Charles Falco (Professor of Optical Sciences at the University of Arizona)

The Science of Optics; The History of Imaging

Abstract: Recently, renowned artist David Hockney observed that certain drawings and paintings from as early as the Renaissance seemed almost "photographic" in detail. Following an extensive visual investigation of western art of the past 1000 years, he made the revolutionary claim that artists even of the prominence of van Eyck and Bellini must have used optical aids. However, many art historians insisted there was no supporting evidence for such a remarkable assertion. In this talk I show a wealth of optical evidence for his claim that Hockney and I subsequently discovered during an unusual, and remarkably productive, collaboration between an artist and a scientist. I also discuss the imaging properties of the "mirror lens" (concave mirror), and some of the implications this work has for the history of science as well as the history of art (and the modern fields of machine vision and computerized image analysis). These discoveries convincingly demonstrate optical instruments were in use -- by artists, not scientists -- nearly 200 years earlier than commonly thought possible, and account for the remarkable transformation in the reality of portraits that occurred early in the 15th century. (for more information see http://www.optics.arizona.edu/ssd/FAQ.html)

Bio: Charles Falco is a Professor of Optical Sciences at the University of Arizona where he holds the UA Chair of Condensed Matter Physics. He is a Fellow of the American Physical Society, the Institute of Electrical and Electronics Engineers, and the Optical Society of America, has published more than 250 scientific manuscripts, most of which are related to various physical properties of thin film materials, co-edited two books, has seven U.S. patents, and has given more than 200 invited talks on his research at conferences and research institutions in some 20 countries. However, in addition to his scientific research, in 1998 he was co-recipient of an award from the AICA for his work as co-curator of the Solomon R. Guggenheim museum's "The Art of the Motorcycle," for which he also wrote the exhibition catalog's introductory essay and bibliography. With over 2 million visitors thus far in New York, Chicago, Bilbao, and the Guggenheim Las Vegas, it is by far the most successful exhibition of industrial design ever assembled, and is the 5th most attended museum exhibition of any kind. More recently, a collaboration with the artist David Hockney that found artists of such repute as van Eyck, Bellini and Caravaggio used optical projections in creating portions of their work has resulted in widespread coverage in the popular media, including an hour-long BBC special and a segment on CBS '60 Minutes', and over 70 invited talks and public lectures on this topic in eleven countries.

Research Website:
http://www.optics.arizona.edu/faculty/Resumes/Falco.htm

Peter Galison (Harvard University, Department of Physics)

Images and the Making of Scientific Objectivity

Abstract: When scientific objectivity became a goal in the early 19th century it was by no means obviously something to be desired. Natural philosophers had to invert the old epistemic virtues that involved finding ideal forms that lay behind the variations of this or that individual. Where genius was, plain-sight observation came to dominate. I will here track how the images and image-making technologies of scientific atlases helped define the modern scientific category of mechanical objectivity-and the new quieted and transparent scientific self that accompanied it. The fate of objectivity kept turning: twentieth century scientists questioned image-based, mechanical objectivity; they demanded more interpretation and modification of images than mechanical objectivity ever allowed. With that shift came a new view of the right scientific self, one that explicitly made use of intuition, expertise, and the unconscious. Now, in the early twenty-first century new kinds of scientific images are demanding quite unexpected ways of being a scientist-selves perched uneasily between scientific, engineering, and entrepreneurial forms of life.

Bio: Dr. Galison is the Joseph Pellegrino Professor of the History of Science and of Physics at Harvard University. In 1997, he was named a John D. and Catherine T. MacArthur Foundation Fellow; in 1999, he was a winner of the Max Planck Prize given by the Max Planck Gesellschaft and Humboldt Stiftung. Galison is interested in the intersection of philosophical and historical questions such as these: What, at a given time, convinces people that an experiment is correct? How do scientific subcultures form interlanguages of theory and things at their borders? More broadly, Galison's main work explores the complex interaction between the three principal subcultures of Twentieth century physics--experimentation, instrumentation, and theory. His books include How Experiments End (1987), Image and Logic (1997), Einstein's Clocks, Poincaré's Maps (2003) and (with L. Daston) Objectivity (forthcoming, 2007). In addition, Galison has launched several projects examining the powerful cross-currents between physics and other fields--these include a series of co-edited volumes on the relations between science, art and architecture. He co-produced a documentary film on the politics of science, Ultimate Weapon: The H-bomb Dilemma and is now working on a second, with Robb Moss, Secrecy about the architecture of the classification and secrecy establishment.

