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Ronald W.P. Drever, © IAU/Gruber Foundation
Kip S. Thorne, © Caltech
Rainer Weiss, © Courtesy of Les Guthman
Ronald W.P. Drever Born in Renfrewshire, Scotland, Ronald Drever studied at Glasgow University and gained his PhD there in 1958. At Glasgow he looked for gravitational waves first by monitoring the vibrations of aluminium bar detectors and then by setting up a 10-metre interferometer. In 1979 he was hired by the California Institute of Technology to lead a new programme in experimental gravitation, which led to the construction of a 40-metre device that tested many of the techniques employed in LIGO. Drever has carried out experiments in a number of areas of physics, including spectroscopic measurements to look for anisotropy of mass and space - his null results providing accurate confirmations of both special and general relativity. However, it is in the study of gravitational radiation that he has left his biggest mark. Among his many innovations is a technique for improving the stability of laser frequencies. Drever has been awarded the Einstein Prize, the Special Breakthrough Prize in Fundamental Physics and the Gruber Prize in Cosmology. He has been elected to the American Academy of Arts and Sciences, the American Physical Society and the
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Royal Society of Edinburgh, having also been vice-president of the Royal Astronomical Society.
tion that can be gathered from images, with particular use for applications in medical diagnostics.
Kip S. Thorne Thorne was born in Utah and studied physics at the California Institute of Technology. After obtaining his PhD from Princeton University in 1965 and carrying out two years of postdoctoral study, he returned to Caltech and has worked there ever since.
Christoph Gerber Christoph Gerber is a Swiss professor of physics and Director for Scientific Communication of the National Center of Competence for Nanoscale Science at the University of Basel, where he has been since 2004.
Thorne has carried out a wide range of theoretical research in gravitation and astrophysics, including having predicted the existence of a type of red supergiant star with a neutron star core, and using general relativity to describe how black holes move and precess. His work has also provided the theoretical underpinnings for LIGO; he and his colleagues have established target sources of gravitational waves and carried out numerical simulations of the kind that allowed the September 2015 signal to be identified as a pair of merging black holes.
After his PhD, Gerber moved to Sweden and in 1964 became group leader in research and development for the company Contraves. In 1966 he moved to IBM Research in Zürich, with which he remained associated until 2004; in the 1980s he also worked temporarily at IBM Almaden and at the IBM physics group in Munich. In the early 1980s he worked with Gerd Binnig, Heinrich Rohrer and Edmund Weibel on the development of the scanning tunnelling microscope. He then continued his collaboration with Binnig, and while at IBM Almaden the two scientists, in collaboration with Calvin Quate from Stanford University, realized the atomic force microscope.
In addition to awards recognising his work as a writer and a science advisor to the film Interstellar, Thorne has won the Lilienfeld Prize, the Niels Bohr Gold Medal, the Special Breakthrough Prize in Fundamental Physics and the Gruber Prize in Cosmology, among others. He is a member of the American Academy of Arts and Sciences, the U.S. National Academy of Sciences and the American Philosophical Society, as well as being a foreign member of the Russian Academy of Sciences. Rainer Weiss Born in Berlin, Weiss obtained his first degree and then in 1962 his PhD from the Massachusetts Institute of Technology. After serving as an assistant professor of physics at Tufts University and then a research associate at Princeton University, he returned to MIT and has been there ever since. Weiss has contributed to a variety of scientific fields, including atomic physics, laser physics and astronomy. As part of the latter, he measured the spectrum of the very faint but ubiquitous radiation known as the cosmic microwave background, and was one of the founders of NASA’s COBE cosmic microwave mission. He cofounded LIGO with Thorne and later Drever, having laid the foundations for the project in 1972 with a paper detailing how an interferometer could distinguish gravitational waves from background noise. He has continued to contribute to nearly all elements of the experiment since then. Weiss has been awarded the Einstein Prize and the Special Breakthrough Prize in Fundamental Physics, and has twice won the Gruber Prize in Cosmology. He is a member of the American Physical Society, the American Astronomical Society and the U.S. National Academy of Sciences to name just a few.
