Making a career out of innovation: Part I of my interview with Dr. Angela Belcher

In the ocean, it took organisms 50 million years to perfect their systems. We’re doing it in a few weeks.Dr. Angela Belcher
I first heard about Dr. Angela Belcher, one day, when on a coffee break, I was flipping through an old Science magazine that my supervisor had given me.  She passed it along because there was an article relevant to our work. But, the article that drew my attention was called, “Fabricating genetically engineered high-power lithium-ion batteries using multiple virus genes” (Lee et al. 2009).  Having recently worked with a virus, I became quite curious about this article.  After reading it, I was stunned at the creativity and elegance of the science.  These researchers had genetically engineered a bacteriophage (M13) to serve as a template for a-FePO4 growth and to have the binding affinity for carbon nanotubes.  Essentially they were able to build a high-powered lithium ion battery cathode that could power a green LED.  How cool is that.  After reading this article, I wondered who was the creative force behind this idea and so I looked up the name of the senior researcher.  Angela Belcher’s lab had not only genetically modified a virus to act as a scaffold for the synthesis of batteries, but also used them in photocatalysis, and the making of solar cells.  After watching her TED talk, I thought here is someone who really is a scientific leader and a role model.
The first part of my phone interview focuses on how she got started at the interface of so many disciplines and the challenges involved in working with viruses to construct batteries and solar cells.
ME:  Your research is at the interface of many different disciplines.  How did you end up going from biology to inorganic chemistry and finally getting involved in using viruses to make electronic materials?
ANGELA:  From the time I was a little kid I wanted to be a physician, but my undergraduate degree was in biology, and during this time I fell in love with larger molecules.  At the same time as I began to think more about the interface between inorganic chemistry and biology and I met Galen Stuky, an inorganic chemist, and Dan Morse, a molecular geneticist and biochemist, who turned out to be a fantastic mentors.  My PhD training involved 2hr meetings every week with a molecular biologist, a physicist, and a chemist to discuss how abalones’ grew shells.  And we looked at it from a physicists’ perspective, from a chemist’s perspective, and from a biologists’ perspective.  I was so lucky to train like that for four years and as a result I became well-versed in the languages of different scientific disciplines.  But I became interested in using biology to work not only on materials that biology had already evolved the ability to work on, but to work with  electronic materials.  During my postdoc I worked with a fantastic mentor (Evelyn Hu) who was both an electrical engineer and a scientist and I was really fortunate to study with her at the interface of electrical engineering and biology.
ME:  Your research focuses on using biological systems to exploit their capacity for green biomaterial synthesis as in the case of the virus-derived batteries.  Could you explain how you came up with the idea to use the processes of evolution to exploit viruses in order to grow batteries or build solar cells?
ANGELA:  Biology naturally works with proteins in growing inorganic materials, as is the case of the abalone shell, which is 98% by mass calcium biocarbonate and 2% protein.
We decided to also focus on proteins.  What we were looking for was a set of proteins that could work with materials that they hadn’t had an opportunity to work with through evolutionary time. I started thinking about this right when I was finishing up my PhD and I really wanted to figure out if I could get proteins to interact with the rest of the periodic table.  Specifically, I wondered whether you could get antibodies to be specific for semiconductors and electronic materials.  I decided to use combinatorial bacteriophage libraries to find proteins that control most of the interactive positions in the bacteriophage’s coat proteins.  Using libraries of random peptide sequences that were about 12 amino acids long, we searched for proteins that could bind to semiconductor materials on metal oxide.  Having successfully worked our way through the periodic table, we began focusing on finding proteins that could control things that were useful, such as batteries, photocatalysis, and most recently virus-enhanced solar cells.  We just wanted to have biology be able to nucleate the crystal structure, control the crystal orientation, the arrangement of several different inorganic materials in order to create the electronic devices of interest.
ME:  So in essence you replaced the phage’s coat protein with amino acid sequences that would bind these different inorganic compounds?
ANGELA:  That’s exactly right.  The idea was to mimic how the abalone creates its calcium based shell, which it does by grabbing ions out of solution and nucleating them.  Originally we did it with commercially available libraries where peptide sequences were randomly expressed in the proteins at the tip of the virus.  Now we use biased libraries made by generating random mutations in the minor or major coat protein  – these libraries are selected for sequences we think may have an effect of growing certain kinds of materials.
ME: How were you able to get the bacteriophage to replicate or reproduce within bacteria when they had coat protein modifications and inorganic molecules fused to their tail?
