really make this functional, we have to be able to create tools that allow you to pattern over large areas, and so that was a problem we wanted to address. And what we looked at this and we said, if you could do this, and you could create a commercial tool, for example, that allowed you to do this, you could really dramatically move the pace of many fields. So, for example, if you could print molecules that were made out of proteins and DNA and carbohydrates, you could begin to control the patterning of substrates so that you could control how cells interact with those substrates. Control, for example, how a cell differentiates, which we can do now, providing the right types of chemical cues to take it down one path or another. You could build very tiny biological sensors where you can put the receptors needed to sense a particular target in a very confined space. And you could, in principle, begin to pattern electronic devices that would ordinarily require you to go to a fab and spend a ton of money at the point of use, which would allow you to rapidly prototype and begin to do experiments at a much faster pace, much like we produce documents at a much faster pace with inkjet printers.. But the other thing, and this is part I said we didn't fully appreciate at the time, was if you can do this, you can begin to think about using those tips to control chemistry in localized areas. And you can begin to build massive libraries that vary in size and composition. And I just told you that if you change size on this scale, you change properties and effectively the identity of the material. So this becomes, if you can do it over large areas with many different types of structures, you can rapidly discover new materials that solve all sorts of problems in principle that we face with respect to a current lack of technology today. And so we call that nanocombinatorics. Whether you're looking, for example, for catalysts that affect different types of chemical reactions, the growth of a carbon nanotube, for example, or the conversion of a low-priced substrate into high-value product., or physical properties where we're trying to screen a class of materials for unusual optical properties or electrical transport properties. It comes down to how you screen in terms of getting out the structures that are of interest. Well, how are you going to do this? You're not going to do it with what I just described. But that kind of set us in motion. We started thinking about this. An AFM cantilever is a spring effectively. It's a long arm with a tip on the end of it. And we said, wouldn't it be great if we could simplify this by moving the spring to the, to the tip. We could put the spring in the tip. And the way you do that is to make the tip out of an elastomeric material, rubber. And if you could do that, you could pack many of them in per unit area. So you can make a mold, for example, and that had pyramidal indentations, pour an elastomer in there. If you had a million of these, you'd form a million tips at once. Put a glass substrate on there, cure it, and peel it off.. And now you have an array of pyramids. And if you coat them with chemicals, each one of those tips can be a point source to deliver molecules to an underlying substrate. And that was the birth of something we call polymer pen lithography. Well, you look at this and you say, wait, that's problematic. Those tips are really soft, so you lose resolution. You can't make as fine a structures. So we said, wait, if that works, we can take the spring and move it from the tip to the backing layer. So we can have the glass substrate, a thin coating of the polymer, That's the compressible material. And then the tips can be made out of silicon, which we can do as well using relatively straightforward microfabrication procedures where we etch these tips down to very sharp points. Or you could take this structure and you could coat it with an opaque material like gold. And you could create tiny little apertures, just dissolve the gold at the tips. And now you can drive light through the back of this array. And if you use something called a digital micromirror device, which is in an ordinary projection TV, you can take one beam of light, split it into thousands of beams of light, and independently drive light down the backs of the pyramids, which are microscopic, and drive it through those little nanoscopic apertures, and now develop anything photosensitive on the other side. That's a powerful advance, because now I have lots of tips that are independently addressable. And in principle, I can make anything, as long as I can stitch fields together. And it turns out you can do that. Then the final thing was somebody asked me how small you can go today. Well, it turns out if you combine this with chemistry, take the top technique, I can take a polymer, the type that Chris would produce. I can load it up with metal ions. And I can use it as an ink. And I can put a blob down on the surface. That blob creates a little nanoreactor. And the volume of that blob controls the number of metal atoms within it.. And that's almost a countable number of atoms on this scale. And if I keep diluting it out, I can get down to a single atom in principle. If I post-treat this then by heating it at high temperature under a reducing environment, all those atoms get reduced and they come together to form one nanoparticle. I'm going to show you