David Heeger (New York University, Department of Psychology & Center for Neuroscience)

Brain Imaging: A New Window Into the Human Mind

Abstract: fMRI has revolutionized neuroscience over the past decade. It is similar to clinical MRI, but instead of making pictures of the anatomy of the brain, fMRI allows us to measure and characterize brain function. It has enabled a new era of research into the function and dysfunction of the human brain, complementary to more invasive techniques for measuring neural activity in animals. I will utilize some examples from research in my lab, to illustrate how fMRI in conjunction with computational theory is being used to understand how vision works in the brain.

Bio: David J. Heeger is a Professor of Psychology and Neural Science at New York University. He received his Ph.D. in computer science from the University of Pennsylvania. He was a postdoctoral fellow at MIT, a research scientist at the NASA-Ames Research Center, and an Associate Professor at Stanford before coming NYU. His research spans an interdisciplinary cross-section of engineering, psychology, and neuroscience, the current focus of which is to use functional magnetic resonance imaging (fMRI) to quantitatively investigate the relationship between brain and behavior. He was awarded the David Marr Prize in computer vision in 1987, an Alfred P. Sloan Research Fellowship in neuroscience in 1994, the Troland Award in psychology from the National Academy of Sciences in 2002, and the Margaret and Herman Sokol Faculty Award in the Sciences from New York University in 2006.

Research Website:
http://www.cns.nyu.edu/~david/

Stefan Hell (Director, Max Planck Institute for Biophysical Chemistry, Department of NanoBiophotonics, 37077 Göttingen)

Breaking Abbe’s barrier:Diffraction-unlimited resolution in far-field optical microscopy

Abstract: In 1873, Ernst Abbe discovered that the resolution of focusing (‘far-field’) optical microscopy is limited to  > 200 nm, with  denoting the numerical aperture of the lens and  the wavelength of light. While the diffraction barrier has prompted the invention of electron, scanning probe, and x-ray microscopy, in the life sciences 80% of all microscopy studies are still performed with lens-based (fluorescence) microscopy. The reason is that the 3D-imaging of the interior of (live) cells requires the use of focused visible light. Hence, besides being a fascinating physics endeavor, the development of a far-field light microscope with nanoscale resolution would facilitate observing the molecular processes of life.
I will discuss novel physical concepts that radically break the diffraction barrier in focusing fluorescence microscopy. They share a common strategy: exploiting selected molecular transitions of the fluorescent marker to neutralize the limiting role of diffraction. More precisely, they establish a certain, signal-giving molecular state within subdiffraction dimensions in the sample [1].  
The first viable concept of this kind was Stimulated Emission Depletion (STED) microscopy. In its simplest variant, STED microscopy uses a focused beam for fluorescence excitation, along with a red-shifted doughnut-shaped beam for subsequent quenching of fluorescent molecules by stimulated emission. Placing the doughnut-beam on top of its excitation counterpart in the focal plane confines the fluorescence near its central zero where stimulated emission is absent. The higher the doughnut intensity, the stronger is the confinement. In fact, the spot diameter follows , with  denoting the intensity of the quenching (doughnut) beam and  giving the value at which fluorescence is reduced to 1/e. Without the doughnut (=0) we have Abbe’s equation, whereas for  it follows that , meaning that the fluorescence spot can be arbitrarily reduced in size. Translating this subdiffraction spot across the specimen delivers images with a subdiffraction resolution that can, in principle, be molecular! Thus, the resolution of a STED microscope is no longer limited by, but on the perfection of its implementation. We will demonstrate a resolution down to /45 ≈ 15-20 nm with nanoparticles and biological samples, i.e., 10-12 times below the diffraction barrier.
The concept underlying STED microscopy can be expanded by employing other molecular transitions that control or switch fluorescence emission, such as (i) shelving the fluorophore in a metastable triplet state, and (ii) photoswitching (optically bistable) marker molecules between a ‘fluorescence on’ and a ‘fluorescence off’ conformational state. Examples for the latter include photochromic organic compounds, and fluorescent proteins which undergo a photoinduced cis-trans isomerization or cyclization reaction. Due to their optical bistabilty/metastabilty, these molecules entail low values , meaning that the diffraction barrier can be broken at low . A complementary approach is to switch the marker molecules individually and assemble the image molecule by molecule. By providing molecular markers with the appropriate transitions, synthetic organic chemistry and protein biotechnology plays a key role in overcoming the diffraction barrier.
Finally, I discuss more recent work of my group showing that the advent of far-field ‘nanoscopy’ has already answered important questions in (neuro)biology, such as about the fate of synaptic vesicle proteins after synaptic transmission. Besides, the emerging far-field ‘optical nanoscopy’ also has the potential to advance nanolithography, the colloidal sciences, and to help elucidate the self-assembly of nanosized materials.

