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Fall 2012 Issue 23

sciencereview.berkeley.edu
6 Lede the Way

AAAS Mass Media Fellowship Graphene enables groundbreaking films Rockets propel PhDs into space

10 Two Thumbs Up

22 Flight of FOXSI

Germ Warfare

Berkeley Science Review

Fall 2012

from the edito r


Editor in Chief
Sebastien Lounis
Dear Readers, Welcome to the 23rd issue of the Berkeley Science Review. As you peruse your fresh copy, I encourage you to think small. Today, perhaps more than ever, UC Berkeley is a hub for explorations of the miniature and miniscule, as reflected by the terrific articles weve collected for you in Issue 23. Zooming in on the world of pathogens in Germ Warfare (3845), Sam Sternberg details the surprising discovery of an advanced bacterial immune system. Defying conventional knowledge, simple bacteria are able to genetically self-vaccinate in a back-andforth battle with voracious viruses. In Manipulative Microbes (3037), Teresa Lee recounts the eerie influence that parasites and microorganisms can have on behavior in animals, including humans. Feeling a satisfying euphoria (or a visceral disgust) grip you while reading our magazine? It could be your lunch, as much as our authors prose, thats controlling your mood. Berkeley researchers are also working hard to maintain control over a rapidly changing global climate. MOFiosos (1621), by Zoey Herm, uncovers the efforts of several Berkeley scientists who are trying to trap carbon dioxide in tiny, porous structures called metal organic frameworks. These materials have rallied both fundamental and applied researchers around a cause with impending implications for our planet. At the same time, some scientists are taking their research beyond the Earths atmosphere. In FOXSI Fires Up (2229), Lindsay Glesener shares the experience and Berkeleys long history of using sounding rockets to send small scale space experiments into orbit. Be sure to keep up with Lindsays account of the FOXSI mission launch on the BSR blog (sciencereview.berkeley.edu) later this year. But Berkeley scientists arent just laboring over the little. On page eight, Shirali Pandya reports on how the two largest black holes ever observed are even bigger than expected, while Ginger Jui (12) tells us how a giant crater in Arizona might reveal clues about torrents of water flowing on Mars. Nevertheless, it may be our youngest citizens that deserve the most attention, as Sharmistha Majumdar explains on page 13. Coincidentally, the BSR is also trying to shrink its ecological footprint. For the second issue in a row, Im proud that our magazine is printed on partially recycled paper thanks to a generous grant from The Green Initiative Fund. The effort to make our magazine more sustainable is ongoing, so contact us at sciencereview@gmail.com with any suggestions. Lastly, big or small, young or old, our readers are the reason we work so hard on the BSR each semester. Please help us serve you better by filling out our readership survey at sciencereview. berkeley.edu/survey-and-award. As a token of our appreciation, youll be eligible for several fun prizes if you do. Also, please help recognize and reward our authors by voting for our readers choice award at the same URL. Id like to thank our incredibly committed team of editors and layout designers for making this issue possible, as well as our authors for their creative and inspiring contributions. Im looking forward to Issue 24! Happy reading,

Editors
Amanda Alvarez Allison Berke Alexis Fedorchak Chris Holdgraf Valerie OShea Anna Schneider Christopher Smallwood Anna Vlasits

Art Director
Asako Miyakawa

Layout Staff
Leah Anderson Kelly Clancy Nikki R. Kong Helene Moorman Amy Orsborn Jen Sloan

Copy Editor
Denia Djokic

Managing Editor
Anna Schnieder

Web Editor
Adam Hill

Web Designers
Anna Goldstein Chris Holdgraf

Printer
Sundance Press

Sebastien Lounis Editor in Chief

Fall 2012

Berkeley Science Review

contents features
16 MOFiosos
Berkeley scientists make carbon a structure it cannot refuse by Zoey Herm

22

22 FOXI fires up

Sounding rocket mission looks at solar flares by Lindsay Glesener

30 Manipulative microbes 38 Germ Warfare

The invisible invaders that influence guts, brains, and decision making by Teresa Lee

Bacteria and viruses adapt for battle by Sam Sternberg

16

1 mm

30
2012 Berkeley Science Review. No part of this publication may be reproduced, stored, or transmitted in any form without the express permission of the publishers. Financial assistance for the 2012-2013 academic year was generously provided by the Office of the Vice Chancellor of Research, the UC Berkeley Graduate Assembly (GA), the Associated Students of the University of California (ASUC), The Green Initiative Fund, and the Eran Karmon Memorial Fund. Berkeley Science Review is not an official publication of the University of California, Berkeley, the ASUC, the GA, or Lawrence Berkeley National Laboratory. The views expressed herein are the views of the writers and not necessarily the views of the aforementioned organizations. All events sponsored by the BSR are wheelchair accessible. For more information email sciencereview@gmail.com. Letters to the editor and story proposals are encouraged and should be emailed to sciencereview@gmail.com or posted to the Berkeley Science Review, 112 Hearst Gym #4520, Berkeley, CA 94720. Advertisers: contact sciencereview@gmail.com or visit sciencereview.berkeley.edu.