Christoph Gerber, © Swiss Nanoscience Institute (SNI)
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Gerd Binnig Gerd Binnig is a German physicist and Nobel Laureate. After obtaining his PhD at the Johann Wolfgang Goethe University in Frankfurt in 1978 he moved to Zürich, where he became a research staff member at IBM. In collaboration with Heinrich Rohrer and other colleagues including Christoph Gerber and Edmund Weibel, in 1981 he developed the scanning tunnelling microscope. In recognition of this work, Binnig and Rohrer were awarded the Nobel Prize in Physics in 1986. Between 1985 and 1988, Binnig was based in California, working at IBM in Almaden and at Stanford University, where he had a visiting professorship. It was during this period that he involved his IBM colleague Christoph Gerber and Stanford Professor Calvin Quate in realizing his idea of the atomic force microscope. When he returned to Europe he was awarded an honorary professorship at the Ludwig Maximilian University in Munich, where he directed an IBM laboratory until 1995. In 1994 he founded Definiens, a company dedicated to developing advanced processing tools for maximizing the informa-
Calvin Quate Calvin Quate is an American engineer and physicist who holds the Leland T. Edwards Professorship in the School of Engineering at Stanford. He obtained his PhD in Stanford in 1950. Between 1950 and 1960 he worked at different research laboratories, first at Bell Labs in Murray Hills, New Jersey, then at Sandia in Albuquerque, New Mexico. He finally moved to Stanford University, where since 1961 he has been a professor of applied physics and electrical engineering. Quate has been interested in scanning probes for a long time. In the early 1970s, working with Ross Lemons, he developed the scanning acoustic microscope, which was reported in a paper in Applied Physics Letters in 1974; t h is inst r u ment ca n be employed to investigate the structural properties of devices, as well as the elasticity of tissues. In the mid-1980s he became interested in realizing an instrument that could provide images of surfaces with very high resolution, and together with Gerd Binnig and Christoph Gerber he developed the atomic force microscope.
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NEUROSCIENCE the Cognitive Neuroscience Society (2012). Michael M. Merzenich Michael M. Merzenich is Professor Emeritus in Neuroscience at the University of California, San Francisco.
Eve Marder, © Wikipedia Commons
Michael M. Merzenich, © University of California, San Francisco
In the last 30 years he has continued to explore the possibility of using scanning probes as imaging, manipulation and diagnostic tools. He is particularly interested in developing biochemical sensors based on atomic force microscopy. Calvin Quate, © Linda A. Cicero
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Born in Lebanon, Oregon, Merzenich gained a first degree in science at the University of Portland in 1964, and earned a PhD in physiology at Johns Hopkins University in 1968. After postdoctoral research at Madison, Wisconsin, he joined the UCSF Department of Otolaryngology, working on a prototype for today’s electronic cochlear implants. He was Co-Director of the Coleman Memorial Laboratory, then Co-Director of the Keck Center for Integrative Neuroscience at UCSF until retirement in 2007. From 1996 to 2003 he led the company Scientific Learning, then cofounded Posit Science, developing computer-based ‘brain training’ for enhancing cognitive performance. Merzenich is a member of the National Academy of Sciences and Institute of Medicine. His awards include the Zülch Prize of the MaxPlanck Institute, the Purkinje Medal, and the Karl Spencer Lashley Award. Carla J. Shatz Carla J. Shatz is Chair of Neurobiology at Stanford University, and Director of Bio-X.
Carla J. Shatz, © Steve Fisch
Eve Marder Eve Marder is the Victor and Gwendolyn Beinfield Professor of Neuroscience in the Biology Department, and Head of the Division of Science, at Brandeis University. Marder grew up in New York and New Jersey, and gained her first degree in biology from Brandeis University, in 1969. She earned her PhD at the University of California, San Diego in 1975, and then worked at the University of Oregon in Eugene, and the École Normale Supérieure, Paris. She then returned to the Biology Department at Brandeis University, becoming a full professor in 1990. She has pioneered understanding of how a neural circuit can generate the necessary rhythmic firing patterns that control rhythmic muscle movements such as breathing, walking, and passage of food through the gut. Marder’s much feted contributions to neuroscience include membership of the US National Academy of Sciences and fellowship of the American Academy of Arts and Sciences. Her awards include the Women in Neuroscience Mika Salpeter Lifetime Achievement Award (2002), the Gruber Award in Neuroscience (2013), and the George A. Miller Award from
Shatz grew up in West Hartford, Connecticut. She did her undergraduate degree at Radcliffe College, and studied with neurophysiologists Huber and Wiesel at Harvard (who later won a Nobel Prize in 1981). After graduating in 1969, Shatz had a Marshall Scholarship to study physiology at University College London. She then became the first woman to gain a PhD from the Harvard Department of Neurobiology in 1976. In 1978 Shatz joined the Stanford University School of Medicine, and UC Berkeley in 1992. She left the west coast in 2000 to become the first woman to lead a basic science department at Harvard Medical School, and set up the Harvard Center for Neurodegeneration and Repair (CNR). In 2007, Shatz returned to Stanford to head Bio-X. Shatz is a member of the American Academy of Arts and Sciences, the National Academy of Sciences, the European Academy of Sciences and Arts, and the Royal Society, UK. Her awards include the Gill Prize in Neuroscience (2006), the Mika Salpeter Lifetime Achievement Award (2009), the Ralph W. Gerard Prize in Neuroscience (2011), and the Gruber Prize in Neuroscience (2015).
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Kavli Prize honours gravitational-wave pioneers The LIGO Laboratory operates two detector sites, one near Hanford in eastern Washington, and another near Livingston, Louisiana. This photo shows the Livingston detector site. Photo: Caltech/ MIT/LIGO Lab
by general relativity, analysed every conceivable source of noise, and even considered the possibility of an elaborate hoax. In the end, about three months later, they were convinced that they had seen a gravitational wave.
