Scott Manalis

Biosketch

Ph.D. in Applied Physics • 1998 Stanford University

Research in Computational and Systems Biology

The overall goal of Professor Manalis’ research program is to develop quantitative, high throughput, real-time measurement techniques for measuring molecular interactions in biological systems. This laboratory uses standard silicon microfabrication principles to develop novel molecular detection schemes and apply them to biomolecular recognition. Successful validation of these methods requires the integration of engineering and biological approaches, and hence this work is thriving within the interdisciplinary environment of CSBi.

Many critical characteristics of a living system can be discovered by monitoring parameters such as DNA sequence variation, gene expression, and protein interactions as a function of time, physiological response, and disease state. The most sensitive assays available today rely on fluorescent or radioactive labeling, which require multistep sample preparation methods and relatively large sample volumes. Hence, assay development and throughput can represent critical bottlenecks for large-scale applications. Therefore, we are developing sensitive and efficient label-free methods for measuring specific proteins and DNA that will be suitable for very large numbers of very small samples.

Mechanical measurement of proteins

We are developing a resonant mass sensor for specific biomolecular detection in picoliter sample volumes. The sensing principle is based on measuring shifts in resonance frequency of a suspended microfluidic channel when molecules accumulate inside the channel walls. This device can be actuated by electrostatic forces and integrated directly with conventional microfluidic systems. So far, we have achieved a sensor with a surface mass resolution that is comparable to a quartz crystal microbalance, and we are now optimizing the system to improve the surface mass resolution to the equivalent of one protein per square micron. We envision that an array of suspended microchannel detectors with this resolution may provide a highly efficient alternative to fluorescence-based detection for protein microarrays, which would have great utility for pharmaceutical and biological research, medical diagnostics and environmental monitoring.

Electronic measurement of DNA

We also are developing electronic methods for selective real-time detection of label-free DNA. This approach uses microfabricated silicon field-effect sensors that directly measure the increase in surface charge when DNA hybridizes on a sensor surface. These sensors can measure nanomolar DNA concentrations within minutes and can detect a single base mismatch within 12-mer oligonucleotides. The sensors are manufactured by conventional, high-yield silicon microfabrication processes that can produce hundreds of sensors in parallel. The optimization of electronic DNA arrays for rapid characterization of nucleic acids would increase the speed and simplicity of assays for infectious agents, for scoring sequence polymorphisms and genotypes, and for measuring mRNA levels during expression profiling. Ultimately, this approach may allow us to detect gene expression from a single cell.

Selected Publications

C.A. Savran, A.M. Knudson, A.D. Ellington, and S.R. Manalis, "Micromechanical detection of proteims using aptamer-based receptor molecules," Analytical Chemistry, 75 3194 (2004).

J. Fritz, E.B. Cooper, S. Gaudet, P.K. Sorger, and S.R. Manalis, “Electronic detection of DNA by its intrinsic molecular charge,” Proceedings of the National Academy of Sciences, 99 14142 (2002).

C.A. Savran, A.W. Sparks, J. Sihler, J. Li, W. Wu, D. Berlin, J. Fritz, M.A. Schmidt, and S.R. Manalis, “Fabrication and characterization of a micromechanical sensor for differential detection of nanoscale motions,” IEEE Journal of Microelectromechanical Systems, 11 703 (2002).

T.P. Burg and S.R. Manalis, Suspended microchannel resonators for biomolecular detection, Applied Physics Letters, 83 2698 (2003).