[1] S.W. Hell, Far-field optical nanoscopy, Science 316 (2007) 1153.

Bio: Stefan W. Hell (44) is a scientific member of the Max Planck Society and a director at the Max Planck Institute for Biophysical Chemistry in Göttingen, where he currently leads the Department of NanoBiophotonics. He is an honorary professor of experimental physics at the University of Göttingen and adjunct professor of physics at the University of Heidelberg. Since 2003 he has led the High Resolution Optical Microscopy division at the German Cancer Research Center (DKFZ) in Heidelberg. He is also an elected member of the Göttingen Academy of Sciences.
Stefan Hell received his doctorate in physics from the University of Heidelberg in 1990. From 1991 to 1993 he worked at the European Molecular Biology Laboratory, also in Heidelberg, and followed with stays as a senior researcher at the University of Turku, Finland, between 1993 and 1996, and as a visiting scientist at the University of Oxford, England, in 1994. In 1996 he received his habilitation in physics from Heidelberg. In 1997 he was appointed to the Max Planck Institute for Biophysical Chemistry in Göttingen, where he has built up his current research group dedicated to sub-diffraction-resolution microscopy. In 2002, following his appointment as a director, he established the department of Nanobiophotonics.
Stefan Hell is credited with having both conceived and validated the first viable concept for breaking Abbe’s diffraction barrier in a light-focusing microscope. For this accomplishment he has received several national and international awards, including the Prize of the International Commission in Optics (2000), the Carl Zeiss Research Award (2002), the Innovation Award of the President of the Federal Republic of Germany (2006), and the Julius Springer Award for Applied Physics (2007).

Research Website:
http://www.mpibpc.gwdg.de/groups/hell/personals/shell.html

Wesley Traub (Chief Scientist, Jet Propulsion Laboratory, Pasadena, CA)

The Firefly and the Searchlight: Direct Imaging of Exoplanets

Abstract: One of the "big questions" that many of us wonder about is "are there Earth-like planets around other stars, and is there life on those planets?" For centuries, only philosophers dared try to answer this question. But today, with space telescopes and new optical tricks, we have the ability to find Earth-like planets and search for signs of life on them. In this talk I will focus on imaging techniques that will be used to isolate the light of a faint planet close to a star that can be ten million to ten billion times brighter.

Bio: Wes Traub is Chief Scientist for NASA's Navigator Program (to find and characterize exoplanets), and Project Scientist for NASA's Terrestrial Planet Finder Coronagraph (TPF-C) mission. He has been at JPL since June 2005. Before that he was at the Harvard-Smithsonian Center for Astrophysics for 37 years. He is particularly interested in coronagraphs and interferometers for detecting exoplanets, and in spectroscopy for characterizing and searching for life on those planets. His other ongoing interests include measuring the infrared spectra of the Earth's stratosphere using a balloon-borne Fourier-transform spectrometer, and measuring the diameters of stars and disks of material around stars using ground-based interferometers in Arizona, California, and Hawaii.