The 2016 Kavli Prize for Astrophysics goes to Ronald W. P. Drever, Kip S. Thorne and Rainer Weiss “for the direct detection of gravitational waves”.
arranged at right angles to one another. Each beam bounces off a mirror at the end of its respective tube and then recombines with the other beam at the beam splitter. The apparatus is set up so that normally the peaks of one beam line up with the troughs of the other and the two beams cancel one another out. A light sensitive detector placed behind the beam splitter therefore registers no signal.
The signal picked up by the Laser Interferometer Gravitational-wave Observatory (LIGO) in the US on September 14 last year lasted just a fifth of a second but brought to an end a decades-long hunt to directly detect the ripples in space-time known as gravitational waves. It also opened up a completely new way of doing astronomy, which uses gravitational rather than electromagnetic radiation to study some of the most extreme and violent phenomena in the universe.
A passing gravitational wave, however, changes the length of the arms. First it stretches one arm and simultaneously squeezes the other, before squeezing the stretched one and vice versa. With the peaks and troughs of the two beams no longer perfectly aligned, the detector registers a signal. More precisely, it registers a characteristic brightening and dimming as the gravitational wave propagates. The first paper describing the principles of such detectors was published in 1962 by a pair of Soviet physicists, Mikhail Gertsenshtein and Vladislav Pustovoit, who argued that interferometers could be far more sensitive than bar detectors because they could be made much longer. Longer devices are better because a given fractional change in distance caused by a passing gravitational wave will translate into a larger absolute change.
Gravitational waves were predicted by Albert Einstein in 1916. A year earlier, Einstein had formulated his general theory of relativity, which describes gravity as warping four-dimensional space-time. Using his theory, he found that accelerated masses would create distortions in space-time rather like the ripples created when a stone is thrown into a pond. These “gravitational waves”, radiating at the speed of light, would carry information about the objects that had produced them. Gravity is by far the weakest force of nature, and its effects are generally only visible when produced by extremely large masses. To look for gravitational waves, therefore, scientists turned to the heavens. The first evidence for such waves actually came in 1982, but it was indirect. Several years earlier, the American physicists Joseph Taylor and Russell Hulse had discovered a pulsar orbiting a neutron star. By carefully monitoring the pulsar’s radio emissions, Taylor and another colleague, Joel Weisberg, found that the object’s orbit was shrinking at just the rate that would be expected if it were radiating gravitational waves. What scientists really wanted, however, was a direct detection - to observe the distorting effect of a gravitational wave emitted by a celestial object that has travelled across the universe and then passed through the Earth. Unfortunately, because the waves are expected to originate from very far away, their distortions will be extraordinarily small once they reach Earth - LIGO’s dimensions being changed by about a thousandth of the width of an atomic nucleus. The challenge is being able to detect such minute variations while screening out far larger sources of background noise, such as vibrations caused by earthquakes or the thermal jiggling of atoms. In fact, until the 1950s, physicists were unsure whether gravitational waves were real physical entities, as
Gravitational Waves, As Einstein Predicted. These plots show the signals of gravitational waves detected by the twin LIGO observatories at Livingston, Louisiana, and Hanford, Washington. The signals came from two merging black holes, each about 30 times the mass of our sun, lying 1.3 billion light-years away. Image Credit: Caltech/MIT/LIGO Lab
LIGO Hanford Control Room. Desks full of computers, and walls covered with projection screens and large monitors keep LIGO’s interferometer operators busy as they monitor the instrument’s status 24 hours a day, 7 days a week. Photo: Kim Fetrow
opposed to being purely mathematical, and whether they carried energy. Efforts to detect them began with the American electrical engineer Joseph Weber, who in 1969 reported having observed that a pair of large, suspended aluminium cylinders he had set up for the purpose had been made to “ring” by a passing wave. However, other groups using their own “bar
detectors” failed to reproduce the result and by the mid-1970s Weber’s claim had been largely discredited. It was at that point that scientists started working with interferometers. The basic idea is to divide a laser beam in two using a device known as a beam splitter, and send the resulting beams down a pair of hollow tubes
It was not until almost a decade later, however, that physicist Rainer Weiss of the Massachusetts Institute of Technology calculated in detail how interferometer-based detectors would perform, given all of the various noise sources they would have to overcome. Weiss started thinking about interferometers after teaching a course on general relativity and finding he was unable to explain to his students how Weber’s bar worked. His interest was further piqued following the null results from other bar experiments, and he then spent an entire summer in a little room in a temporary building on the MIT campus working through his interferometer calculations. His results, which he published informally in 1972, would form the basis of LIGO. LIGO has turned out to be the largest ever facility funded by the US National Science Foundation (NSF), costing many hundreds of millions of dollars and involving over 1000 scientists from across the globe. But its founders, Weiss and Kip Thorne, a theoretical physicist at the California Institute of Technology (Caltech), had no idea of such grandeur when they first met in a Washington, D.C. hotel room in the summer of 1975. The two were in town for a NASA meeting, and Thorne took the opportunity to discuss how Caltech might set up a new group in experimental gravitation. Weiss described his work on interferometers and Thorne was sold;
