Nanotech Titan: Part One

Did you always want to be a scientist?
 

Actually, I wanted to be an NBA basketball player! When that didn’t work out, I even considered becoming a movie critic. I was always good in school, but my drive to succeed was mostly about the competitive aspect of it rather than a particular passion for any one field. It wasn’t really until late in college and maybe even early grad school that I realized science was something I truly wanted to do – and do at a high level.

Science was like a never-ending game where there’s always another level to reach. You open one door, discover something, and then realize there are two more doors to open beyond that. It’s a bit like playing Dungeons and Dragons: you don’t know what’s in front of you, but you follow your curiosity and find something interesting. In our field, it’s even more rewarding because once we make a discovery, we can ask, “Can we put this to good use? Can this help the world?” That element of discovery and potential for impact motivates me.

Why chemistry?
 

Well, my parents weren’t scientists – my dad was a federal judge and my mom was a physical therapist. If my father had his way, he would have had four philosophers, but instead, he ended up with four scientists. I was the youngest, and each of my siblings had chosen a different scientific path: my oldest brother was a geologist, my second brother was a biologist turned spine surgeon, and the third was a physicist. That left chemistry for me.

At that point, I didn’t have a burning passion for a specific field, but I knew I was good at chemistry and thought it offered a lot of options. I wasn’t sure what path I’d take – maybe med school, maybe grad school, or maybe working in the chemical industry. But once I got to grad school, I had a couple of professors who were really influential. They were not only inspiring but also made the field both fun and engaging. They showed me how exciting the pursuit of knowledge in chemistry could be. That’s when I got hooked – and I haven’t looked back since.

Do you consider yourself an analytical scientist?
 

First and foremost, I consider myself a scientist. We work across different fields, so my view is that if you learn to do science well – ask meaningful questions and apply the scientific method – you can use that in many areas. I think my career reflects that. Before coming to Northwestern, we hadn’t worked with DNA, and now we’re one of the leading labs in DNA synthesis and structural design globally. We also hadn’t worked with scanning probe microscopes, but we trained ourselves, invented a technology known as dip-pen nanolithography, and essentially pioneered a technique that’s now used all over the world in commercial applications.

So, while the scientific questions and techniques may differ, the process of doing rigorous science is fundamentally the same. It’s really about whether you feel you have the right background to pursue a question; if not, you can still go after it if you have strong collaborators. I don’t need to have the best idea in the room to recognize and pursue the best idea in the room. Science is also about building a strong team and constantly learning and expanding capabilities. If you’re a bit fearless in that way, it can lead to big achievements.

Analytical scientists often feel undervalued. What are your thoughts on the perception of the field?
 

I think if analytical scientists feel undervalued, they’re not as proud as they should be! Analytical science is absolutely central to scientific discovery. Science is largely driven by two things: access to new materials and access to new tools. Tools that set new analytical benchmarks drive entire fields forward. Just look at the Nobel Prizes – a significant number are awarded for analytical techniques like NMR, fluorescence, IR, or picosecond spectroscopy.

I’ve never let anyone else’s opinion dictate what I find important. I don’t chase what’s fashionable. In fact, I often go in the opposite direction. However, I am very self-critical, and I encourage everyone in my group to be as well. I tell students and postdocs that we need to be our own toughest critics so we can justify what we’re doing, even if others don’t initially see its value. If we’ve chosen the right problems to tackle, others will eventually recognize the importance of the work, and I think that’s been proven throughout my career.

Thinking about some of the big societal problems, which ones do you think science – especially analytical science – could significantly impact or even help solve?
 

There are so many areas, especially on the medical side, where analytical science could drive major breakthroughs. One area I see growing is structural nanomedicine. If you look back 20 years, the top drugs were all small molecules – engineered by chemists to treat specific diseases with incredible precision down to the bond, the atom, or even the enantiomer. Just look at something like thalidomide, where one enantiomer was therapeutic, and the other was teratogenic. Fast forward to today, and the top drugs are often biologics, large macromolecules, or even more complex materials, like mRNA vaccines. And that’s where our work on particle technology has played a part, especially in how lipid particles carrying nucleic acids are engineered for vaccine delivery.

But this shift represents something more significant in medicine – moving from small molecule engineering to large, complex structures like antibodies or lipid particles, which enable treatments that small molecules can’t address. I believe drug development 3.0 will involve engineering these large structures with molecular precision using the principles of structural nanomedicine. Imagine having the components – nucleic acids, proteins, carbohydrates – and arranging them within a single structure to create optimal medicines. That’s a huge analytical and engineering challenge because there are potentially hundreds of thousands of combinations. What’s the optimal presentation of components for maximum efficacy and minimal toxicity?