Berkeley Science Review

Fall 2012

Fall 2012 Issue 23

departments
1 From the editor 4 Labscopes
Blind Mice See by Sebastien Lounis

48 Faculty Profile 52 Book review


Cathryn Carson

Carlos Bustamante Re-creating life in the lab by Susanne Kassube

48

Elemental Christening by Christopher Smallwood From Air to Zeolites by Rachel Hood So Long, Franklin by Keith Cheveralls

Heisenberg in the Atomic Age: Science and the Public Sphere by Aaron Harrison

From the field


by Amanda Alvarez

53 Toolbox

Monte Carlo method by Christopher Ryan

current briefs 8 Supersized 12 Crater Clues


Largest known black holes come to light by Shirali Pandya Finding water on Mars, on Earth by Ginger Jui

10 Graphene Blisters
Colloidal nanocrystals make their film debut by Kaitlin Duffey

13 Higher Hopes

FOSS improves Californias science education by Sharmistha Majumdar

11 Some Like It Hot


Thermophiles clean up biofuel production by David Hershey

14 Good Vibrations

Piezoelectricity goes viral by Samantha Cheung

CLOCKWISE FROM TOP-RIGHT:MICHAEL DEEM; MAREK JAKUBOWSKI; LYNET TE COOK ; HEXIANG DENG AND OMAR YAGHI; KELLY SCHIABOR; NASA

COVER: Colorized transmission electron micrograph of T2 virus invading bacterial host, Escherichia coli. Copyright: Lee D. Simon

Fall 2012

Berkeley Science Review

l abscopes
Blind Mice See
he results of a new UC Berkeley study may offer some hope for the nearly 40 million people who suffer from blindness worldwide. In a recent paper published in the journal Neuron, researchers led by Professor Richard Kramer of the department of Molecular and Cell Biology have shown that a simple chemical, known as AAQ, can restore light sensitivity to the retina for prolonged periods of time. AAQor acrylamideazobenzene-quaternary ammonium when spelled out in its full, tongue-twisting formis a small molecule that acts as a photoswitch, responding to light by making neurons in the retina more or less excitable and likely to fire. This switching can replace the action of dead, degenerated or missing (due to genetic mutation) rods and cones, the normally photoactive cells in the vertebrate eye. By injecting AAQ directly into the eyes of blind mice with fully degenerated rods and cones, Kramers group showed its ability to restore both the electrical firing of neurons in the retina, as well as light-induced behavioral responses. In particular, the treated mice showed pupils that contract in response to light and also avoided bright light, much like fully seeing animals. The first time we observed them responding to light, it blew us away, says Kramer. Perhaps most exciting about the efficacy of AAQ as a retinal photoswitch is the simplicity and reversibility of treatment. Other current remedies for the loss of visual acuity, while also promising, require highly invasive or permanent procedures to restore sight, and typically target only a fraction of the retina. AAQ is able to render nearly every cell in the retina light sensitive, says Alexandra Polosukhina, the lead author of the study. Requiring only a minor injection and fully reversible, treatment with AAQ is also much less risky for the prospective patient. Eventually, an even less invasive slow release pill could be viable. Despite its promise, however, Polosukhina is careful to stress the early stage of this research. Its still a little too soon to guess exactly what type of vision AAQ and related compounds could restore, she cautions. Nevertheless, they could someday allow for contrast sensitivity, object recognition, and a better standard of living for individuals suffering from blindness. Sebastien Lounis

Elemental Christening
TOP: DESIGN: JEN SLOAN; MOUSE: GEORGE SHULIN/FLICKR.COM; SUNGLASSES: CLAIRE L. EVANS/FLICKR.COM BOT TOM: DESIGN: JEN SLOAN; PERIODIC TABLE: FERNANDOBRASILIEN/COMMONS.WIKIMEDIA.ORG

