Imaging and Detection of Single Molecules Workshop: Challenges and Opportunities
On August 13 and 14, 2012, the W. M. Keck Foundation hosted, for the first time, a workshop focused on a single interdisciplinary field. For this inaugural workshop, held at the Arnold and Mabel Beckman Center of the National Academies of Science and Engineering in Irvine, California, we chose to concentrate on single-molecule imaging and detection.
The staff and Foundation’s board of directors convened a group of Keck grantees in the fields of physical, biological and biomedical imaging to brainstorm about the opportunities and challenges in imaging sciences at the single-molecule and single-cell levels. We asked them to share their perspectives on potential areas of future progress, and to identify some of the obstacles to realizing those visions. The Keck Foundation is grateful to this segment of the imaging community for their thoughtful and forward-looking discussions and guidance.
The workshop was organized into three panels. Each panel was chaired by a distinguished expert: John Hemminger for Physical Sciences, Scott Fraser for Biological Sciences, and Paul Weiss for Medical Sciences. The Foundation’s perspective for the meeting was provided by Ed Stone and Steve Ryan, chairs of the Keck Foundation board’s Science and Engineering and Medical Research Grant Committees, respectively. A list of all of the participants follows this report.
Both in individual presentations and group discussions, the participants examined many lines of inquiry. While each has his or her “molecule of choice,” they seek many of same pressing answers, ranging from mass and chemical composition to its structure and interaction partners. In order to begin to answer these questions each contributor dreamed of novel instrumentation that is multi-modal (i.e., different observational approaches within the same instrument), multi-scale in regard to size (i.e., from sub nanometer to tens of microns), and multi-scale in regard to time (observations that last from femtoseconds to days), in every case without the loss of sensitivity or selectivity. Success in building such next-generation data acquisition tools, however, will bring a second challenge by making today’s data analysis challenges even more daunting. Handling the large datasets such instruments could record will require new hardware, theory and computational analysis strategies, including compressed sensing (efficient use of smaller but relevant data sets), and new knowledge extraction pipelines.
Consensus emerged around the “meso” scale as one size scale that deserves greater attention. It requires new technological developments to make it more amenable to study, but one where the pay off would be great. “Meso” is loosely defined as spanning the scales between single atoms and classical systems. At the meso scale, assemblies of molecules create complexity that enable new functionality and phenomena that have not been observed to date. For example, Ali Yazdani described the power of the scanning tunneling microscope, which has enabled investigators to probe with precision how exotic macroscopic electronic phenomena, such as superconductivity, emerge from local individual electron spin interactions.
Figure 1. Revealing how quantum states emerge from nanoscale interactions, at the mesoscale, scanning tunneling microscope techniques show isolated higher temperature "islands" of superconductivity. (Image courtesy of Ali Yazdani)
The consensus of the participants was that combining modalities and scales will be challenging. The hurdle of adding the fourth dimension of time without losing sensitivity imposes another daunting obstacle. Imaging at depth, particularly in biological samples, presents an additional complication. This will require both pushing current technologies further and bringing tools and technology from other fields to imaging. In the process of repurposing technologies such as adaptive optics, it will be necessary to modify and to adapt existing technologies in clever and creative ways.
In optical imaging, Michael Naughton is developing an approach to nanoscale optical imaging that bridges near- and far-field optics with sub-diffraction-limited resolution. The basic concept is a type of “superlensing” using metamaterials comprising an array of nano-scale coaxial waveguides. Beyond optical imaging, he further speculates that the waveguides could be used for lithography to fabricate devices such in semi conductors.
Figure 2. Transmission of visible radiation (light) through a coaxial wire is possible for a subwavelength wire, i.e. d<λvis = 400-700 nm.
Figure 3. A "converging lens" array of optical nanocoaxial cables, with inter-cable separation greater than the wavelength λ on one side of the "lens", and less than λ on the other. In reverse, light directed through the coaxial cables can pattern a semi-conductor device. (Images courtesy of Michael Naughton)
Adaptive optics (AO) have been used in ground-based astronomy to correct image aberrations caused by light passing through earth’s turbulent atmosphere. The same approach has been successfully used in vision science to correct for aberrations caused by the eye itself when imaging the retina. Both applications require a bright point source that is used to correct for the aberrations. Joel Kubby has taken on the challenge of creating this point source in biological samples so that AO could enable super-resolution imaging deep within a cell or tissue.
Figure 4. Schematic for telescope adaptive optics. A wavefront sensor measures distortions and applies the complementary shape on an adaptive mirror using a feedback control system. (schematic courtesy of University of California Center for Adaptive Optics, CfAO)
Figure 5. Adaptive optics correct for wavefront aberrations in astronomy (top: images of Neptune, C. Max, et.al.) and biological imaging (bottom: images of centrosomes, X. Tao, et.al.)
Having communicated their vision of multi-modal, multi-scale, faster and 4D imaging capabilities, workshop participants challenged each other to articulate a problem or problems around which the scientific and funding communities could unite to enable the development of the new technologies. Although no consensus was reached by this group, the Keck Foundation welcomes ideas about such opportunities from the wider physical and life science communities and invites the funding community to participate in such conversations as well.
As we learned from our 2009 2010 grant program evaluations, funding for the development of new technologies, instruments and methodologies has been a successful niche for Keck support. While we will continue funding other types of basic research as well, this remains a priority for the Foundation’s board of directors.
We thank all of our participants, who represent both senior and early career investigators from institutions located across the United States:
Physical Sciences
John Hemminger (Chair), University of California, Irvine
Andrew Hillier, Iowa State University of Science & Technology
Ali Yazdani, Princeton University
Michael Naughton, Boston College
Nongjian Tao, Arizona State University
Hrvoje Petek, University of Pittsburgh
Biological Sciences
Scott Fraser (Chair), California Institute of Technology
Mark Sherwin, University of California, Santa Barbara
Gary Friedman, Drexel University
Jean-Claude Diels, University of New Mexico
Norbert Scherer and Aaron Dinner, University of Chicago
Enrico Gratton, University of California, Irvine
Deirdre Meldrum, Arizona State University
Joel Kubby, University of California, Santa Cruz
Medical Sciences
Paul Weiss (Chair), University of California, Los Angeles
Akos Vertes, George Washington University
Natalie Ahn, University of Colorado at Boulder
Lydia Sohn, University of California, Berkeley
Gang-yu Liu, University of California, Davis
Joseph Ecker, Salk Institute of Biological Sciences |