the latter went away and established an interferometer group at Caltech that would later build LIGO together with Weiss and colleagues at MIT. Thorne worked on the scientific aspects of the project, such as the computations needed to predict the gravitational-wave signals from different kinds of astrophysical object. But he also played a vital role in the project management. In particular, he brought to Caltech the third of the LIGO “troika” - Ron Drever. Drever, a Scottish physicist who had been conducting his own research on interferometers at the University of Glasgow, was recruited by Thorne in 1979. Renowned as something of a technical genius, he devised many improvements to the basic design put forward by Weiss; these have enabled LIGO to become the ultra-sensitive device it is today. For example, he showed how it was possible to greatly increase the effective length of the interferometer arms by creating what is known as a Fabry-Pérot cavity, in which the laser beams bounce back and forth many times between mirrors at either ends of the arms before their recombination at the beam splitter. LIGO, approved in 1990, actually consists of two interferometers, each having arms 4 kilometres long, located on opposite sides of the US - one in Washington state and the other in Louisiana. It initially operated between 2002 and 2010 but saw no gravitational waves during that time (as was largely expected). Over the next few years it was upgraded in order to boost its sensitivity - its noise being reduced, in part, thanks to more
The discovery provides the first confirmation of general relativity in very strong gravitational fields (as opposed to the weak fields of Earth and other planets). But what most excites scientists about the find are the prospects it opens up for astronomy. The shape of LIGO’s signal showed it was generated by two black holes in a distant galaxy that spiralled in on one another and then coalesced about 1.3 billion years ago - the time it has taken the wave to reach Earth. The fact that those black holes were more massive than was thought possible - weighing in at about 29 and 36 times the mass of the Sun - is intriguing in itself. But astronomers are looking forward to many more breakthroughs in the future. One tantalizing possibility is being able to observe merging neutron stars and then to follow up those observations with electromagnetic spectroscopy, since it is possible that such mergers are where gold and platinum are made. The potential for such observations will be enhanced when new and existing interferometers start up alongside LIGO, allowing improved sensitivity and better pinpointing of gravitational-wave sources. Virgo in Italy, currently being upgraded, is due to be turned back on by the end of the year, while KAGRA in Japan should be ready to join in the hunt towards the end of this decade. Looking further ahead, scientists are planning a ground-based interferometer with 10km long arms, as well as a spacebased observatory with virtual arms millions of kilometres in length. To get as far as they have, and detect gravitational waves directly for the first time, scientists have had to take a long and, at times, difficult road. The Norwegian Academy of Science and Letters acknowledges the vital contributions made by hundreds of individuals around the world, whose technical innovations have beaten down the many sources of noise that would otherwise plague observations. However, for the Academy, the contributions of Ronald Drever, Kip Thorne and Rainer Weiss stand out. Their “ingenuity, inspiration, intellectual leadership and tenacity”, it says, were the “driving force” behind the discovery of gravitational waves. By Edwin Cartlidge, science writer
“The contributions of Ronald Drever, Kip Thorne and Rainer Weiss stand out. Their ingenuity, inspiration, intellectual leadership and tenacity were the driving force behind the discovery of gravitational waves” The Kavli Prize Committee for Astrophysics powerful lasers, better isolation of the mirrors, as well as mirrors that are both bigger and more highly reflective. It then started operating again last September. The erroneous claims of Weber from 45 years ago have induced immense caution in gravitational-wave physicists ever since. So when LIGO researchers saw the now-famous signal just a few days after switching their machine back on, they carried out a series of painstaking checks to make sure it was real - even though they could see it with the naked eye, unaided by statistical analysis. They compared it to waveforms predicted
NANOSCIENCE THE KAVLI PRIZE WEEK 2016
A scanning microscope for all surfaces biological process to be followed in real time, for example the movement of individual proteins in biological membranes (Fig. 3). The AFM is not only a measuring and imaging instrument. In the last few years, it has been shown that the tip of the instrument can be used to modify the surface of materials with atomic precision. Initial experiments have shown that it is possible to swap an atom of Sn deposited on a Si surface with an atom of Si adsorbed on an AFM tip (Fig. 4). The tip can also be used to move atoms adsorbed on surfaces by literally pushing them from one adsorption site to the next.