Research Website: http://science.jpl.nasa.gov/people/Traub/

Roger Tsien (University of California, San Diego, Department of Chemistry)

Building Molecules to Spy on Synapses and Tumors

Abstract: Because many forms of long-lasting learning and memory involve growth or de novo formation of synapses, visualizing recently expanded or created synapses may indicate where memories are stored. A plausible strategy may be to selectively image newly synthesized proteins that preferentially accumulate in growing synapses.  However, existing methods for visualizing newly synthesized copies of specific proteins involving sequential chemical labeling or photoconversion are incompatible with deep tissues or freely behaving animals and have toxicity and sensitivity limitations. Here we report on TimeSTAMP, a new method in which a protein of interest is fused via hepatitis C viral protease to an epitope tag. The protease constitutively removes itself and the accompanying tag until a small-molecule inhibitor is administered; subsequently all newly synthesized fusion proteins remain epitope-tagged. TimeSTAMP shows that new synapses in cultured hippocampal neurons preferentially contain new copies of postsynaptic density proteins. In intact flies, TimeSTAMP reveals patterns of new CaMKII synthesis distinct from total CaMKII localization. TimeSTAMP should allow retrospective identification of new synapses and their key proteins anywhere in the nervous systems of freely behaving animals.
We have synthesized and tested novel imaging agents based on activatable cell-penetrating peptides (ACPPs) that are substrates for matrix metalloproteinases (MMPs), proteases highly expressed in the tumor microenvironment. A simple ACPP is glu9-[MMP-cleavable linker]-arg9-Cy5, in which the polyanionic glu9 prevents the polycationic arg9 cell-penetrating peptide (CPP) from sticking to and entering cells. Proteolysis of the linker separates the glu9 from the arg9, freeing the arg9-Cy5 to be taken up onto and into cells in the vicinity of the protease activity, where the Cy5 can be visualized by its far-red fluorescence. Such ACPPs give useful in vivo fluorescence contrast, peaking a few hours after intravenous injection, in xenografts of various human tumor cells into nude mice as well as in MMTV-polyoma-middle-T (PyMT) mammary tumors in immunocompetent transgenic mice. This fluorescence contrast looks promising as a real-time guide to surgical resection. Analogous ACPPs in which Cy5 is replaced by Gd chelates constitute smart magnetic resonance (MR) contrast agents, which highlight PyMT tumors or downstream lymph nodes in T1-weighted MR images at 7 Tesla. Thus ACPPs offer a promising new general strategy to detect protease activities in vivo and to concentrate imaging and perhaps chemotherapeutic agents within tumors for diagnosis, intraoperative localization, and treatment, although much optimization will still be required.

Bio: Roger Y. Tsien was born in New York City in 1952 and received his A.B. in Chemistry and Physics summa cum laude from Harvard College in 1972. A Marshall Scholarship then took him to the Physiological Laboratory at the University of Cambridge, where he received his Ph.D. in 1977 and remained as a Research Fellow until 1981. He then became an Assistant, Associate, then full Professor in the Dept. of Physiology-Anatomy at the University of California, Berkeley. In 1989 he moved to the University of California, San Diego, where he is an Investigator of the Howard Hughes Medical Institute and Professor in the Depts. of Pharmacology and of Chemistry & Biochemistry. In 1996 he was a scientific co-founder of Aurora Biosciences Corporation, which went public in 1997 and was acquired by Vertex Pharmaceuticals in 2001. In 1999 he was a scientific co-founder of Senomyx, Inc. His honors include 1st prize in the Westinghouse Science Talent Search (1968), Searle Scholar Award (1983), Passano Foundation Young Scientist Award (1991), W. Alden Spencer Award in Neurobiology from Columbia University (1991), Artois-Baillet-Latour Health Prize (1995), Gairdner Foundation International Award (1995), American Heart Association Basic Research Prize (1995), Pearse Prize of the Royal Microscopical Society (2000), Award for Creative Invention from the American Chemical Society (2002), Anfinsen Award of the Protein Society (2002), the Max Delbruck Medal (2002), the Heineken Prize in Biochemistry and Biophysics from the Royal Netherlands Academy of Arts and Sciences (2002), the Wolf Prize in Medicine (shared with Robert Weinberg, 2004), the Keio Medical Science Prize, Keio University (2004), the J. Allyn Taylor International Prize in Medicine (2005), and the Rosenstiel Award for Distinguished Work in Basic Medical Sciences (2006). He was elected to the Institute of Medicine in 1995, the National Academy of Sciences in 1998, and to the Royal Society (as a Foreign Member) in 2006. Dr. Tsien's research has been at the interfaces between organic chemistry, cell biology, and neurobiology, starting long before such interdisciplinary efforts became fashionable. He is best known for designing and building molecules that either report or perturb signal transduction inside living cells. These molecules, created by organic synthesis or by engineering naturally fluorescent proteins, have enabled many laboratories including his to gain new insights into signaling via calcium, sodium, pH, cyclic nucleotides, nitric oxide, inositol polyphosphates, membrane potential changes, protein phosphorylation, active export of proteins from the nucleus, and gene transcription. The optical reporter molecules are also valuable in miniaturized high-throughput screening of candidate drugs in the pharmaceutical industry. His current research goals are to understand how the spatial and temporal dynamics of signal transduction orchestrate complex cellular responses such as gene expression and synaptic plasticity. These goals will require improved molecular techniques to see and manipulate small-molecule messengers, protein phosphorylation, and protein-protein interaction in live cells and organisms. He is also developing new ways to target contrast agents and therapeutic agents to tumor cells based on their expression of extracellular proteases.