an example of that in a second. So you can control a reaction on the nanoscale where you can set up the number of atoms that can interact and they must work within that reactor. This is not— you know, a pie-in-the-sky thing. This is actually a commercial product. We just created it and started producing last year. It's something called the TeraFab system. It now works with 160,000 tips patterning over large areas with tremendous control in terms of the types of materials that you can work with, shown here— DNA, proteins, virus particles, block copolymers, nanoparticles, really anything that will flow from tip to surface. Here's an example of a polymer pen array, 11 million tips in this array. These are just 11 million elastomeric tips. It costs about $2 in terms of materials to make these types of structures. And you can see the size of the structure here. And this is actually the pattern result, 44 million features now made in a fraction of a second. 4 dots 11 million times. Well, yeah, 4 dots 11 million times, so 44 million features in that case. But you can begin to play tricks with this. So this is what we didn't anticipate when National Geographic kind of picked it as this really important thing. We could take the array and we could intentionally misalign it. And when you do that, look what happens. This side of the array hits first. This side hits last. And we have an intermediate state in between. Well, that compresses the tips. So what that leads to is a gradient of features where they systematically change in size from small to large. Why is that important? Well, think of that experiment I just described. That controls the size of the reactor, and therefore that controls the size of the nanoparticle you're going to get. So 11 million of these can produce 11 million particles that subtly vary in size now. And then if I spray onto these tips, this array, different chemicals, I can begin to mix and match components of the periodic table to make an incredible library of nanostructures rapidly. They would be almost impossible to conceive of synthesizing any other way. And I can use that then to begin to think about identifying materials that have properties that can be useful for a given application. So here's an example. If I take this polymer, I load it up with two metals. In cartoon fashion, I create a structure like the one shown here with one blob coming down. If I treat under argon, in this case, first at 150°C and then at higher temperature under hydrogen, I blow away the polymer. The salt's aggregated.. And then it gets reduced. And every atom goes into forming one particle. And so by controlling the stoichiometry here, the ratio of the metal precursors, in principle, I can control the identity of the particles that I generate. So we wanted to prove something. And so recently we just published this in Science magazine. We said, let's go take 5 elements. Nobody's ever done this before. And let's ask if we can use this technique to make every combination of them. First, the pure. Structures. So each of these are particles—pure gold, pure silver, pure copper, pure cobalt, pure nickel. The cartoons in the upper left, this is what we call an EDAX image. It's a technique that allows you to get an elemental map of what you produce. So you can see they're all one color because they're all one element. But now I can load up the polymer reactor with different metals—gold and silver, gold and cobalt, and every combination thereof. And you can see two different types. Those that mix, we call those alloys. And those that phase segregate, they don't like each other. They stay separate from one another. Those are fundamentally different structures. People know a little bit about what these do. They know nothing about what these do, these tricomponent systems. Nobody's ever conceived of making the tetracomponent systems. And here's the one 5-component system. So 16 of these particle types have never existed on the planet before. And that kind of shows you what we're thinking here. Now when you then think about how far you can go with this and how far you need to go with it, just do a math experiment. You know, if I think of 13 metallic elements in every combination of 5, I've got 286 million combinations. And if I go with every combination, I end up with 11 billion combinations. And so think about the challenge of trying to do that one at a time. You're gonna grow very old trying to probe what's possible. And so we think this is going to be an incredible materials discovery tool that allows you to quickly find promising leads that then we can challenge great synthetic chemists like Rongqiao to go back and synthesize en masse. But that's a lot better than asking Rongqiao to go in there and try to figure out which of the 11 billion combinations we should spend a lot of time on and scale up to large quantities. And so companies like Exxon and Shell are interested in this from a catalysis standpoint. A lot of the pharmaceutical companies are also interested in catalysis standpoint, looking for materials that, as I said, have unusual optical properties or magnetic properties. All of this is kind of in play. And we're kind of having fun now looking at how we can do that. Let me turn to medicine, because that's another area where materials discovery is going to make a huge difference on the nanoscale. You might ask, well, why and where? Well, diagnostics, in