Monday, September 5, Oslo 09.00 - 16.15 The Kavli Prize Laureate Lectures at the University of Oslo, Blindern Campus
Tuesday, September 6, Oslo 14.00 -15.30
The Kavli Prize Award Ceremony at Oslo Concert Hall hosted by Alan Alda and Lena Kristin Ellingsen
19.00 - 00.00 The Kavli Prize Award Banquet at Oslo City Hall
Thursday, September 8, Trondheim More generally, AFM is at the basis of a number of techniques known collectively as scanning probe lithography. For example, a conductive tip can be used to write patterns on different materials by locally oxidizing or reducing a surface, a method that has been used to create conductive channels in, for example, graphene and oxide interfaces. In dip-pen nanolithography, the AFM tip is used to write patterns by depositing liquids of different types. Alternatively, the tip of the AFM can be used to locally heat up polymerbased surfaces and create patterns by removal of atoms.
Figure 1: The first atomic force microscope, 1985. Made by Calvin Quate and Gerd Binnig of Stanford University, and Christoph Gerber of IBM Research. Photo: Science & Society Picture Library/Getty Images.
“Atomic force microscopy is a powerful and versatile scientific technique that continues to advance nanoscience for the benefit of society.” The Kavli Prize Committee for Nanoscience The ability to image matter with atomic resolution and to modify the properties of materials by moving atoms one by one are among the ultimate goals of nanoscience.
electron microscopy had also enabled a resolution of a few nanometres to be reached, although this was based on high-energy electron beams that could damage the materials being studied.
In making their award, the Kavli Prize in Nanoscience committee has selected three scientists who first realized an instrument that could provide images of surfaces of any type of material with a resolution of fractions of nanometres — one that is used today in a variety of scientific fields for imaging and manipulation.
The turning point came in 1981, when scientists at IBM Zürich, led by Gerd Binnig and Heinrich Rohrer, realized the scanning tunnelling microscope (STM). This instrument consists of a conductive tip that is placed at such a small distance from a conductive sample that a current flows between the tip and the sample. Because the current depends very sensitively on this distance, by scanning the tip over the sample surface it is possible to obtain an image of the surface with a resolution of only a few nanometres.
Towards the end of the 1970s, efforts to push the limits of imaging resolution had led to very promising results. Although the resolution of optical microscopy is limited to fractions of micrometres, developments in near-field microscopy had pushed this limit to a few tens of nanometres. Advances in
Figure 2: AFM images of Sn, Pb and Si atoms on a Si(111) surface. The atoms can be distinguished in the top image by their size and brightness. The bottom panel reproduces the top one, but with added colour in the centre part of the image to distinguish between Sn (blue), Pb (green) and Si (red) atoms. Reprinted by permission from Macmillan Publishers Ltd: Nature 446, 64-67 (2007).
Despite its immense potential, the STM only works on conductive samples. Gerd Binnig came up with an idea to modify it and create an instrument that would provide images of all types of sample, conductive or insulating, and in 1985 filed a patent for an instrument that he called the atomic force microscope (AFM). The ingenious modification was to place a conductive cantilever, terminated by a tip, just under the tip of an STM. The current between the cantilever and the STM tip would therefore vary with the vertical movement of the cantilever. By scanning the cantilever over the sample’s surface, the vertical movement of the cantilever, hence the profile of the sample, could be recorded by monitoring the changes in current. The idea seemed simple enough, so Gerd Binnig involved Calvin Quate from Stanford University — where Binnig himself was temporarily working — and his IBM colleague Christoph Gerber, with whom he had already collaborated for the development of the STM, and together they realized the AFM along the lines proposed by Binnig in his patent (Fig. 1). The results of their experiments are described in a paper published in Physical Review Letters in March 1986. As the three scientists explain, the cantilever moves because of the finite though small interaction between electrons associated with atoms on the surface and those in the tip attached to the cantilever. For the movement to be large enough to be detected, the cantilever needs to have a small mass and a small spring constant. The AFM was tested using different combina-
In their 1986 paper, Binnig, Quate and Gerber had simply reported profile lines of an Al2O3 surface, but the legacy that their work has left, thanks also to further developments by other scientists, has been immense. As Professor Arne Brataas, of the Norwegian University of Science and Technology, and chairman of the Kavli Nanoscience Prize Committee said “Atomic force microscopy is a powerful and versatile scientific technique that continues to advance nanoscience for the benefit of society.”
