NEB Podcast Episode #2 -
Interview with Angela Belcher: Seeking Inspiration for Innovative Science

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Interviewer: Christopher Noren, recently retired Scientific Director of Chemical Biology Research, New England Biolabs, Inc.
Interviewee: Angela Belcher, James Mason Crafts Professor of Biological Engineering and Materials Science at the Massachusetts Institute of Technology in Cambridge, Massachusetts

Welcome and thank you for joining us for this episode of Lessons from Lab and Life. I am Christopher Noren. I'm the scientific director for chemical biology at New England Biolabs, and today I am ecstatic to be joined by the James Mason crafts professor of biological engineering and material science at MIT, Angela Belcher. Angie has spent her career at the interface of molecular biology and material science, specifically the use of filamentous bacteriophage as a template for material deposition. So, Angie, thanks for joining us today.

Thank you Chris, it's great to be on this podcast and it's great to have you in my lab.


The very first time we met in person, you gave me an abalone shell. So, the question is, how did abalone shells inspire your research?

Well, I've been interested in how biology makes materials, hard materials like calcium carbonate, and calcium phosphate, and iron oxide-based materials, because nature, through a very long evolutionary time period, learned how to make inorganic materials at the nanoscale, under ocean conditions and ocean pressures and didn't use toxic materials. And, to me, that was fascinating.

I did my PhD on how abalone's grow shells. They use proteins to nucleate and control the crystal structure. They grow the metastable crystal structure, which is the beautiful mother of pearl like structure, and they grow calcite, which is the thermodynamically most favored structure, and they do that as a quick way of growing calcium carbonate. And, they can switch back and forth between in, and it's all controlled by proteins. Which means it's controlled at the genetic level.

So, I've always thought that life did a great job at making inorganic materials, hard materials, but could have had more opportunity, could have used more elements and made more kinds of materials besides the handful of materials they made. So, my goal, when I was finishing graduate school, and when I was a post-doc, was, wow, how do you get biology to make more technologically important materials, like semi-conductor materials?

When I was finishing graduate school and when I was a post-doc, it was the explosion of nanoscience. So, nano, just like it is today, was becoming more and more important, because people were realizing, to get to the next generation of electronic devices, we were going to have to shrink the electronic structures. Well, biology already makes interesting materials at the nanoscale, they just don't make interesting electronic and optical materials at the nanoscale. So, my goal was to make materials like an abalone makes Calcium carbonate, or shell, but have an animal, or an organism, or biology make electronics.

So, you told me, that first time we met, that your approach to recapitulating the construction of complex materials on a biological template is based on glancing through the New England Biolabs catalog. So, can you tell us how that inspired the projects going on in your lab?

So, I had heard about this idea of phage display. I'd read some papers on it, but I thought there's ... being a solid state inorganic chemist, it's going to be hard to make a phage display library. But, about the same time, I was flipping through the NEB catalog and phage display libraries were available. You could buy them, I didn't have to make one, which would've taken all my time to figure out how to make one. At the time, we were interested in gallium arsenide and indium gallium arsenide.

And I remember, we were talking back and forth with tech services, and we were like, "Okay, well, we have this single crystal gallium arsenide, and it's in an Eppendorf tube, and what we want to do is we want to bind the phage to the single crystal semi-conductor and elute it off." So, we were going back and forth talking to you about how to approach that. So, I think we used gallium arsenide, we used iron oxide and we tried maybe indium phosphide material at the time.

Tell us about the airplane wings.

Well, so we started working in batteries. That was really our first device application we started working in, in the lab, because, you know, first we started using phage display to discriminate and bind materials. Then we started using phage display to start growing materials.

So, we started playing around with that. We started making all kinds of materials. We started making column II, column VI semiconductor materials like zinc sulfide, cad sulfide, solenoid-based materials. We started making metals. We made fuel cells, kind of record-breaking fuel cells out of phage. And we started making battery electrode materials, because battery electrode materials, like lithium-ion batteries ... One of the things that is allowing them to get better and phones to get smaller and such is nanostructuring these materials, because nanostructuring the anode and cathode materials of lithium-ion batteries allows favorable kinetics for energy storage.