This is where analytical science will make a massive impact. We’re going to see a rise in structural nanomedicine, and those who develop the tools to characterize these complex materials with precision will shape the field. Top-down proteomics is another example – Neil Kelleher here at Northwestern is advancing this field significantly. I’d argue there will never be a time when we won’t need analytical chemists. They’re essential for breakthroughs in everything from characterizing new materials to advancing medical treatments.

Are there too many silos in science?
 

Yes, definitely – and that’s not really my cup of tea. Some people do prefer those boundaries, and I don’t think it’s bad; I don’t disparage it at all. The scientific world thrives on diversity – not just in people but in ideas and approaches. Science wouldn’t be what it is if everyone did what I do. You need all types: the plodders who work steadily, those who fill in the gaps, and those who push big ideas forward. It’s all about the ecosystem. 

For me, I find it most interesting and impactful to move across disciplines and take on big, challenging questions. But I also think it’s valuable to have people who refine and develop existing knowledge even if that’s what they’ve been working on since their graduate studies. If they’re making meaningful progress, that’s a substantial contribution, too. Ultimately, it’s the combination of all efforts that really makes a field robust and progressive, creating depth and innovation.

Are you driven more by scientific curiosity or the desire to make an impact on the world?
 

I’d say it’s definitely a combination, but scientific curiosity comes first. That’s the main difference between a scientist and an engineer, in my view. An engineer might say, “I want to solve this problem for the world. What existing tools can I combine to create the most efficient solution?” But as scientists, we’re more driven by curiosity about new forms of matter. For example, with spherical nucleic acids (SNAs) – globular forms of DNA and RNA we developed by merging ideas from nanotechnology and DNA synthesis – we created a structure with no natural equivalent. It has unique properties and interacts with living systems differently from conventional DNA and RNA, which took us about a decade to understand fully. That curiosity led us to many discoveries and, ultimately, to ways of engineering these structures for real-world applications, like new diagnostics and therapies.

I always tell students that, while it’s great to want to impact the world, if your goal is purely technological, there’s a high bar – you’ll need to create the best solution because no one wants the second-best sensor or cancer treatment. So, I encourage them to start with a fundamental question. If you answer a critical question, you’ll likely discover new structures or properties that can lead to impactful technologies. And even if those don’t pan out, your work adds to the encyclopedia of knowledge in a way that lasts. A fundamental scientific discovery can be relevant indefinitely, whereas a technological solution is valuable only as long as it addresses a current need.

And do you believe in the idea of a “eureka moment” in scientific discovery?
 

Absolutely. The first spherical nucleic acid discovery was one of those eureka moments. It happened late one night in the lab. I was there with one of my students, Bobby Mucic, at around 11 pm – I’m a big believer in working hard, and I think the students follow that lead. I had asked Bobby to create a set of particles to be used as “programmable atoms” by linking DNA and particles together. So we’re there and he says, “Chad, you’ve got to see this.”

He took two batches of particles that could be connected with a complementary DNA strand. The particles were gold, which naturally appears ruby red in color. When the DNA linked them, they formed a network, turning the solution a deep blue or purple – what we liked to call “Northwestern purple.” But that wasn’t the most amazing part. Bobby said, “Watch this,” and put it in a drying oven. The color turned back to red, and when he took it out, it slowly turned purple again on the bench. The process could be repeated, switching from red to purple as the DNA unraveled and raveled, amplified by the particles’ colorimetric shifts.

We almost simultaneously realized this could be a new sensor for DNA – a simple, visible way to look at genetic signatures of disease. That discovery laid the foundation for the company Nanosphere, which commercialized the Verigene System. It was eventually acquired by Luminex and then Diasorin, and today it’s in use at top hospitals worldwide. That night was clearly a eureka moment, and it opened up new possibilities.

We imagined creating programmable atoms that could assemble into programmable crystal structures, with each particle placed precisely. I remember a magazine did a cartoon of gold statues with arms, reaching out and linking to other particles to build new systems. They said we were “redefining matter from the bottom up.” We had the concept but were far from achieving it back then. Today, however, we can make thousands of crystal structures with over 100 different crystal symmetries, including ones you won’t find in nature, using hundreds of types of nanoparticles. By controlling shapes, we control bonding directionality – like using cubes for octahedral arrangements – and we’ve developed what we call “colloidal crystal engineering with DNA.” This has opened up an entirely new field.

Chad Mirkin is Director of International Institute for Nanotechnology & George B. Rathmann Professor of Chemistry, Professor of Chemical and Biological Engineering, Professor of Materials Science and Engineering, Professor of Biomedical Engineering, Professor of Medicine, Northwestern University, USA