Research Website:
http://www.tsienlab.ucsd.edu/

Penn Speakers

Ivan Dmochowski, Chemistry

Xenon’s Paradoxes and Zebrafish Tails

Abstract: The Dmochowski lab is developing a new class of biologically responsive magnetic resonance imaging (MRI) contrast agents that exploit the unique properties of xenon-129. This spin-½ nucleus is extremely sensitive to its molecular environment and can be hyperpolarized to generate 10,000-fold signal enhancements. The lab developed the first enzyme-responsive Xe-129 biosensor, which detects peptide cleavage by matrix metalloproteinases. Lab members have generated much higher affinity xenon-binding cages, as well as fluorescence and ITC-based methods for measuring xenon binding. These advances are guiding the design of new Xe imaging agents. The Dmochowski lab is also developing photochemical methods for controlling gene expression in vivo with high spatial and temporal resolution. The lab has synthesized “caged” antisense oligodeoxynucleotides (asODNs) whose activity is transiently blocked by a complementary sense strand attached via a photocleavable linker. Using caged asODNs, the lab has photoregulated expression of the genes chordin and bozozok within living zebrafish embryos, and c-myb in human leukemia cells.

Bio: Ivan Julian Dmochowski was born in Meridian, Mississippi on March 12, 1973 and grew up in Falmouth, MA (Cape Cod). Ivan graduated from Falmouth High School in 1990 and was named a U.S. Presidential Scholar. He attended Harvard College and majored in Chemistry. Ivan was inspired by Prof. George Whitesides to investigate self-assembled monolayers on gold and silica surfaces. After graduating Magna cum Laude in 1994, Ivan spent a year working in the labs of Prof. Helmut Ringsdorf in Mainz, Germany. Ivan returned to the U.S. to study bioinorganic chemistry under the mentorship of Prof. Harry Gray at Caltech. Research focused on the design of laser-activated molecules for transferring electrons and holes to the heme of cytochrome P450. For this work, Ivan received a Ph.D. in 2000, and the McCoy Award from the Chemistry Department. He was later awarded a Helen Hay Whitney Postdoctoral Fellowship to perform fluorescence spectroscopy in living embryos with Prof. Scott Fraser, Director of the Caltech Beckman Biological Imaging Center. Ivan became an Assistant Professor of Chemistry at the University of Pennsylvania in 2003. Dmochowski lab members are working in forefront areas of biomolecular imaging that intersect Chemistry, Biology, and Materials Science.

Research Website:
http://www.sas.upenn.edu/%7Eivandmo/

Michael Lampson, Biology

Control of cell division: spatial and temporal phosphorylation patterns in living cells

Abstract: Maintenance of genome integrity over cell division requires coordination of chromosome segregation and cell cleavage, so that each daughter cell inherits a complete copy of the genome. Cleavage occurs at the center of the dividing cell, midway between the segregated chromosomes. How signals are generated to position the cleavage site is unknown. We use FRET-based sensors in living cells to examine the dynamics of protein phosphorylation due to Aurora B, a widely conserved kinase required for both proper chromosome segregation and cell cleavage. Quantitative analysis of phosphorylation dynamics reveals a spatial gradient with maximal phosphorylation midway between the separating chromosomes in anaphase. These results suggest that patterns of Aurora kinase phosphorylation provide spatial cues to designate the center of the dividing cell.