lements 114 and 116, known previously by the temporary monikers ununquadium and ununhexium, have officially been recognized as flerovium (Fl) and livermorium (Lv). The names honor the collaborative efforts of research teams at the Flerov Laboratory of Nuclear Reactions in Russia and Lawrence Livermore National Laboratory (LLNL), and were formalized last May by the International Union of Pure and Applied Chemistry (IUPAC). The new elements were synthesized by using a cyclotron to blast plutonium or curium targets with calcium ions, then waiting and hoping for instances of fusion. Its actually a very rare process, says chemist Ken Moody of LLNL, a U.S. Department of Energy National Laboratory that is operated in part by UC Berkeley. It can be frustrating waiting for weeks at a time while the cyclotron runs. You have to be stubborn. Stubbornness has paid off this year. Flerovium joins group 14 of the periodic table, taking a seat beneath lead and tin. Livermorium shares a column with smelly tellurium, and radioactive polonium. At present, however, the defining characteristic of both elements seems to be brevity of existence: livermorium isotopes decay within milliseconds to flerovium, and Fl-289, fleroviums most stable isotope, has a half-life of a minute or less. The announcement is part of an ongoing effort by researchers to manufacture superheavy elements, which inhabit the bottom of the periodic table. Progress has been steady, and an IUPAC Joint Working Party has already been established to weigh the relative merits of discovery claims for elements 113, 115, 117, and 118. With enough evidence, flerovium and livermorium may soon have named company. BSRium, anyone? Christopher Smallwood

Berkeley Science Review

Fall 2012

From Air to Zeolites


wo-thirds of the electricity generated in the United States comes from power plants that burn fossil fuels and emit vast quantities of carbon dioxide (CO2). If this greenhouse gas could be captured before it escapes into the air, its effect on the global climate could be mitigated. One popular strategy, known as carbon capture and sequestration (CCS), involves capturing CO2 before it is released and storing it underground. The downside of this method is that CCS requires energy input of its own, known as parasitic energy. This makes it difficult to limit CO2 release without simultaneously increasing the amount of fossil fuel that must be burned, undermining the benefits of capturing carbon in the first place and driving up energy costs. However, recent UC Berkeley research might tip the scales toward a brighter future for carbon capture. Led by Professor Berend Smit of the Departments of Chemical and Molecules of carbon dioxide (blue and green) are captured within Biomolecular Engineering and Chemistry at UC Berkeley, a team of scienthe pores of a zeolite mineral (red and tan). tists at Cal, Lawrence Berkeley National Laboratory, Rice University and the Electric Power Research Institute have developed a computational method to identify molecules that bind and sequester CO2 more effectively than current technologies, decreasing the amount of parasitic energy required for CCS. This method estimates the ability of specific compounds to capture CO2 and evaluates databases of millions of candidate compounds much more quickly than was previously possible. Since we can do these calculations so efficiently, Smit explains, we can compute the lowest parasitic energy among all possible structures within a class of materials. Smits group identified a number of minerals called zeolites (commonly used in industrial processes) that could reduce the energy diverted to CCS from a power plants overall output. Having this ability to predict a particular molecules effectiveness at sequestering CO2 will be a powerful tool for making our energy industry cleaner. Ultimately, Smit says, our biggest hope is for the community to know that we are working on solutions. Rachel Hood

So Long, Franklin

TOP: MICHAEL DEEM, RICE UNIVERSIT Y BOT TOM: LAWRENCE BERKELEY NATL LAB - ROY KALTSCHMIDT, PHOTOGRAPHER

ust as each iteration of the iPhone dethrones its predecessor from the pinnacle of consumerelectronics to a quaint reminder of product cycles past, so too do supercomputers fall victim to the march of progress. After five years and over one billion computational hours, Franklin the supercomputer was retired in early May of this year. Maintained by the National Energy Research Scientific Computing Center (NERSC) at Lawrence Berkeley National Laboratory (LBL), Franklin was a Cray XT4 supercomputer, formerly the seventh most powerful computer in the world, and a scientific workhorse used by thousands of researchers to simulate everything from ocean currents to atomic nuclei to novel rechargeable batteries. The Franklin machine enabled discoveries that improved our fundamental understanding of biology, chemistry and physics, says Kathy Yelick, the Associate Laboratory Director for Computing Sciences at LBL and a professor of Electrical Engineering and Computer Science at UC Berkeley. Over its lifetime, Franklin was as prolific as it was powerful. I would estimate about 5000 scientific papers were produced using computations run on Franklin, Yelick says. The burden of continuing this impressive scientific output now rests with Franklins replacement, a Cray XE6 supercomputer that is already up and crunching. With around 150,000 processor cores, it is the eighth most powerful computer in the worldfor now. Keith Cheveralls

Fall 2012

Berkeley Science Review

from the field


Or: How I Learned to Stop Worrying and Love the Lede
Bees, bats, and BPA were all in a days work for me this summer, and my PhD research isnt about any of these. So how did I wind up at a Midwestern newspaper writing about these topics and more for two months? And perhaps more importantly, how did I convince my advisor that this was not a complete folly? The American Association for the Advancement of Science (the worlds largest general scientific society, as they like to be known) runs an amazing program that is essentially a crash course in science journalism for graduate students. This past summer, I was fortunate to be one of the Mass Media Science and Engineering Fellows, working at the mid-sized Milwaukee Journal Sentinel in Wisconsin. You might think newspaper readers in the land of cheese curds and cheap beer wouldnt be too interested in science, and to some extent youd be right. One of the biggest challenges of science communication is translating jargon and acronyms into plain language and making opaque experiments relatable (as my editor told me, write the story so your grandmother would find it interesting). Sometimes the challenge is daunting (how do you explain the Higgs boson for a fifth grade