Figure 3: Successive high-speed AFM images of bacteriorhodopsin proteins adsorbed onto a mica surface. Reprinted by permission from Macmillan Publishers Ltd: Nature Nanotechnology 5, 208-212 (2010). By Fabio Pulizzi, science writer
09.00 - 12.00 The Kavli Prize Laureate Lectures at NTNU The Norwegian University of Science and Technology 14.00 - 17.00 The Kavli Prize Symposium in Nanoscience at NTNU Lectures by: • Professor Shuji Nakamura, College of Engineering, University of California, Santa Barbara, USA • Professor Krijn de Jong, University of Utrecht, The Netherlands • Professor Dimos Poulikakos, Institute of Energy Technology, Zurich, Switzerland • Professor Stacey F. Bent, Stanford University, USA 14.00 – 17.00 The Kavli Prize Symposium in Neuroscience at NTNU Lectures by: • Dr. Botond Roska, FMI Basel, Switzerland • Professor Leslie Vosshall , The Rockefeller University, USA • Dr. Vivek Jayaraman, Janelia Research Campus, USA
Thursday, September 8, Oslo 10.00 - 16.00 The Kavli Prize Symposium in Astrophysics at the Norwegian Academy of Science and Letters Opening address by Silvia Torres-Peimbert, President of IAU, Universidad Nacional Autonoma de Mexico
Figure 4: Substitution of Sn atoms deposited on a Si surface with individual Si atoms initially adsorbed on an AFM tip. The letter ‘S’ can be written by depositing Si atoms one by one. Panels A and N show schematically how two different atoms can swap places; with results shown in B–M and O, respectively. From Science 322, 413-417 (2008). Reprinted with permission from AAAS. tions of experimental conditions, and they managed to obtain a surface profile with a lateral resolution of 30 Å and a vertical resolution of less than 1 Å. The instrument reported in the Physical Review Letters paper is now known as a contact mode AFM. Major developments in instrumentation that followed were the demonstration of non-contact mode AFM in 1987 and tapping mode AFM in 1993, which is probably the most common way in which AFMs are used today. In this mode the tip oscillates over the sample, occasionally tapping it for a short enough time to avoid damage to the surface while still measuring topology and interaction between the tip and the surface; this measuring mode would become essential for studies of biological samples. Also in the early 1990s, a new technique was introduced to monitor the deflection of the cantilever in an AFM through the reflection of a laser, rather than through an STM signal. Advances in sensitivity and resolution as well as developments in modelling and analysis led to milestones in the experimental studies of chemical bonds using AFM. In 2007, scientists in Japan, Spain and the Czech Republic were able to identify individual atoms of different elements, namely Sn, Pb and Si, deposited on a Si(111)
surface (Fig. 2). In 2009, scientists at IBM used an AFM with a CO2 molecule adsorbed on the tip, and using the interaction of this molecule with carbon atoms, they were able to resolve with high detail the chemical structure of small molecules like pentacene. Using the same technique, a few years later they succeeded in distinguishing different types of chemical bond between carbon atoms in a hydrocarbon molecule. The AFM has also had wide use in biology by allowing high-resolution images of a variety of membranes, viruses and bacteria. Furthermore, the instrument can be employed to measure the force between the tip and a surface, and in some cases even the force between a molecule stuck to the tip and other molecules in a biological tissue. This has allowed investigation of the mechanical properties of cells, which, according to some research studies, could have applications in medicine, for example by enabling cancer cells to be distinguished from healthy ones. In genetics, both highresolution imaging and force microscopy have been used to study the DNA–RNA polymerase interaction, as well as to identify small defects in chromosomes. Finally, the realization of short but soft cantilevers, as well as other improvements in instrumentation, have led to the development of high-speed AFM, which enables a
Lectures by: • Professor Jochen Liske, Universität Hamburg, Germany • Professor Ofer Lahav, University College London, UK • Dr. Cathy Olkin, Southwest Research Institute, Boulder, Colorado, USA • Dr. Hans-Thomas Janka, Max-Planck-Institut für Astrophysik, Garching, Germany • Professor Mario Santos, University of Western Cape, Sør-Afrika
NEUROSCIENCE
How the brain remains stable yet flexible BDNF to have a role. Animals reared in the dark in the first few days of life had reduced levels of expression of BDNF in the visual cortex. Blocking BDNF activity during this time reduced the fine sculpting of layers in the LGN, and bands in the higher visual cortex. Because the release of BDNF from nerve endings is known to strengthen synapses (the connections between neurons), this could provide the ‘on switch’ that promotes the remodelling of neural pathways. Shatz set out to investigate which other genes might be involved in controlling brain plasticity after birth. Surprisingly, she found that some of the active genes were ones that were better known for their role in the immune system, where they help fight infection. Known as MHC (Major Histocompatibility Complex) genes, they code for cell surface proteins. Shatz revealed that in mice which were deficient in certain MHC genes, their visual neurons were more randomly arranged and had many more synapses. Their brain remodelling seemed to be constantly switched ‘on’.