ANGELA:  That’s a really good question.  We separated the selection and growth process.  First, we selected for the ability to bind the material of interest and we did that by isolating the material through either ion competition or lowering the pH.  And then we collected the viruses that were able to bind as function of time and then we amplified them up into a million copies and put them into a separate reaction where we tested their ability to grow materials.  Sometimes the ability to grow materials will knock out the function of its ability to replicate itself.  But sometimes it doesn’t.  It depends on the conditions that you are working in solvent, pH, ions, things like that.
ME:  I could easily imagine how a trade-off might constrain your ability to grow these materials.
ANGELA:  We’re able to overcome it in certain instances and certain instances we aren’t.  In our current project we’re trying to really make modifications in the major coat protein and we’re having a lot of trouble with it.  I have two really talented biological engineers right now, who are pushing the limits of what you can do to the coat protein and still have it do what we want it to and still replicate but these viruses are slow growers.
ME:  How do you get multiple viruses to form structures that you want it to form, like for example a long wire or a crystal structure?
ANGELA: There are a couple of different ways of doing it.  First of all the virus M13, as you know, are very monodispersed.  It’s always the same length and width, its anisotropic (directionally dependent), and these viruses are long and skinny.  All these properties can be a huge advantage for growing crystals or liquid crystals, in this case.  Because individual viruses are the exact same length, long and skinny, they will naturally pack and actually naturally pack so well that you can form beautiful crystals of these materials.  Our research really exploits the liquid crystal properties of these viruses based on their size and shape. A second way is to engineer the virus head to bind to a small semiconductor connector particle and a second virus to bind that same particle so you can make long skinny structures small particles long skinny structures.  You can assemble the viruses that way, essentially by taking advantage of engineering their heads and their tails.   A third way is that you can engineer the bodies to like polymers and then you can get them to all line up on a polymer surfaces the way we’ve done with some of our battery materials. It’s all based on size, charge, identity, and structure.
ME:  The organisms you work with are quite simple, ie bacteriophage.  Is the simplicity of the bacteriophage what attracted you to using the virus as a scaffold to build biomaterials.
ANGLELA:  Well simple enough for someone who is not a really good biologist to use and that was probably one of the things that was most attractive to me. You know it’s one of those things that I’d love to take credit every step of the way –  that I picked M13 because it was long and skinny.  I would love to say that I picked M13 because it forms liquid crystals and because it forms wires.  None of that is actually true.   I picked M13 because it was commercially available, inexpensive, and you could buy already made libraries.  When I first came up with this idea people called me insane and I couldn’t get a lot of funding but I could buy a commercially available library for $400 that was enough to start the first experiment.  And the biolabs that I bought the libraries from were always really helpful.  As it turned out it was a fabulous choice for us with respect to structure.   At first all we were trying to do was find a DNA sequence that would lead to a peptide which could bind to a semiconductor and from there it all kinda of exploded into making batteries, making catalysts making solar cells.
ME:  In the TED talk you gave you talked about your dream of being to drive a virus-powered car.  I’m wondering how scalable are these processes? And what if any challenges are you facing in making these processes scalable?
Will I be able to scale it to make myself a virus-powered car? I’m quite sure about that.  But will I be able to make enough to cover the whole country, that’s a really different concept.  We’re in the scale-up process right now.  Most of what we’re trying to do is to figure out, what’s the best technology that will give the biggest return on our technology.  And in the case of the virus battery, there is still a lot of biology unlike the solar cells.  There we only added 0.1% biology to our solar cell to get an increase of 3% total conversion, a huge return.  We have a 10.8% solar cell and it’s only by adding 0.1% biology.  In the case of the solar cell, we’re really, really optimistic about it.  In addition we’ve looked at other applications, I have a new company, which takes methane and converts it into more useful materials like precursors to plastics or liquid fuel.   And in that case, its a little easier to think about than making solar cells to cover the entire country.
ME:  Do work with any other organisms and if so what do you do with them?
ANGELA:  We don’t work with any other viruses but we do work with yeast.  We have a project where we’re trying to take CO2 from a coal plant and convert it into green building supplies like tiles.  In that case, things are easily scalable.   But 90% of what we do in in M13 bacteriophage.
ME: Earlier you mentioned how difficult it was for you to get funding?  How did you support this idea?
ANGELA:  I was pretty lucky because I had really strong ties with my programme officers as a graduate student.  So I had people who believed in me from the beginning which was very, very nice.  And even though people called my idea insane, I was lucky enough to get funding from a couple of different sources: the army, the Beckman Foundation, and Dupont.  I won The Dupont Young Investigators award very early on mostly based on what I had done as a graduate student and that enabled me to get my lab going.  When I wrote out my first faculty research program, I didn’t include the virus ideas because it seemed a bit farfetched and I had other ideas. But by the time I got my lab established, some of the experiments we did were the early experiments using viruses.  I think it was roughly year from that point that we published our first Nature paper on the idea and then it really off from there.