A Scientist Joins the Media

reading level?). Other times the stars align and the reporter can flourish some creativity while still keeping the hard details front and center for a perfect fusion of fact and art. While science is increasingly being sidelined in favor of political rhetoric or the latest Lindsay Lohan drama, AAAS continues to advocate for science by putting scientists themselves in places where their voices can be heard. Four radio stations and eight print outlets played host to this years Mass Media Fellows, whose combined output was 309 stories over the 10-week program. While the impact factor calculation is still pending, Im convinced that my group, as well as the 38 years of preceding fellows, has helped fill a crucial void by informing the general public about science with wit, acumen and, most importantly, accuracy. With the newspaper industry imploding and well-known outlets like CNN cutting their entire science news teams, the average citizen may have very little exposure to science on a daily basis. Misinformation about science (climate change, anyone?) and gripes about wasted tax dollars are also abundant in the media. The goal of the Mass Media Fellows program isnt to combat these phenomena, but rather to raise the bar and increase the amount of high quality science content that is available in print, online, and over the airwaves. An amazing array of expertsfrom soil scientists to neuroscientists, plant geneticists, retinal biologists, and particle physicistslent me their knowledge this summer, not just because they believe in what they are doing but because they see the value in disseminating their work. I got to act as the mouthpiece for research both obscure (desert fairy circles) and profound (the discovery of the Higgs boson). While my primary motivation during the fellowship was to hone my writing and get out of my own little scientific niche, if any of my stories inspired someone to read an original research paper or do some citizen science, I would consider my work with the Mass

Media Program a success. If any BSR readers are feeling the call to action, they are in luck, as Berkeley has an excellent track record in fielding Mass Media fellows. Former BSR editor-in-chief Rachel Bernstein, for example, spent her 2010 fellowship at the Los Angeles Times. She found that contextualizing scientific resultsoften the outcome of years of workfor a general audience is one of the biggest challenges in the 24-hour news cycle. Science isnt like sports or politics; there arent daily events that can be reported on and speculated about, said Bernstein. Instead, with science journalism, you have to artfully weave together community relevance and timeliness with previous and ongoing research. At a general interest newspaper serving a large urban area, Bernstein says, it is never enough to let the science speak for itself: The stories were generally very application-driven, with relevance to health or daily life. At the Journal Sentinel, I also found myself selecting for stories with local or health angles, often following the journal publication schedules by reporting on papers just being released. The publication date makes it timely, but as scientists, we all know that the work was actually completed long before the paper finally made it to publication, said Bernstein. One of her biggest hitsa front page story on local HIV researchwent beyond the press release, creating a more thorough and compelling read than if she had just stuck to the published results. She also realized that, as scientists, our instincts may sometimes be off: Things that seem the most interesting to me dont

FROM TOP: ASAKO MIYAKAWA; KYLE GRILLOT

actually have that much of an impact [to the general audience], and sometimes the studies that interest readers are just painfully boring or esoteric [to me]. When it comes to reporting on science in the lay press, it seems that its the what that is important, and the how doesnt really matter. The Mass Media fellowship can thus be an experience in shifting your perspectives, as well as in writing. Like Bernsteins PhD advisor, mine was aware that I had strengths and interests beyond the lab, and she fully endorsed my leave of absence (your mileage may vary with your own advisor). Some Berkeley alums have transitioned into careers in science writing and communicationyou can find 2005 Mass Media fellow Kaspar Mossman serving as director of communications at QB3, and Bernstein works as an editor at PLOSwhile others have chosen to keep pursuing research. Whatever their paths, no doubt the fellows carry with them skills that help demystify the lab bench and make science accessible, whether they are performing it or reporting on it. At the newspaper, my own daily mission to demystify usually started with reading an upcoming research paper. Since Im not an expert in genetics or engineering, I was often approaching these papers from the position of the newspaper reader who has little to no background. My goal was to gain a thorough understanding of the experiment and its results in a very short time, procure some compelling quotes from the author and an outside expert, and get the reader hooked in the nut graph the early part of the story that explains its news value and convinces you to keep reading. One of the main lessons of the Mass Media Program is that scientists and non-scientists communicate in fundamentally different ways: the former present background, justifications, and methods before even arriving at the results or the bottom line, which is what the latter want to hear about first. This inverted pyramid structure

requires a shift from what scientists are used to, but also allows for the injection of some levity (The nose knows, at least in fish). Besides changes in communication style, the novice science writer also experiences extreme acceleration. The pace in the newsroom is anything but slow, and can be

The Mass Media Fellowship and Journalisms Five Ws


WHO:
Graduate students, recent postdocs, or advanced undergraduates in science fields who are interested in science communication. per or radio station, reporting on science and learning journalism skills. A summer break from research with a stipend of $4500.