And so, you think about the beautiful phage as being, you know, only, 880 nanometers length and, you know, 10 nanometers or so in diameter. Now, you can grow a lot of small nanoparticles on that structure that are strung together as a linear string. And now you can make millions or billions of those. And so, we started using those battery electrodes. I think we started working on anode materials first and published a pretty high-impact article on that. And then we started making cathode materials and published some high-impact articles in cathode materials.

But then we started making films and foams out of these, because remember that they're monodispersed, and so if you ... We made liquid crystals out of them. We got high-impact journal articles out of that. But you can make kind of random foams of these materials that go towards aerogels, meaning that they're mostly air or mostly space, but then you can put a smaller amount of templated inorganic materials on them.

And so, then we started making them into shapes, and now we make them into shapes like airplane wing shapes. And we started a project where we're trying to double the distance or the time that an unmanned vehicle or a drone can fly, based on what we call structural batteries. In this case, the battery is part of the structure of the drone. And so, it's not like you have a drone and then you clip in the battery. In this case, the wing of the drone is the battery. And the wing of the drone is also a virus-based battery. And so that's an area that we're working on.

Another thing that we worked on, on phage, were, at one point that relates to airplanes, is that we used phage to find defects in airplane engines blocks as well. And the idea there was that, at defects, you're going to have a change in the chemical structure. You'll have more oxide at the surface or more dangling bonds. And so, a phage should be able to see the difference between a collection of dangling bonds and a perfect structure, and we showed that as well.


So, working at the interfaces ... I've spent some time at interfaces myself.  So, do you find that there's a certain amount of issues with communication. Do you have to evangelize your position at the interface? Because so many people like to be in the middle of a discipline rather than around the edges, like we are.

So, I do ... I think that now it is becoming much more acceptable to do that. And I have, you know, faced a lot of scrutiny in the past. Every time I tried to go into a new field, I find pushback. And I think it's, you know ... I never say, "I want to be the world's expert in X." I basically say, "Is there something in our approach or toolkit that can help solve this problem?"

And, you know, my PhD adviser said to me when I was a graduate student ... He wasn't sure I was tough enough to be a professor because I took things personally. My first grant proposal I wrote as a young professor was on using phage display to find a DNA sequence, a coder for a protein sequence for gallium arsenide and indium gallium arsenide and such. And the review came back that I'm insane. And it says, "She is insane!" Exclamation point. That was the only thing on my review, and it was quite crushing.


Well, you showed them!

Yeah, I did show them. But now, being, you know ... having insane ideas are great, right? But you should have sane ideas, or somewhat grounded in reality. I felt completely comfortable that our ideas weren't grounded because organisms had done it already.



But just not with these materials. Now, you know, gallium arsenide ended up being the wrong material to choose, ultimately. Or not the best material to choose, but we went through the ... systematically through the Periodic Table, and I did a report recently, which ... I think we've made 150, maybe more than 150 materials that are phage-based materials, that phage have ... Well, obviously phage have never genetically coded for these materials before, but biology has never coded for them.

And so, I mean, I have pushback, but I think that, like any person, you have to, you know, pick yourself up, and dust yourself off, and move forward. And not everything has been successful, but not everything is going to be successful. I think, you know, keeping your eye on the big picture, what you want to do ... A lot of things students get really excited about, new directions we come into in the lab, students say, "Oh, I really want to work on this particular topic. We've never worked on it before." And we'll sit down, and we'll sketch it out, and we'll say, "Okay, we can see an avenue of getting there." And then we'll approach it.


So can you tell us about any other, besides abalone shells and the NEB Biolabs catalog, any other blue sky sources of scientific inspiration?

So, to me... I mean I tell my kids this that I hope you meet many people that love science as much as me, but you'll probably never meet anyone who love science more than me because I just love it. I love everything about it and I love proteins and I love molecules and I like thinking about how they interact. And it's such a joy to be able to do this for a living, think about molecules, build structures, solve problems ... that it just fills my day.