Bio:

Harvard University. 1990-1994.
A.B. cum laude, Physics, June 9, 1994.

Cornell University, Weill Graduate School of Medical Sciences. 1997 – 2002.
Ph.D., Physiology and Biophysics, 2002.
Laboratory of Dr. Tim McGraw.

Postdoctoral fellow, Rockefeller University,
New York, NY. 2002 – 2006 .
Laboratory of Dr. Tarun Kapoor.

Assistant Professor, Department of Biology, University of Pennsylvania. 2007 –
Investigating mechanisms that ensure genome stability during cell division, particularly signaling mechanisms that ensure high fidelity segregation of chromosomes between daughter cells.

Research Website:
http://www.med.upenn.edu/camb/faculty/cgc/lampson.html

Gary Bernstein, Physics & Astronomy

Gravitational Optics

Abstract: Many lines of evidence suggest that ordinary visible matter comprises only 6% of the contents of the Universe. The remaining "dark" matter and energy neither absorb nor emit light, but their gravitational fields do deflect light, altering the appearance of objects behind them. I will show examples of this gravitational lensing effect, and explain how gravitational optics differ from typical lenses and mirrors. Large imaging surveys of the sky can, paradoxically, be used to map and measure the invisible components of the Universe, via their lensing effects. I will describe new billion-pixel telescopes being built by Penn and collaborators to exploit the gravitational lensing effect and open a new era in astronomical imaging.

Bio: Professor Bernstein joined the Penn faculty in 2002 after positions at Bell Laboratories, the University of Arizona, and the University of Michigan. His research projects involve the extraction of rare or subtle signals from large astronomical imaging datasets, either using gravitational lensing for cosmological measurements, or searching for small objects orbiting beyond Neptune in our own Solar System. This work is supported by the National Science Foundation, NASA, and the Dept. of Energy. He was an NSF CAREER Fellow and recently served on the Dark Energy Task Force to formulate an interagency approach to this exciting new development in astrophysics.

Research Website:
http://www.physics.upenn.edu/~garyb/

Amishi Jha, Psychology

Brains at Work: Imaging Working Memory with Functional MRI

Abstract: Working memory is the ability to maintain and manipulate information over short intervals. This cognitive operation is critical for higher order mental functioning including comprehension, reasoning, and problem solving. Functional brain imaging has been an important tool in uncovering the neural bases of working memory in humans. In my presentation I highlight the utility of functional MRI for addressing many key questions regarding the basic processes of working memory. How is the maintenance of information over time achieved by the brain? How does the brain protect this maintenance from becoming compromised by distraction? How is maintaining information distinct from using it? Several studies using a delayed-recognition paradigm were conducted during functional MRI scanning to address these questions. These results show that working memory maintenance requires the coordinated effort of specialized subregions of prefrontal and parietal cortex. In particular, fronto-parietal structures act to modulate information processing in favor of memory items. Understanding the neural mechanisms by which working memory is instantiated in the human brain clarifies what goes wrong in mental diseases (ADHD, anxiety, depression) and what changes during normal aging.

Bio: Amishi P. Jha, Ph.D., is an Assistant Professor of Psychology at the University of Pennsylvania. She received her Ph.D. from University of California-Davis in 1998, and received her post-doctoral training in the Brain Imaging and Analysis Center at Duke University (Durham, USA) in functional neuroimaging. Her research centers on the cognitive neuroscience of attention and working memory. Using functional MRI, electroencephalography (EEG), and behavioral measures she has demonstrated that there are two complementary processes that aid "tuning" attention systems to better maintain information over time. There is an active effortful enhancement of neural representations of items that should be maintained in working memory (the memory items), as well as a selective suppression of items that may be very distracting and lead to memory errors. Recently she has begun to explore how these tuning features may be damaged in disorders of attention, such as ADHD. In addition, she is conducting an NIH-R21 funded project to investigate if attention training may lead to improvements in attentional tuning. Specifically, she will examine the role of mindfulness meditation training in altering functioning of alerting, orienting, and conflict monitoring subsystems of attention. She teaches courses on attention and memory, the cognitive neuroscience of meditation, and research experience in functional MRI. She is the 2007 recipient of the Charles Ludwig Distinguished Teaching Award.

Research Website:
http://www.amishi.com/lab/