vitro, in vivo molecular imaging, and therapeutics are the natural areas. Those are the big drivers. Why would it make a difference here? Well, materials make a huge difference there. New types of materials can lead to probes that provide higher sensitivity and selectivity in terms of molecular diagnostics. In the case of imaging, a better contrast and what we call theranostic capabilities, the ability to image a problem, for example, and then deliver a therapeutic payload. Ways of going into cells and genetically manipulating them, I'll actually talk about that. And then new and potentially better approaches to drug delivery and gene regulation. Therapy. So here is an example. You know, I told you everything is different, right? This is, I think, a very important— most people know what DNA is, at least have heard of it, a discovery made by Rosalind Franklin and James Watson and Francis Crick. They identified what we now know as the double helix, a very iconic structure. This is the blueprint of life. Its understanding has led to so many advances in biology and more recently in medicine, Without that structural understanding, without that structure, we would be nowhere, at least in terms of developing those fields. Led to lots of new types of diagnostic tools and medical tools, some of which I'll share with you today. How does nanoscience come into play? Well, we've been thinking about this a different way. As I said, restructuring matter on this length scale can lead to structures with unusual properties. And so one of the things we did in 1996 was we began to think about how we could link to nanoparticles. And this is an example of going down one path— we still go down that path— but then shifting because we learned something. Chris talked about the concept of a programmable atom. That was the idea. We wanted to learn how to take particles and create programmable bonds. And we could take and then functionalize these types of structures with dense layers of oligonucleotides. And you can see this is the cartoon type of structure. And you could see then this type of entity here. This is the electron microscopy image where you can see the central nanoparticle core. And the shell of a ligonucleotide surrounding it. So big deal. What's important about that? Well, that's highly programmable. But it turns out if you compare these types of structures— nobody had seen these before— to normal DNA, they're completely different in terms of properties. What are some of the properties? They'll soak up, they'll bind complementary DNA. DNA forms a duplex when complementary DNA is encountered, and that duplex is much more tightly held than normal DNA. Why is that important? Well, you can think about using these, for example, as probes in biodetection schemes, and we've done that. You can actually see here there's something called the Verigene system that's designed by a company called Nanosphere, which was sold to Luminex, to identify and sort oligonucleotide targets associated with disease. And so the idea is that you can take a sample—blood, saliva, or urine—and quickly figure out whether a person has a particular type of genetic abnormality or is infected with a viral or bacterial pathogen. These are FDA-cleared tests. This is an example of very high sensitivity detection, but also detection that can be done at the point of care. We'll go back to Mr. Pogue. He actually came to Northwestern, was talking to me about this. I said, look, this is too complicated. Head up to Nanosphere and you can get, you know, a picture, or what you see is worth a thousand words. And he did.

And I want to share that with you because it's kind of interesting. Chad Mirkin has developed a technology that harnesses the unique properties of gold and silver nanoparticles to test for genetic variations in patients. Sequencing DNA is expensive and time-consuming, but Chad's revolutionary test takes less than 2 hours.

I offered to bleed for science to see how it works.

And your name is?

David. Okay, so we're doing a low blood draw today. You can relax. Is this the extraction bench? Yes, this is. First, a technician extracts pure DNA from my blood sample. This is my DNA. This is your DNA. He then loads it into a small disposable cartridge and inserts it into the machine for testing. This test can actually read the letters of my DNA, and using gold nanoparticles, it flags variations that might make me unusually sensitive to particular drugs, or even mutations that signal heightened risk for disease. Less than 2 hours after drawing my blood, the results are in. It turns out that the test has some interesting news for me about my sensitivity to a blood-thinning drug called warfarin, or Coumadin. It's commonly prescribed to stroke and cardiac patients. It's a potentially life-saving drug, but if the dosage is wrong, it can cause fatal bleeding.

So what's my What's my warfarin dosage? What they call a double hit, I'm sorry to say. A double hit? You're a double hit. So you have two genes that are mutated, and therefore you're very sensitive to warfarin, and your calculated dose is 2.7 milligrams.

See, I knew it. My mother always said it would be like 2.6 or 2.5, but I always said, "No, Mom, mine's 2.7." You should always listen to your mom, David. The nanosphere test gave me some crucial information. This is the mutation. Ah. Quickly enough to save my life if I'd been ill. It's a diagnostic tool.