WHAT: 10 weeks of immersion at a newspa-

WHEN: Application deadline January 15, 2013. Program runs early June mid-August. WHERE: Washington DC for an orientation.
Placements at outlets from the LA Times to NPR, the Chicago Tribune, Scientific American, etc. profile of science, or are looking for an alternative career in media, scientific publishing, policy, or outreach.

WHY: You enjoy writing, want to raise the

and finally http://www.aaas.org/programs/ education/MassMedia/ And to see the work of the 2012 Mass Media Fellows, check out http://www.twitter.com/ AAASMassMedia

HOW:

a welcome change for anyone who has ever felt frustrated by the glacial speed of research. The immediacy of the print news cycle gives you the satisfaction of seeing concrete results on a daily basis. Unlike working in the lab, you may even get to leave the windowless newsroom and venture into the outside world, all in the name of science. One of my more exotic (and stickier) experiences came when I interviewed a local beekeeper. Little did I realize as I donned some protective gear that I would be learning more than anyone would ever want to know about hive structure and bee behavior, all while standing in the sweltering heat in a cloud of bees. No sting, no foul, though! The story on bees gained some great color and atmosphere from my interview that day, and I walked away with the best honey I have ever tasted. Savoring the thrill of being published was also a major departure from the average graduate student experience. While Im sure I never reached a massive readership (though one of my stories got about 4,000 page views online!), most of the responses to my stories were positive. If people can see how basic research is applicable to their own lives, or are inspired by audacious efforts to explore new worlds, they may be more willing to take action to defend science, for example by calling their representatives when funding is threatened. The Mass Media programs greatest impact is at the grassroots level, where science converts are created one at a time through conversations between scientists and readers and listeners. Even if most graduate students, at Berkeley and beyond, are never going to become professional science communicators, we would all do well to talk about our work to family, neighbors, or policy makers. If ever there was a time to be boldly vocal about science, it is now.

ASAKO MIYAKAWA

Amanda Alvarez is a graduate student in vision science.


Fall 2012 Berkeley Science Review

current briefs
Largest known black holes come to light
It doesnt get much bigger than this. Astronomers at the University of California, Berkeley have recently found two black holes that dwarf all others. Weighing in at 10 and 21 billion times the mass of our Sun, respectively, these behemoths trounce the former heavyweight, which has a mass 6.3 billion times larger than our Sun. These newly discovered celestial objects arent simply the biggest black holes found to datethey are also making a large impact on our understanding of the Universe. A team led by Professor Chung-Pei Ma found the supermassive black holes residing at the centers of their namesake galaxies, NGC3842 and NGC4889, which are in turn part of two galactic clusters over 330 million light years away. Using measurements from the Gemini and Keck telescopes in Hawaii and the Hubble Space Telescope, astronomy graduate student Nicholas J. McConnell calculated the mass of these black holes by using the speed and distance of the stars orbiting around them. Black holes are the mind-bending prediction of Einsteins theory of relativityextraordinarily heavy objects that severely distort the space-time continuum. These cosmic bodies are so dense that the escape velocity required to break away from their gravitational field exceeds the speed of light. While the mass of the black hole itself is concentrated at an infinitesimally small point, nothing within a certain radial distance from this pointdefining a boundary known as the event horizoncan escape its pull. Beyond the event horizon, the black hole exerts a gradually decreasing (but still powerful) gravitational force on objects within its sphere of influence. The motivation for the UC Berkeley groups research and the import of the findings extend far beyond their recordshattering dimensions. We went into the project not really to break the record or to

Supersized

Gemini observatory/ AURA artwork by Lynette Cook

purposely look for the biggest [black hole], explains Ma. We really just [wanted] to understand how they evolve and how they become so big. Indeed, the new findings are changing astronomers theories of how black holes and their host galaxies co-evolve by providing a missing piece of an outstanding scientific mystery. Scientists have predicted the existence of dormant black holes as large as 10 billion

solar masses based on measurements of their younger, actively growing relatives, luminous objects known as quasars. A quasar is believed to be a primordial black hole engaged in a gaseous feeding frenzy. As gas spirals into the center of a black hole, it emits light due to rapid acceleration. The more massive the black hole, the faster the gas accelerates toward the center, and the brighter the quasar. Quasars were ubiquitous in the