And so ... we’re constantly thinking about what are the most pressing problems on the planet? Because my group is focused on: what is the most pressing problems on the planet? And so, we organize around themes, energy, the environment, health care, water are some of the major topics that my group works on. So then also, just like you're flipping through journals, we're always doing the same thing to try to understand what are the limitations to solving things around batteries or on solar cells or on water purification or on finding small structures. And we kind of delve in, we jump in and say well what are the limits of the current technology? And then the question we ask: does biology have a way of getting around that? Because biology obviously is good at solving problems and getting around issues. Usually it takes millions and millions of years but using phage display and basically the technologies that we've developed for my lab around growing these kinds of materials, we try to see if we can have a biological solution to that.


Angie has two small children, and obviously you're trying to get them interested in science. But how did you become interested in science?

I was very young when I got interested in science. And neither of my parents were scientists, but I had this idea from a young age that I wanted to do something important. And I thought about two things: one, I ... First thing I wanted to be was an inventor but I didn't have any good ideas. And I grew up in Houston. Houston and San Antonio, and it's hot there, and I go in the summers and say, "I'm not going to leave the garage until I invent something new!" And I'd be in there sweating and everything, and I'd be like, you know, six or seven or eight, and I never came up with any, you know, great ideas, but I thought invention is something that's important.

And then I thought ... after that I thought medicine. That's something that's important, so maybe I'll be a doctor. And so, I was also lucky as a young teenager and a teenager to live in Houston, near the medical center. And I got to know ... I got to go to, you know, visit the hospitals and hang out in the libraries in the medical schools. And I started studying, you know, what I could figure out about medicine. But what I really realized is that I loved molecules. And I got interested in genetics when I was, you know, 13, 14 years old. And I thought, "Wow, that's so interesting. You know, how do you go from DNA to a person?"

And so, yeah, I started thinking I was going to be a doctor, but by the time I was in my first and second year in college, I loved molecules so much that I knew I wanted to go in that direction. But, you know, now you think, "You can be a doctor and love molecules." But, you know, I think I loved molecules more than the idea of being a doctor. And so, then I pursued a study, which is design your own major, and I did a major that was chemistry, biology, physics, geology, because I was interested in the origin of life.

My first degree is in creative studies, which is basically design your own major, because I was interested in so many topics I didn't want to specialize. And I got really interested ... and this is so related to phage display, so it was, like, written in the stars since the time I was a kid, but ... I was interested in how did we get from the first small molecules to larger, replicating molecules, and then cells in humans and everything else.

And I remember reading about ... well, it probably happened at interfaces. It probably happened at the interface between, you know, rocks at the ocean shores. And that was, you know, silica-based structures, and clays, and, you know, maybe carbonates. And so I was thinking, "Wow, it's the interface between rocks and small molecules ... and organic molecules ... that led to life." And now everything I do is the interface between, you know, proteins and rocks, basically.


Oh, well speaking of interfaces, you just dovetailed very nicely into my next question. All your science ... all your science seems to be at unexpected interfaces ... of disciplines such as between molecular biology and material science, rather than falling squarely within a single discipline. So what is it about you, personally, that enables you to think so far outside of the box?

Well, I think that I feel really ... It was my undergraduate degree in creative studies, which basically allowed me to study ... put any fields together that I wanted, and so I feel lucky. And I try to emphasize this with my children as well, is what's important is to find what you love, and then to do that. And I've been very fortunate that, my whole career, I've only studied what I love to do.

And then, for my PhD, I worked between Gaylord Stuki, who is a materials chemist, Dan Morris, who's a molecular biochemist, and Paul Hanson, who's a physicist, and I worked between the three of them. And I think that was instrumental in learning to think about a problem from multiple disciplines. Because if you think about an abalone, an abalone doesn't say, "I'm going to build a shell like a physicist would," or, "I'm gonna ..." You know, basically it takes different disciplines together and works together to build the best shell it can. And that's what I'm interested in doing.

Ultimately, I'm an engineer so I want to solve problems. And I don't care how I get to the problem as long as itis economic, as long as it's environmentally friendly But I just want to solve problems, and so I basically use what's in the toolkit to solve the problems. And then it goes back to, you know, relating to the problems of the world that I'm interested in, but a lot of it is student-driven. So here I am talking about, you know, "We do this, we do this." Of course, I'm a professor so I don't do anything. And so when ... The first couple of tech calls, that was me. But, you know, since then, my students do, you know ... I haven't done an experiment myself in 15 years.