The next goal is to fight illness in the body at the same tiny scale. Yeah, so this is amazing. This guy had a 1 in 25 chance of having both mutations. He found out almost in real time that he had it with the technology, which was, you know, a shock to us. You couldn't have set it up in any other way, but it was actually important to him in terms of knowing that. 'Cause a lot of people don't know that when they're put on warfarin and certainly don't know that when they're going into surgery, and so there's actually a big push to try to get these types of tests used across the world population. The big use of this is the ability to do point-of-care analysis of things like sepsis, bloodstream infections, 'cause there you need the information really quickly, because every hour you go undiagnosed, mortality goes up by 8%. And so this is an example of where nanotechnology can play a very big role in, first of all, doing better doctoring, reducing the cost of doctoring, because right now if they think you have sepsis, they just put you on a huge flood of antibiotics, $21,000 worth, and also reduce the costs and also the problem associated with antibiotic resistance. So that's kind of a neat example. The last example I'll show you is that this structure, you know, as I said, which we didn't develop it for biological purposes, but on a sequence-for-sequence basis is completely different from linear DNA. One of the things it will do is it will naturally enter cells, and it will go into those cells freely without the need for what we call transfection agents. So here you can see cells that are treated with normal DNA. They don't light up. These have little fluorophore indicators on them. Here's the same sequence, identical concentration on a DNA-for-DNA basis, 100 times more dilute on a particle-for-particle basis, and you can see that the cells not only take them up, they take them up better than anything known to man. That has significant consequences, and I'll just show you quickly what I mean by that. You can begin to create products and technologies based upon that, because you can begin to use these types of structures that naturally enter cells to go into cells and make intracellular measurements. There are structures called nanoflares based upon these architectures that are designed to bind to RNA inside the cell that's at a high level, and in the process release a short oligonucleotide with a fluorophore that's bound to the oligonucleotides in the on the surface of the particle. That allows you to measure for the first time the genetic content of live cells. Why is that important? Let's say I'd like to take a patient's sample of blood and look for circulating tumor cells. Are they the very early stages of cancer, breast cancer for example? Can I go in and measure those and pull them out and keep them in live form so that I can study how those cells, for example, respond to a different type of therapeutic? So it opens up the ability to think about personalized medicine in a new way. So Millipore has actually commercialized these these. They now have over 1,600 different versions of these, all that vary subtly in terms of sequence, but for you— used for those types of purposes, looking for rare cells. But the other thing you can do is you can begin to think about using these types of structures as therapeutics, because now you can begin to get nucleic acids into organs they ordinarily don't go into. And you don't want to do that with gold, because you're going to build up a gold content with a therapeutic in a living person. But you could do it with other forms of SNAs. And one of the things that we've been looking at is how we can replace the gold with organic materials that are considered biologically benign. And so here's an example of a structure of the liposomal core. Even proteins modified with high-density shells of oligonucleotides behave like these types of structures. And when exposed to different types of cells, are rapidly taken up. That opens up the idea of creating new types of medicines. Nucleic acid medicines, where instead of you looking for small molecules or biologics, proteins and antibodies, which is the way we develop drugs today, we can begin to create drugs based upon sequences, short snippets of DNA and RNA that can go into cells and begin to correct disease cells. We call that gene regulation therapy. So here's an example. We're not the only ones to do this. Other people are doing this. In fact, there are commercial entities that are very close to launching drugs, but all of those drugs target diseases of the liver, because when you systemically inject these, that's where everything gets processed. That's the low-hanging fruit. When you recognize that these go into any tissue or cells that they're exposed to, you can, for example, begin to think about using them as creams, and we have, where you put them into creams and rub them on skin, they go right into the skin, and you can flip genetic switches, in this case associated with psoriasis. We knocked down a gene called TNF-alpha and begin to reverse the effects of psoriasis. That would be a really big deal because right now people are treated systemically for psoriasis, but imagine having a cream that was very effective and very targeted with respect to the types of genes that you can go after. These are in human trials already. They've already passed Phase 1 in Europe and they're going into Phase 2 very shortly. But this is the really exciting one. So one of the things that's interesting about these types of structures is that you can use the sequences that they're encoded with to begin to trigger the immune system in very selective ways. It turns out through studies of bacterial and viral infections that we know different sequences engage with different parts of the immune system in a sequence-specific way. So one of the things we've been looking at is how we can make a spherical nucleic acid that can be locally injected— again, this is a local type of application, right? It's what we call subcutaneous injection— and prime the immune cells to effectively trigger an immune response that tells T cells to go out and eradicate a specific type of cell type. So you're kind of locally