ME: In times of economic constraint, people become more conservative about the kind of science that gets done, how important is innovation to this country?
ANGELA:  I’m very worried about losing innovation. Innovation is what this country was built on and it’s what we do so well.  Basic research leads to very different ideas and you can’t really predict where its going to take you.  My basic research on abalone shells took me in the direction of engineering viruses to make solar cells and batteries, and developing companies that are trying to solve major technological issues.   I had no idea of that when I first started trying to understand how an abalone made its shell.  Basic science is so important for as an educational process.  It’s an important way to learn how to think, to get young people excited and motivated.  And almost every important technological discovery that I can think of was rooted in basic science.
ME:  Earlier you mentioned that you got your start as an interdisciplinary researcher during your PhD and that you benefited greatly from it.  Do you continue to encourage this in your students?
ANGELA:  One of the important things for me now is that I choose students who are willing to admit that they know nothing and start from the beginning and that’s what we have to do all the time.  Admit you know nothing and start from the very beginning.
ME:  Is this the advice you give your students about developing an interdisciplinary research program?
Yes and have great collaborators. When you have a meeting with a collaborator, check your ego at the door.  Bring to the table what you have and what you understand but be completely open to new ideas, new approaches, and new ways of thinking.  This is the way we do it in my lab.  Everything we do in my lab is collaborative. It’s so much easier to learn if you’re just willing to try your best to understand the problem and not have any preconceived ideas or be constantly worried about other people. Who cares.  Go in there and do the best you can.  I think that we’re really good at several things but not everything and we try to partner with people that are really good in the areas we aren’t or in the areas that we’re trying to interface.  It’s all about partnership.
ME:  In a Scientific American article and in Time Magazine, you talked about committing yourself to learning a new field every five years.  What’s next?
ANGELA:  We’re in cancer now.  It’s a huge challenge.  It’s much more difficult than any of the other areas we’ve walked into.  Hopefully you’ll see several publications of ours coming out in the next few months describing our version of trying to understand and diagnose cancer.
ME: Would this be using virus-based technology?
ANGELA: Of course it would.
Angela Belcher obtained her undergraduate degree in biology at UC Santa Barbara (1991) and then went on to graduate from a PhD program in chemistry at UCSB in 1997 (Dan Stucky and Dan Morse).  After completing a postdoc in electrical engineering under the supervision of Eveyln Hu, she joined the faculty at the University of Texas, Austin but left to become a member of the Massachusetts Institute of Technology in 2002. Dr. Belcher’s  research focuses on using biological systems to exploit their capacity for green biomaterial synthesis.  Her work has garnered attention from President Barack Obama who visited the lab in 2009.   She won the famous MacArthur Fellowship Award in 2004 and has been named a “Hero” by Time Magazine – Climate Change (2007).   She has been recognized as Scientific American’s Researcher of the Year (2006) as well as one of Fortune’s Top 10 Innovators under 40 in 2003.
Selected Publications:
Yoon Sung Nam, Andrew P. Magyar, Daeyeon Lee, Jin-Woong Kim, Dong Soo Yun, Heechul Park, Thomas S. Pollom, Jr, David A. Weitz, and Angela M. Belcher, “ Biologically Templated Photocatalytic Nanostructures for Sustained Light-driven Water Oxidation.” Nature Nanotechnology (2010) 5:340-4.
Yoon Sung Nam, Taeho Shin, Heechul Park, Andrew P. Magyar, Katherine Choi, Georg Fantner, Keith A. Nelson and Angela M. Belcher. “ Virus-Templated Assembly of Porphyrins into Light-Harvesting Nanoantennae.” J. Am. Chem. Soc. (2010) 132:1462-3.
Lee, Y.J., Yi, H., Kim, W., Kang, K.,Yun, D.S., Strano, M.S., Ceder, G., Belcher, A.M. “Fabricating Genetically Engineered High-Power Lithium Ion Batteries Using Multiple Virus Genes.” Science (2009) 324:1051-5.
Whaley, S. R., D.S. English, E.L. Hu, P.F. Barbara and A.M. Belcher, “Selection of Peptides with Semiconductor Binding Specificity for Directed Nanocrystal Assembly.” Nature 405, 665-668, 2000.
Belcher, A.M., X. H. Wu, R. J. Christensen, P. K. Hansma, G. D. Stucky and D. E. Morse, “Control of Crystal Phase-Switching and Orientation by Soluble Shell Proteins.” Nature 381, 56-58, 1996.
Next week Angela Belcher describes some of the challenges she faced personally and offers her advice.

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