Message in a molecule: Lindsay’s career explores the physics of life

Reading Hour

Lindsay insists that his wide-ranging research is complemented by a passion for teaching biophysical concepts to a new generation of talented students. His forthcoming book, Introduction to Nanoscience, published by Oxford University Press, offers young researchers worldwide a first-of-its kind comprehensive treatment of the exploding discipline of nanoscience, centered on the themes of fluctuation at the nanoscale level and emergent complexity. The book, Lindsay explains, is an outgrowth of his lectures in nanoscience, which he’d spent years refining, with invaluable input from his students. Oxford University Press learned of the course and suggested Lindsay assemble the material into a book.

Given the pace of scientific advance, Lindsay chose to include a wealth of fundamental principles in the text that would remain relevant over the long term. The book is divided into three parts. Part I (The Basics) is a self-contained introduction to quantum mechanics, statistical mechanics and chemical kinetics, requiring only basic college calculus. Part II (The Tools) covers microscopy, single molecule manipulation and measurement, nanofabrication and self-assembly. Part III (Applications) covers electrons in nanostructures, molecular electronics, nano-materials and nanobiology. “If you wander around the lab,” Lindsay says, “you’ll see dog-eared copies of the Xeroxed version of the book at students’ desks—it’s really a compendium of everything I think they need to know in nanoscience.”

The most promising days for nanoscience are on the horizon, Lindsay insists, due in part to a new crop of young researchers trained to nimbly cross the borders between diverse scientific disciplines. “I think that the scientific revolutions that we have seen to date are but nothing compared to what could and I hope will come from institutions like Biodesign,” he says. Dr. Lindsay is the embodiment of this new ethos, blending sophistication in multiple domains of physics with detailed understanding of molecular chemistry and theoretical and applied areas of nanoscience. “Seeing this incredible emergence of life, born of complexity, gives one enormous respect for the individuality of each organism,” he marvels. “It’s a very different worldview now from the one I had when I started.”

Stuart Lindsay, a biophysicist and Regents’ professor at Arizona State University’s Biodesign Institute, finds it hard to remember a time when he wasn’t fascinated with science.

“As a little kid, I collected rocks, played with chemistry sets and built radios,” Lindsay says.

A favorite teacher in high school introduced Lindsay to physics, even attempting to teach the boy the rudiments of quantum theory. These early inspirational experiences laid the groundwork for an extraordinary and wide-ranging career in science, culminating in his appointments as Edward and Nadine Carson Presidential Chair in Physics, professor in the Department of Chemistry and Biochemistry in the College of Liberal Arts and Sciences and director of the Center for Single Molecule Biophysics at the Biodesign Institute.

Foundations

Lindsay founded ASU’s biophysics program, after completing his doctorate at the University of Manchester, and working for a time with Philips Industries in London, where his research in solid-state physics advanced. Reading James Watson’s seminal book on the double helix however, marked a turning point in Lindsay’s scientific outlook.

“I was so impressed that Watson could use what was really an undergraduate knowledge of physics and together with Francis Crick produce this unbelievable revelation about how life works.”
Though the field of biophysics was quite remote from Lindsay’s area of expertise, he resolved to radically alter the path of his career.

“From the day I finished that book, I knew I wanted to apply the methods of physics to living things.” 

Arriving at ASU in 1979, Lindsay initially worked under challenging conditions, at times conducting chemical synthesis experiments in the only available space – a janitor’s closet. Lindsay says the early days at ASU were a far cry from the world-class biophysics program he and the university have since assembled. Nevertheless, he found the academic structure in the United States liberating, compared with the British system to which he was accustomed. From the start, he was encouraged to pursue his own investigations, and seized the opportunity to begin serious research into his adopted field of biophysics.

One of the key developments in Lindsay’s evolution as a scientist came in the 1980s, with the development of powerful new tools for probing the microworld. These were the scanning tunneling- and atomic force microscopes. These inventions opened the door to a new domain known as scanning probe microscopy, in which delicately honed probes, usually composed of platinum/iridium or gold, are used to make extremely sensitive measurements at the molecular scale.

Lindsay soon took up these instruments, using them for far-flung research into nanomaterials, rapid DNA sequencing, microelectronics, solar energy applications, condensed matter physics and other areas.