Berkeley Science Review

Fall 2012

DEISGN BY NIKKI R. KONG. SUN-NASA GODDARD SPACE FLIGHT CENTER; EARTH: NASA EARTH OBSERBATORY; PENNY: WIKI COMMONS; CAR: 123FREEVECTORS.COM; MOUTAINS: RESOURCESGRAPHICS.COM

younger days of the Universe; at that time, black hole nuclei grew rapidly by devouring, or accreting, the plentifully available gases in the early cosmic soup. Fast-forward a few billion years, and fuel is depleted. The black holes have now stopped accreting and have become sleeping giants. NGC3842 and NGC4889 are examples of this type of mature black hole, lying in galaxies that have been devoid of gas for eighttonine billion years. These dormant giants are counterparts to the colossal black holes found at the centers of distant quasars. Not only are these the most massive black holes ever known in the Universe today, says McConnell, but they are also massive enough to compare to the most massive ones weve seen from the young Universe. Now, with snapshots of both nascent and more mature versions of supermassive black holes, as well as their individual cosmic milieux, scientists can begin piecing together the puzzle of the formation of supermassive black holes and the galaxies that host them. The discoveries have yielded an interesting surprise for astronomers, suggesting that the growth of the most massive black holes occurs by different processes than that of

more ordinary ones. The scientists focused their quest on the centers of large galaxies, because it was thought that the mass of a black hole scales with the size of its host galaxy. However, McConnell and his colleagues found that these supermassive black holes are about twice as large as this trend would suggest. In addition to growth by gas accretion, these supermassive black holes may have grown rapidly when smaller black holes combined in galaxy merger events. Scientists believe that galaxy mergers were frequent in the early Universe, and the new discoveries will provide insight into just how frequently such events occurred. As such, it will be important to determine whether these supermassive black holes are simply outliers from the standard predictions of black hole size, or if astronomers need to tweak their current models at the higher end.

Ma, who is primarily a theoretical astrophysicist, began the research project based on some clues from her groups work that current models of black hole size may not apply for the largest supermassive black holes. She credits the collaborative spirit and rich resources at UC Berkeley with enabling the data collection: An environment like Berkeley was important for making this project feasible. Having these facilities, resources and smart people, youre not held back. If the current instruments can do it, lets do it.

Shirali Pandya is a postdoctoral fellow in molecular and cell biology.

Mt. Diablo

Nicholas J. McConnell, a former graduate student in the astrophysics department explains: Imagine that the Earth has the size and mass of a penny. On this scale the Sun would be about as large and heavy as an economy-sized car. A 10-billion solar-mass black hole would have close to the mass of Mt. Diablo. All of this mass is presumably crushed to an infinitesimal point at the center of the black hole. In the same analogy, the event horizon of the black hole would span a diameter of about 100km, similar to the distance from Berkeley to Santa Cruz.
Fall 2012 Berkeley Science Review

BRIEFS Methylation Graphene Blisters

Colloidal nanocrystals make their film debut


Most scientists will never be film stars, and neither will their research subjects. But two graduate students at UC Berkeley have come close. By combining two kinds of filmsvideo microscopy, and atomicallythin carbon sheetsJungwon Park of the chemistry department and Jong Min Yuk of the physics department have opened a new window onto nature, allowing them to record the first-ever movies of atoms forming crystals inside a liquid. Their camera was a transmission electron microscope, or TEM, which works by focusing a beam of electrons onto a very thin sample. Some electrons are deflected by the atoms of the sample while others pass through to a detector to create an image. TEMs have allowed scientists to see fine details of crystal lattices and biological structures, but its scope has been limited to solid specimens. A liquid sample will evaporate under the vacuum inside a TEM unless it is confined within a tiny compartment called a cell, but the atoms of the cell block the electron beam and blur the image. Biomolecules floating in their natural aqueous environments, for example, have been impossible to viewuntil now. To create a TEM cell that blocks the minimum number of electrons, Park and Yuk used the slimmest material possible: single-atom-thick sheets of carbon, or graphene. Graphene liquid cells are an inspiring example of what can be achieved when scientists from different fields come together. Park, a member of Professor Paul Alivisatoss group, was studying the mechanism of colloidal (liquid-suspended) nanocrystal growth using a TEM, but the 25-nanometer-thick silicon nitride cells he was using did not allow him to see individual atoms. Yuk, a visiting

