In the Biodesign Center for Single Molecule Biophysics, the little things add up
By Logan Alvarado
In honor of National Nanotech Day on October 9, we are featuring Stuart Lindsay, director of the Biodesign Institute Center for Single Molecule Biophysics, and his work focusing on atoms — the tiny building blocks of matter that make up everything.
“The big things in life are decided by the way the little atoms inside us move,” says Stuart Lindsay, director of the Biodesign Center for Single Molecule Biophysics at Arizona State University. That’s why the center’s research explores biological molecules at an atomic length scale, to understand how they function in health and sickness, determine what interventions might work and develop new types of sensors and devices.
In addition to leading the center, Lindsay is a University Professor, a Regents Professor, and Nadine and Edward Carson Presidential Chair of Physics and Chemistry at ASU. He has 56 U.S. patents and co-founded two different startup companies, Molecular Imaging (now part of Agilent Technologies) and, more recently, Recognition AnalytiX. Adding to his recognitions, he has published over 200 research papers and authored “Introduction to Nanoscience” (Oxford University Press). Lindsay’s research focuses on nanoscale biophysics.
Below, Lindsay talks about the center’s latest efforts, its challenges and successes, and his own career path. Answers are edited for length and clarity.
Question: What is the research focus of your center?
Answer: My team focuses on single molecule measurements with an emphasis on biophysics. We have developed imaging techniques to study the structure of biological molecules. We are currently developing single molecule electronic devices, with the goal of ever more rapid and accurate DNA sequencing as well as sequencing of proteins and biological sugar molecules.
Q: Why is this work important to society?
A: Taking the example of DNA sequencing, it is still too expensive to be a point-of-care tool. We are learning that many diseases leave their footprints on DNA. And many treatments turn out to be strongly dependent on unique features of the disease and the patient — features that can only be accessed widely if individual sequencing was as cheap and rapid as a blood count, for example. Furthermore, if DNA sequencing is made cheap enough, it could be used to read DNA synthesized as a digital storage medium, revolutionizing data storage by enabling a many thousand-fold increase in data storage density. We hope to enable these applications.
Q: What is the biggest challenge in this field of research?
A: Electronics based on biological molecules is an emerging field. The technology has to be built from the ground up. The computer chip industry has had more than half a century to figure out how to use and process materials that are compatible with the step-by-step assembly of these complex devices. Introducing a radically new material like a protein, and all the chemistry needed to link it to electrodes, is very challenging.
Q: What is something you consider one of the center’s biggest successes?
A: Spinning out a scanning probe microscope company, Molecular Imaging, which has had a significant impact on chemistry and biology. The company made scanning probe microscopes (scanning tunneling microscopes and atomic force microscopes) capable of imaging atoms in complex chemical environments. This enabled many atomic-scale studies of chemical processes at interfaces for the first time. To this day, I meet scientists who tell me, “I did my PhD research on one of your machines.”
Q: How are students involved in the center’s research?
A: Students are involved through experimental projects. For example, the current method for preparing microscope probes was the work of an undergraduate student pursuing an honors college thesis. Over the many years that the center has been in existence, many students have trained in a uniquely interdisciplinary environment and gone on to jobs in academia, industry and medicine. Physics requires some extra determination to master the quantitative skills, and I think this has been useful for all the students who have passed through the center, even if their chosen field was far from physics.
Q: If someone gave your center $100 million, what would you do with it?
A: I would use it to get our sequencing technology across the finish line and commercialize it. This means solving the materials science challenges I referred to above. It also requires massive scale up. Right now, our chips have tens of devices on them. To make the technology fast enough and cheap enough, we would need chips with hundreds of thousands of devices on them. This would require transferring the processes to a modern semiconductor fab, a very expensive process.
Q: How did you become interested in science, and in particular, the field you are in?
A: I have always had an interest in science — collecting fossils, building radios and using chemistry to make loud bangs. But the decisive point was an extemporaneous lecture on quantum mechanics by a high school teacher. Physics it had to be.
Q: What key events set you on your research path?
A: The invention of the scanning tunneling microscope in 1981. This opened a path for experiments on the atomic scale on the lab bench top. Up to that point, imaging atoms required million-dollar electron microscopes that focused tiny electron beams on a sample in a vacuum. The scanning tunneling microscope moves a tiny probe over a surface (in vacuum, liquid or ambient air) guided by the electrical conductivity of the surface. Here was a chance to image biological molecules in water! Our first images of the DNA double helix appeared on the cover of Science magazine in 1989.
Q: What is the most fun aspect of your work in the center?
A: Learning new things from experimental data. There is a preconception that biological systems and molecules are too complex to understand at a fundamental physics level. But there is often one experiment that shines a light on a simple aspect of a complicated problem. To give an example, we have been trying to understand what makes proteins conduct electricity. We know that solvent played a role, so we compared results from proteins in ordinary water (H2O) and heavy water (D2O), seeing a big effect. However, there was one exception, a protein containing residues that do not form hydrogen bonds. These were unaffected by the change in solvents, pointing the finger at hydrogen bonding as a key factor.
Q: What is your favorite thing about working at Biodesign?
A: Great colleagues and fantastic and devoted support staff. I have been here for a long time, and many years ago, getting a proposal out was almost harder than writing it in the first place. The ROAD team at Biodesign is truly exceptional and makes the whole process flow. I am almost embarrassed when I get an e-mail reply from Lacey Ward at 10 p.m. on a Sunday. The same goes for lab management. I don’t think Mike Dodson sleeps!
Q: Describe your experience with Biodesign’s collaborative, interdisciplinary research culture.
A: We need to build state-of-the-art microchips, synthesize and characterize new molecules, and understand how complicated systems work at the atomic scale. This only works when rubbing shoulders with chemists, biologists, engineers and physicists.
Q: Has your teaching and mentorship helped inform your research, and if so, in what ways?
A: I have always learnt from even the most elementary of classes I have taught. And one of the particular pleasures is that “dumb” question from a student that one has never thought about before!