Molecular inquisitions

Studies at the single-molecule level present unique challenges and offer new insights, as matter tends to behave quite differently at these tiny scales, so remote from everyday experience. Random fluctuations such as Brownian motion dominate affairs at the nanoscale and have implications for chemistry, biology, physics, materials science, engineering and other fields, Lindsay says. In biological systems, fluctuations at the microscale are able to produce profound alterations in the characteristics (phenotype) of organisms and play a vital role in species diversity.

“The more I study the components of biology, the more I would say that such fluctuations aren’t just a nuisance to be lived with, they actually are the story of biology.”

Indeed, Lindsay argues that Darwinian principles of chance mutation and natural selection can be thought to operate all the way from the macroworld to the molecular realm, allowing nature to generate a staggering level of complexity of living forms from a limited genomic template. Nature, it turns out, can cut genes into component fragments and shuffle them like playing cards, yielding a vast repertoire of resultant proteins. This process of random gene splicing is believed to guide many biological events, from the formation of our neural pathways to the ability of innate immune responses to liberate a profusion of antibodies when confronted with novel infectious threats.

One of the most exciting avenues of new research involves a novel technique for rapidly sequencing DNA. Known as sequencing by recognition, the method may soon permit the reading of an uninterrupted strand of a DNA molecule. Current methods for sequencing are limited in the length of the read, requiring many chopped up bits of DNA to be read, then painstakingly stitched back together by computer, with the procedure accumulating errors in proportion to the length of the desired read. New support from NIH will now extend Lindsay’s work. One hope for this research is that it may eventually permit discrimination between healthy and diseased tissues by measuring so-called epigenetic markings, variations at the molecular level, which sit atop the genome and are implicated in differential gene expression between cells.

Currently, Lindsay is involved with several new collaborations. Under a recent NIH grant, he joins Biodesign professors Hao Yan and Deidre Meldrum, (dean of the Ira A. Fulton Schools of Engineering and director of Biodesign’s Center for Ecogenomics), in a project to probe and measure the inner workings of a cell using nanostructures based on DNA origami—a method for creating two and three dimensional shapes through the nanoscale folding of DNA. Lindsay hopes such multidisciplinary projects will one day find their way into new biomedical advances, particularly in the areas of personalized genomics and epigenomics, with the potential to radically alter the course of medical diagnosis and treatment.  Lindsay is also part of the new “Physical Sciences in Oncology” center at ASU, a NIH-funded program led by colleague Paul Davies that aims to focus the tools of physics on the problem of cancer.  He hopes that new tools to read the “epigenetic code” will contribute to a better understanding of cancer.

Mind over matter

Lindsay’s versatility and scientific creativity have earned him not only numerous awards and accolades (including a 2008  year’s Regents’ professorship, the highest honor bestowed on research faculty), but the admiration of his many colleagues, collaborators and students.

“One of the most amazing things about Professor Stuart Lindsay’s career is the absolute synergy between education and research,” says Neal Woodbury, the deputy director of the Biodesign Institute. “While many professors try to simply balance the two activities, Stuart weaves one into the other, performing fundamental measurements of molecular electronic parameters while explaining the electronic states of matter in his freshman chemistry class. His breadth of understanding – which covers much of physics, biology and chemistry – is nothing short of astounding. If there is such a thing these days as a renaissance scientist, Stuart is it.”

Otto Sankey, associate director of the Center for Biological Physics agrees. “What defines Stuart’s approach to science is passion for the subject at all levels. He is fascinated by its mysteries, leaves no stone unturned in his pursuits, and is satisfied only with finding truth.”

Adding to the intellectual fruits of his research, professor Lindsay holds 29 U.S. patents relating to atomic force microscopy and molecular electronics. He is a technology advisor for the Atomic Force Microscope Division of Agilent Technologies, which acquired Molecular Imaging Corporation, a company Lindsay co-founded in 1993. Author of over 175 peer-reviewed journal articles, he sits on the editorial boards of Biophysical Journal and AIP Press International Series in Basic and Applied Biological Physics. He also holds the position of Associate Editor for Probe Microscopy at Ultramicroscopy. He is a fellow of the American Association for the Advancement of Science and the American Physical Society.

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Written by Richard Harth
Harth, with the Biodesign Institute, can be reached at richard.harth@asu.edu.