Caption: Healthy adult human brain viewed from the side. The brain is viewed as if looking through the head from a person’s right ear. Brain cells communicate with each other through these nerve fibers, which have been visualised using diffusion imaging tractography. (Credit: Henrietta Howells, NatBrainLab, Wellcome Images)
The 2016 Kavli Prize for Neuroscience goes to Michael M. Merzenich, Carla J. Shatz and Eve Marder “for the discovery of mechanisms that allow experience and neural activity to remodel brain function.” Early 20th century pioneers of neuroscience used the power of microscopy to marvel at the intricate wiring of the brain and peripheral nerves. They photographed and traced the long processes and connections and saw that these took shape early in life and then apparently remained fixed. The brain, it seemed, was hardwired and inflexible once we reached adulthood. This appeared to match the notion that it is easier for children to learn new skills such as a language or musical instrument than it is for adults. Adults seem to have to work harder at learning new skills and memorising information, but no one understood why. Over the past 40 years, however, the three Kavli neuroscience prizewinners of 2016 have challenged these assumptions and provided a convincing view of a far more flexible adult brain than previously thought possible – one that is ‘plastic’, or capable of remodelling. Working in different model systems, each researcher has focused on how experience can alter both the architecture and functioning of nerve circuits throughout life, given the right stimulus and context. They have provided a physical and biochemical understanding of the idea of ‘use it, or lose it’. This new picture of a more adaptable brain offers hope for developing new ways to treat neurological conditions that were once considered untreatable. Michael Merzenich Embarking on his research career in the late 1970s, Michael Merzenich was interested in how the brain’s outer layer, the cerebral cortex, located and responded to sensory information. Using microelectrodes to monitor individual neurons in the brains of owl monkeys, he found that the somatosensory cortex has a complete topographical ‘map’ of the entire body surface, in which adjacent areas of the map responded to body parts that were next to one another, such as the fingers. Each point on the map was a cluster of neurons responding to stimulation of a different patch of skin. Previous work by others had shown that nerve damage, or limb
amputation, led to a reorganisation of neuronal pathways in the cortex of very young animals. Merzenich questioned whether the same could be true for adults, and during the next two decades performed studies which revolutionised understanding of the mature brain. Studying owl monkeys and squirrel monkeys, he found that damage to a nerve, or loss of one or two fingers caused the portion of the map that had lost its input to be overtaken by neighbouring maps, as neurons in the affected area became responsive to other areas of skin. It was rather like redrawing the political boundaries on a map of the world after a power struggle – borders shifting as some territories expanded while others shrank. Conversely, when the monkeys had two fingers strapped together for some months, the cortical maps for the two fingers merged, as though they were for one finger. But after separating the two fingers again, their individual representations reappeared. Provocatively, Merzenich concluded that the potential for brain remodelling, or plasticity, was not lost beyond childhood, but could be switched on again in adulthood. It was a physical explanation for something that psychologists had known for decades – that the adult brain is capable of learning new tasks and compensating for brain damage, with the right training and therapy. The influence of sound Merzenich extended his findings to sound perception, showing that the auditory cortex also forms sensory maps corresponding to different sound frequencies, and that these maps are equally malleable in adulthood. For example, in monkeys that learnt to associate certain sound frequencies with a food reward, the auditory maps representing those frequencies became enlarged in trained animals compared to untrained controls. These findings helped lead to the development of prototypes of the electronic cochlea implants now available today. These stimulate areas of the brain that would normally respond to the different sound frequencies of human speech. In another twist, Merzenich and co-workers found that they could trigger the rearrangement of the auditory maps by exposure to a combination of sound frequencies
Subsequently, Shatz and colleagues identified a receptor on neurons called PirB (paired immunoglobulinlike receptor B), through which MHC molecules normally delivered the ‘off’ signal. Mice genetically engineered to lack PirB, or treated with an infusion of soluble PirB directly into the brain, also showed an increase in synaptic density and signalling in the visual cortex. Curiously, in a mouse model of Alzheimer’s disease, PirB serves as a receptor for the beta-amyloid protein that accumulates during the disease. Thus signalling through PirB could be responsible for the loss of synaptic plasticity and memory in these animals. These findings have led Shatz and others into a new line of research on the role of MHC molecules in learning and memory, and how they may contribute to conditions such as stroke damage, Alzheimer’s disease, autism and schizophrenia. It may also be that these molecules provide a possible link between these disorders and viral infections in early life.