Graphene Blisters

scholar in Professor Alex Zettls group, was experimenting with sandwiching solid materials between layers of graphene. The two met fortuitously on the soccer field. After playing soccer, I told Jungwon about my experiments and he suddenly became very excited, Yuk recalled. Through subsequent conversations, they developed the idea of covering liquid droplets with graphene. We started dreaming about putting a liquid sample in between two layers of graphene, said Park. We thought it would be really difficult, but it was worth trying. With Parks intuition for colloidal liquids and Yuks expertise in making graphene, implementing their idea was easier than they expected. The resulting experiment was strikingly elegant. Drops of platinum solutionthe nanocrystal precursorwere placed onto two sheets of graphene. When one sheet was overlaid upon the other the drops were trapped between them, forming tiny liquidfilled blisters. When the TEM was focused onto one of these blisters, the electron beam turned positively-charged platinum ions into neutral atoms, initiating crystal growth. The transparent graphene skin allowed this growth to be imaged with unprecedented resolution. Park and Yuk used the worlds highestresolution microscope, the Transmission Electron Aberration-Corrected Microscope I at Lawrence Berkeley National Laboratory, to film their graphene-encased crystals. Many hours were spent depositing graphene layers onto the microscope stage, scanning the stage to find a cell, focusing the beam, and hoping to see crystal formation. Initially, Yuk had doubts about whether they could zero in on a single crystal inside the relatively large bubble of liquid. I was afraid, he said, that since we focused in the center of the bubble,

Liquid drops containing platinum atoms (yellow spheres) were trapped between 2 layers of graphene. Growth of nanocrystals (cubes) could be observed with a transmission electron microscope (TEM).

TEM images of a platinum nanocrystal evolving inside a graphene liquid cell. The black arrows point to two smaller nanocrystals coming together (the size of each frame is six by six nanometers).

Kaitlin Duffey is a graduate student in chemistry.

10

Berkeley Science Review

Fall 2012

JUNGWON PARK AND JONG MIN YUK

we wouldnt be able to see a nanoparticle that was slightly above or below. When they finally captured images of a crystal forming, they were exhilarated. We kept repeating the process for 16 hours, and after all that effort we ended up with a perfect growth movie. . . . It was a really exciting moment, said Park. Yuk shook his head and smiled. I was so surprised. I thought, Im the first man to watch the actual growth of particles inside a liquid! They looked like bacteria, moving around and then coming together. It was amazing! The movies provided direct observational insight into how quickly colloidal nanocrystals grow, how their shapes evolve, and how small crystals came together to form larger ones. Before, chemists just made particles inside a flask, pointed to it, and said theres a nanocrystal in there, but no one really knew what was going on inside the flask. Graphene is a great viewing window, just like a fishbowl. Now we can watch the fish inside the bowl, explained Yuk. Nanotechnology is not the only field that will benefit from the invention of graphene blisters. Any liquid can be encased in graphene and observed at the atomic scale using a TEM. Park and Yuks work was published in Science on April 6, 2012, and since then many other research groups have begun using graphene liquid cells. Members of the Alivisatos and Zettl groups have continued to collaborate in exploring new applications of the cells. They have succeeded in imaging aqueous solutions, and have begun working with biological samples. The next grapheneclad movie stars may be proteins folding or DNA strands replicating . . . stay tuned!

Thermophiles clean up biofuel production

Some Like It Hot


Along with fellow PMB professor Tom Bruns, Taylor collected samples from farms at the University of Illinois and sugarcane plantations in Louisiana by isolating fungi that grew on powdered Miscanthus giganteus, a promising crop for biofuel production. To increase the chances of isolating useful environmental fungi, Taylor employed a classical ecological sampling technique called dilution to extinction. Before introducing the samples into the growth medium used for isolation, they were diluted extensively. By diluting to the point where each tube can have at most one living fungal cell we avoid selecting for fast growing species, Taylor says of his approach. This process allows him to find strains that are less abundant or slower growing, and it is these rare strains that are often the most exciting. Indeed, many of the fungi isolated from Miscanthus released more sugars from the plant tissue than Trichoderma, confirming the potential for identifying useful fungal strains from the environment. After the success of this first sampling excursion, Taylor worked with EBI on identifying new fungal targets to improve biofuel production. In practice, industrial biomass conversion and fermentation suffer from contamination by other microbes that can ruin both raw materials and equipment. An attractive remedy to this problem is to perform the process at elevated temperatures where potential contaminants cannot grow. However, in order for such a process to work, the active fungi must be resistant to these elevated temperatures. To find fungi compatible with this technique, Taylor, Bruns and their team again looked to nature, isolating cellulose-degrading fungi from high temperature environments. These microbes are named thermophiles: literally heatloving organisms. Taylors team sampled from active compost piles, which are often extremely hot due to the energy released from decaying plant matter. We were sampling from sites where you couldnt reach your arm in up to your elbow without getting burned, Taylor describes. The fungi isolated from this set of samples can now be used to produce enzymes for high temperature cellulose degradation processes. To complete the process, Taylor and his team also sought thermophilic yeasts for conversion of sugars to ethanol. Fortunately, a unique farming practice at the original sampling sight in Louisiana provided another ideal high-temperature environment. After extracting sugar from sugarcane, farmers discard the fibrous waste, called bagasse, in large piles where it breaks down slowly. Much like compost piles, the bagasse gets quite hot as it decomposes. By sampling from these piles, Taylor found two promising species of yeast, Kluyveromyces marxianus and Issatchenkia orientalis, both capable of growing at high temperatures. Eventually, he hopes these yeasts can be used for more efficient fermentations. Though the fungi already isolated could complete a novel high-temperature cellulosic ethanol process, Taylor is not yet satisfied. Moving forward, he hopes to sequence the genomes and perform association analysis on variants of his newly discovered strains isolated from a variety of locations. This approach involves correlating temperaturesensitivity and fermentation efficiency to specific parts of the fungal genome. In this way, Taylor hopes to identify genes that could be useful for engineering microbes optimized for biofuel production. Thanks to his new projects, Taylor is no longer feeling slimy. As a basic biologist, its been nice to work on something that has a direct application. With any luck, his continuing research will play an important role in advancing the next generation of biofuels from the laboratory to your gas tank.