training a person's immune system to get a system-wide response. Now, how do you get selectivity out of that? Well, it turns out there are drugs called checkpoint inhibitors that are selective for cancer cells. And what they do is they bind to cancer cells and they stop them from going through apoptosis, cell death. I'm sorry, they bind them and allow them to go through apoptosis, cell death. The problem is, for that to actually work and work well, it must work with an inflamed immune system. And when you only use checkpoint inhibitors alone, you get a really— you get a good patient response for a small percentage of the population, in the case of breast cancer, for example, 15%, but the 85% remain unaffected, or it's not an effective treatment for them. So we've been looking at— is asking with a company that we started called Execure, can we use the spherical nucleic acid to prime a patient's immune system in combination with checkpoint inhibitors to begin to get a combined therapeutic type of response? And the data are really stunning. So this is a mouse model of breast cancer, and this is just tumor growth. That's not good. Tumor grows, animal dies. If you treat with these types of structures, you can stop the tumor growth in its tracks, and you can actually reverse it. Completely cure the animals in this case. This is called a rechallenge, where we take normal animals and challenge them again with the tumor, try to grow the tumor. It takes off again. But with the animals that have been treated with this therapy, it continues. Their immune system continues to reject the tumor. And so that's really exciting. And it works across many different types of cancers. This is a melanoma model. Same type of thing, a different type of checkpoint inhibitor. You see anti-PD-1 in the previous case, anti-CTLA-4 here. But look at the flat line again with the spherical nucleic acid again and the combination type of a therapy. So this is really a promising advance and one that we're taking rapidly to the clinic. And in animal studies, it looks really, really promising, and we're hopeful that translates into human use as well. So where is nanotechnology? Again, I said I'd talk a little bit about realized promise. Obviously, on the diagnostic front, diagnostics move faster than therapeutics. I think you're seeing a lot in the therapeutic coming. Bone scaffolds and regeneration. Clearly the integrated circuit market is an example of a mature type of nanotechnology that will continue to grow. But it's everywhere. You look in terms of particle uses in sunscreens. This is why we no longer have the pasty white types of creams that we put on ourselves. Tiny particles still absorb UV light, but in the visible you don't see the type of creams that we saw in the old days in the '60s and '70s. Sporting goods used as strengtheners, carbon nanotubes for example. Home appliances use silver nanoparticles to effectively kill bacteria. Same is true in the case of fabrics, but also particles used to change the wetting properties of the fabric so that it resists staining. So these types of concepts and materials are beginning to slowly be used by really lots of different folks to solve lots of important problems that affect our daily lives. Many of the times we don't even know that they're present. But they are improving the performance of the materials that we rely on and the devices that we rely on. Okay, I'll finish with this. This is my group at Northwestern. This is a fantastic operation. These are 70 of the most talented people in the world, heavy on chemistry, but also, as I said, biology, physics, material science and engineering, many different aspects of engineering, and now even a few medical doctors are involved. And while I still think the challenges are very large, the small technology in this case is is, I think, portending a very bright future, and I'm looking forward to developing the next couple of decades of it as well. Let me stop there. Again, thank Carnegie Mellon. It's really been a pleasure to be here.

I'll be happy to answer any questions. Thank you, Dr. Murkin, for giving us such a wonderful lecture. Now we open the floor to our guests. For questions.

If you have a question, please raise your hand and our staff will hand you a microphone. Hi. I was wondering that computations are displacing experiments in many areas of science. And I was wondering in this field, Do you see computations displacing experiments or guiding experiments? Computation is actually a very important part of this field, and simulations are a really important part of this field. Many of the types of structures that I work with and Rongqiao works with here, you can model optical properties and understand what you should get way before you even make the types of particles using a combination of what's called Mie theory and and a variety of calculation types that allow you to predict optical response. It's one of the few areas where I think simulation and computation are way ahead of any sort of experimental validation. And oftentimes when we make a structure in the lab, in that case, that doesn't have the properties that we predicted computationally or from a simulation standpoint, it's usually that we're wrong in terms of how we characterize the material. For example, let's say we were trying to make triangular prisms. Of silver and we expect a certain optical property. It might have been that we made them in the lab, but they weren't perfect triangular prisms. They weren't fully formed structures. And that lack of definition in that case led to a disagreement between the theoretically predicted properties and what we're realizing in the lab. If we go back and refine it, we actually did some of this, you actually see more of a convergence between the two. We have time for a few more questions. Guy. There are many medical problems that we face in humans, too many for you to focus on. How do you choose those that you're going to do? I mean, how about type 1 diabetes, for example, or the heart? It's a great question. So I didn't put in here, but we're also going into clinical trials for glioblastoma, which is brain cancer. That's starting this quarter, which is really exciting. We actually build up