So, this is a two-part question. This is a two-part question. The first part is: what advice would you give to a scientist at the beginning of their career? And then, as a follow-up: what advice would you give to a scientist at the middle of their career?

So, for undergraduate, the advice that I give students when they're, you know, trying to decide their major or, you know, classes to take, are to study what you're very excited about. And so I think that's the most important, is to find something that you're really passionate about. And the other thing I give people at that stage is, even though I didn't follow this myself ... hmm, is I think it's good to pick a major and become an expert in it. At, you know, at the undergraduate level. You can add on, you know, double majors, you can add on minors.

But people say, you know, "What if I do a little bit of this and a little bit of this?" I think you should become an expert. You know, become an expert in chemistry, or biology, or mechanical engineering, you know. Pick an area, become an expert, and then add on to it.

The other thing I say is, for graduate school, it's the opportunity to make a pivot. And so, okay, I've become an expert in chemistry, or biology, or, you know, geology, any of those topics. Add something else on that you think is interesting and become an expert in that.

I think, instead of picking and choosing, you know, a little bit of depth in everything, is what I kind of do now, but I have a very deep underlying knowledge in a couple of fields. And then, as you add on, it gets easier to learn, it gets easier to see the connection between those. And so that's what I say.

And then, I think, post-doc, if you do a post-doc, again it's this time to really take a kind of an extreme pivot, because now you have all this expertise that you've spent years cultivating. And now you can really go outside your comfort zone and add another field to it. And, you know, I think times are different than when I went to school, and the world is different and everything, but I really think that if you can, you know, find something ... and I tell this to graduate students: you know, graduate school has ups and downs. You want to have more ups than you have downs.

Pick something that you really love, and that you're passionate about, because you have to have that to keep you going ... to keep the big idea, because there's going to be days when experiments do not work. There's going to be days when classes are hard, and when you get rejected. But if you keep getting rejected on something you don't love, you know, that makes it hard. So, you're going to have ups and downs, so try to have more ups than you do downs. And like I said, I feel like the most fortunate person in the world because I get to study what I'm very interested in.


Okay, so what advice do you have for someone in their 40s who's been doing science for 20-some years?

So, I think that it's keep adding new things to the mix. And, you know, I'm a focused person and a unfocused person at the same time. I've always kept my expertise focused around organic-inorganic interfaces. But I keep adding different fields, like we added cancer to the mix, you know, six or seven years ago in my group, where I had to learn everything from the beginning. And of course I have really smart students, who ... and a great colleagues who helped teach it to me, but I don't get bored because there's always something new to think about. And I'm the kind of person who loves to think and learn all the time. And people say, "Don't you feel uncomfortable when, you know, you walk in, and you're not even not the smartest person in the room, you're maybe the least knowledgeable person in the room?" I say, " That's a great starting point because all you have to do is go up! You can't go down, right?"

And so, you know, I'd say that ... to keep adding new fields, and learning, and thinking about new interfaces. Now mid-career is tough, just in general, because funding gets much tougher in mid-career. And so, I'm not trying to make light out of that, but I do think it's important to keep fundamentally grounded in what you're interested in and what your expertise is. But then look around and see: what are the new directions that are being funded in science, and what is your expertise that you can have that helps pull you in a new direction you're interested in? And it might be a direction that has, you know, a new area of funding. And then, everything that we've ever done in my group has been a collaboration. And so, working with other people that you really like ... collaboration of the graduate students ... I think working with students keeps you young-


I've found that as well.

I like working with freshmen and sophomores, too, because they still think anything's possible. You know, they're in that upswing-


They're so dewy-eyed. It's like, you can ... "I have all these minipreps " "Oh! I'll do them!"

Yeah, because it's super fun, right?



But then, I think working with students keeps you young, keeps you motivated, and it keeps you on the edge of technology, because, you know, the grad students that I get coming in today, what they had as an undergraduate in their biology classes is completely different than what we had in our biology classes. And they're always pushing me outside my comfort zone. And so I think that's great.


Okay, well thank you very much for joining us today, Angie, and thanks for fitting us into your busy schedule. And here's to many more years of working with beautiful m13 bacteriophage and doing interesting and fascinating things with it.

Look, thank you so much for having me, and for coming to visit my lab, and for helping me prove that my initial idea was not insane.


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