Caption: Illustration showing the action of neurotransmitters such as serotonin and noradrenaline in the synaptic cleft. Vesicles containing the neurotransmitter (green) move towards the pre-synaptic membrane where they fuse with the cell membrane, releasing their contents into the synaptic cleft. The neurotransmitter molecules act on the post-synaptic cell by binding to specific receptors on the cell surface (purple). They can also be taken back up by the presynaptic cell via other receptors (orange) for re-use. (Credit: Arran Lewis, Wellcome Images)
plus electrical stimulation of the part of the hindbrain called the nucleus basalis. This is involved in learning and memory, especially when attention is heightened through fear, or anticipation of reward, and involves the release of the neurotransmitter acetylcholine. Reprogramming the brain Merzenich believes that the machinery and conditions required for brain plasticity are permanently switched on during childhood, and can be switched on again in adulthood. The necessary circumstances, he suggests, include ensuring that a person’s attention is focused on a task, and that they are experiencing either motivation or success. Merzenich is now applying his basic research findings to the development and testing of new tools for improving brain function in people with a range of neurological and psychiatric conditions, such as Alzheimer’s disease or schizophrenia, or following brain injury. Carla Shatz Carla Shatz has elegantly revealed how the brain is sculpted in early life, both before and after birth, as animals make the transition from the protective environment of the womb to the vibrant and stimulating outside world. In the late 1970s, Shatz followed up on the Nobel Prize-winning work of Hubel and Wiesel showing that soon
after birth, in monkeys and cats, light stimulation of the eye promotes the self-organisation of the visual cortex – the part of the brain responsible for vision. Neurons projecting from the retina cluster into a series of bands across the visual cortex; each band is either leftor right-eye responsive. Closure of one eye during a critical ‘sensitive period’ of several days after birth disrupts this pattern as the bands corresponding to the deprived eye shrink in relation to those receiving signals from the active eye. Little was known, however, about what happened before birth, when the eyes have yet to be fully developed. Shatz focused on the lateral geniculate nucleus (LGN), where nerves projecting from the eye first become sorted into an orderly set of layers. Shatz’s first major scientific finding was that this layering of neurons in the LGN began before birth, in response to repeated bursts of spontaneous firing by retinal ganglion cells, which spread in waves across the retina. The size of the LGN layers, and the connectivity between neurons within the layers, depended on the intensity of the spontaneous electrical activity. Switching plasticity on and off Shatz wanted to understand in more detail what stabilised these arrangements of neurons in the visual cortex as the brain matures. In 2000, her team found the factor
Eve Marder Eve Marder has made it her life’s work to understand the properties of neural circuits controlling digestion in lobsters and crabs. It may sound like a rather esoteric choice, but to Marder it is a way to work out the more general rules by which the nervous system in different animals produce rhythmic behaviours including breathing, walking and swimming. She has revealed that neural circuits can be both flexible in response to stimuli and stable over time. Marder’s focus on the movements of the crustacean gut was due to the exceptional ease with which the entire neural circuit - the stomatogastric ganglion (STG) could be removed intact from the body and kept alive in the laboratory. It has a well-defined anatomy, with about 30 neurons, 24 of which innervate muscles, and six which cross-link to other ganglia. In the laboratory, this circuit continues to show spontaneous bursts of coordinated electrical impulses for many hours. In the animal, it elicits a pacemaker-like rhythm that prompts gut muscles to contract and relax rhythmically. Crustaceans do not chew their food in the way vertebrates do - instead they tear and swallow large coarse pieces of food which are moved along the oesophagus to the stomach-like cardiac chamber, where calcified teeth-like projections known as the gastric mill - crush, cut and grind the food. The finer food particles then pass through the pyloric valve into the pyloric chamber and beyond. The STG is part of a wider stomatogastric nervous system that controls the
passage of food along the full length of the digestive tract. Between 100 and 250 nerve fibres project onto the STG from the brain and spinal cord, enabling central nervous system (CNS) regulation. Marder wanted to understand how the STG was regulated by external influences, such as hormones or substances released by CNS nerve fibres projecting onto the STG, or produced by STG neurons. Others had shown that the neurotransmitter glutamate was released by some STG motor neurons. Marder’s PhD work - which earned her a paper in the journal Nature - was to reveal that a second neurotransmitter, acetylcholine, was released by other STG neurons. This finding set the scene for further studies to identify how neurotransmitters and neuromodulators might modify the rhythmic firing of the STG. During the 1980s, Marder led studies using antibodies and the technique of immunocytochemistry to reveal the presence of many different neuromodulators in nerve fibres around the STG of crabs, including serotonin, proctolin and GABA. Electrophysiological experiments then led to further significant findings including the first demonstration that two different neurons that were electrically coupled could produce different neurotransmitters. The neuromodulator dopamine, for example, affected STG neurons in different ways - inhibiting some and stimulating others. In this way, Marder was able to work out key principles about the regulation of neural networks, including the fact that the same neuromodulator can have differential effects in different parts of the network. But why were so many neuromodulators involved in regulating such a relatively small number of neurons? Marder hypothesised that this enabled a whole range of effects to be elicited which fine-tune the end behaviour. It meant that that neuronal circuits, once thought to be hard-wired and fixed in their firing patterns, are capable of considerable variation in output. Neuromodulation, wrote Marder, ‘adds extraordinary richness to the dynamics that networks can display.’ Another of Marder’s key contributions was the co-development of the dynamic clamp tool, in 1993. This allows computer-controlled stimuli to be applied to neurons in culture, and measures their effects on cell membrane conductance. This enables the development and testing of computational models of neural circuits. Lately, Marder has scrutinised how neural circuits can tolerate perturbations to individual neurons and remain functionally stable. Her team is currently examining the ion channels that open and close to allow the flow of ions as electrical impulses pass along the nerve cell membrane. Changes in ion channel expression, induced by neuromodulators, can change the polarisation of the cell membrane and its electrical conductance. This, in turn, affects the magnitude of release of neurotransmitter at the nerve terminal and the strength of muscle contraction. Marder hopes eventually to have a fuller picture of how neural circuits maintain their robustness over time despite the changes induced by neuromodulators and the routine turnover of membrane and other cell components throughout life. Such insights may also contribute to the understanding of functional decline in different neurological conditions. Julie Clayton, science writer/editor
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