a lot of our understanding of these systems with that disease. Now, why aren't we doing that at the company, for example? The problem is the bar is really high in that case. So that is one where we are trying to run it through the university with philanthropic funds, get through those trials. We expect to have a lot of failure, but learning from that particular failure and going through a revision type of process that no startup company, for example, could sustain. So in terms of selecting what to go after, you're exactly right. If you look at this, this is a gene regulation type of approach. There are 200 diseases of the skin where we can, in principle, develop a therapeutic. That's really exciting, right? But it's also challenging. Which ones do you pick and how do you decide what to go after that will not cause you to run out of money before you get to an endgame, right? And so from both a science and business standpoint, it's really important to have a strategy that looks at this incredible potential, but to make the right bets early on. Because if you fail early on, you won't have the opportunity to go after some of the bigger, more challenging types of problems because you will be viewed as somebody who— an entity that, you know, couldn't really bring the technology to fruition. So if you look at what we have done, we focused on, first of all, diseases that we can treat locally or topically. So the skin is a great app. Nobody else can do that. Prior to that work, nobody has— that's the first example of anybody ever doing gene regulation in human skin. Usually, I mean, but where it's directly applied. Usually you have to use needles, for example, to inject these things. Patients can't withstand that type of application. So that's a really validating type of principle that extends in principle to 200 different types of targets that we can go after in skin-related types of diseases. The eye, the ear, the colon, the bladder, the lungs, all of those can be topically addressed. So our view was, let's go after that. Let's prove that we've got something nobody else can do. And that's also a lower bar because the toxicity issues that we have to deal with, with a topically applied drug versus a systemically administered, completely different. So we can get through the trials a lot faster and get to a point where we can make a difference in a lot of patients' lives but also begin to validate the platform so people say, hey, let's now move the bar. Let's keep trying to go after things like diabetes, things like glioblastoma, and ones where the challenge is far greater. And the other part of this is that immunotherapy, which is really exciting. That also is a local application because you're not giving— that's not a bloodstream injection. You're accessing the lymph nodes and getting a local priming of the immune system to get a system-wide response. So to me, strategically, It is a very sound way of thinking about this and one that is likely to give us the best shot at success. You know, we're still a long way from there, from what I'd call really proving all of this out on a therapy standpoint, but the data so far look really promising. Thank you. We may have one last question. Curious about the nanospheres. Was the improved uptake of those sort of an Edisonian discovery, or was there something about packing DNA that you felt would lead to enhanced— That's a great question. So this violates everything you're taught. There's a lesson here to students, grad students. In the literature, and if you talk to experts in both chemistry and biology, they'll say don't try getting oligonucleotides to go into cells. They won't go into cells because The cell wall is negatively charged and the DNA and RNA is negatively charged. They repel one another. And for that reason, there's a whole field of polymer chemistry and viral transfection agent development that encapsulates the oligonucleotide, sometimes changes the charge so you can effectively trick the cell into taking it up. We didn't try this for a long time because of that. You're like, you know, it's not going to work. No, don't waste any time. We do what we call Friday afternoon experiments where students are supposed to go out and try something a little bit crazy. Doesn't work, you don't need to tell me about it. If it does, you can come back and exclaim you're a genius and go from there. Well, this guy David Gillohan and a few others in the lab, I think Nat was in, Nat Rossi is in the lab too, is involved with it as well as at Pitt. They go and do this experiment and you see this type of result and it's kind of a shocker. It's not what you'd expect. But that's a great moment because then you say, why? And that's where the science is. So serendipity, discovery that you make in part by accident, should always be followed up if you think it's important enough. And so here we thought, now we have the ability to move large amounts of DNA and RNA into cells, let's figure out why. And it turns out we think we know why. There are things called scavenger receptors on your cells.. And they're responsible for moving things in and out of cells. They don't bind to normal DNA, but they bind very tightly, it turns out, to this clustered structure that we call a spherical nucleic acid. And there was actually a clue that that was the case. If we were really smart, we might have been able to figure it out and design it. They recognize things called G quadruplexes naturally, which are bundles of DNA. They're not spheres, but they're bundles of DNA. That's a natural ligand for a scavenger receptor. So we think the spherical nucleic acid architecture mimics that ligand and creates an entity now that hijacks natural machinery and leads to very rapid and efficient internalization. And so we've studied all those pathways, and that's become the basis for many PhD theses. But I'm a big proponent of that. I give students and postdocs a lot of freedom, and we discover things. We sometimes make mistakes, but we come back and correct correct them.

But we follow big discoveries, and sometimes that leads to something even more exciting than what you were originally pursuing. Before we finish, please join me in thanking Dr. Merkin again. Thank you.