In the hunt for more sustainable biofuels, microbes derived directly from crop environments are heating up the chase. Recent research led by Professor John Taylor at UC Berkeleys Energy Biosciences Institute (EBI) has shown that fungal and yeast strains taken from hot decomposing plant matter will thrive at high temperatures, enabling higher yielding industrial processes for cellulosic ethanol production. Taylor, who is a professor in the Department of Plant and Microbial Biology (PMB), has made his career studying fungal evolution, focusing heavily on the organization of fungal populations in the environment. Now, he is using his expertise to take on the challenge of rising atmospheric carbon dioxide (CO2) levels and global warming. Taylor had been troubled for some time by the environmental effects of modern societys dependence on fossil fuels. When EBI was established at UC Berkeley in 2007, he saw it as an opportunity to take action. After years of talking about CO2, I almost felt slimy not to get involved, he says today. Together with other EBI scientists, Taylor has since been working on a particularly difficult problem in advanced biofuel production: the conversion of cellulose obtained from sustainable crops into clean burning ethanol. Cellulose is the long-sugar polymer that forms the rigid scaffolding of plant cell walls. Thus, while it stores an enormous amount of energy, it is also highly robust. For this reason, making biofuel from cellulose is far more challenging than conventional methods, which start with sugars and starches directly. The sturdy polymers must first be broken down before sugars can be converted to ethanol. State-of-the-art industrial processes already exist to digest cellulose chains into sugars using enzymes that are secreted by the fungus Trichoderma reesei. Yeast can then ferment these sugars into ethanol. However, low fuel yields have prevented these processes from being cost-effective alternatives to current fuels. Taylors initial study at EBI focused on finding new fungi that could break down cellulose better than existing industrial strains. We suspected that the environment would provide much more efficient strains.

ELECTRONIC MICROSCOPY IMAGE OF YEAST SPECIES L. ORENTALIS BY STEVE RUIZIN. MESCANTHUS IMAGE BY JOHN TAYLOR

Drs. Bruns and Taylor next to a crop of Mescanthus

David Hershey is a graduate student in plant and microbial biology.


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BRIEFS Methylation Mars Crater

Finding water on Mars, on Earth


Standing on the dusty rim of Meteor Crater in Northern Arizona, UC Berkeley Professor William Dietrich thought, It looks just like Mars! The crater (called the Barringer Crater by scientists but officially named after the nearest post office in Meteor, AZ) was created approximately 50,000 years ago, when a 45-meter-wide asteroid impacted earth. The crater is nearly one mile wide, but Professor Dietrich was particularly impressed by the erosion gullies that had formed at the craters rim. These gullies, he thought, bear some striking similarities to those observed on Martian craters. Debris flowsliquified landslides of mud, rock, and waterare responsible for the gullies cascading down Meteor Craters rim. Marisa Palucis, a graduate student in Professor Dietrichs lab in the Department of

Crater Clues

Earth and Planetary Sciences, believes debris flows also formed the gullies observed on Mars. The automobile-sized boulders found at the bottom of Martian craters are a big tip-off. Debris flows on Earth are able to carry bouldersas well as logs, cars, and even buildingsfor very long distances. The Martian gullies also culminate in lobe-like fans of eroded material, which are characteristic of debris flow gullies on Earth. According to Palucis, f lood-like processes cannot be responsible for these features. She believes floods require more liquid water than would have been available on Mars at the time of gully formation. While there is ample evidence that oceans and river deltas were present for at least some of Martian history, scientists believe that Marss water is now frozen in ice caps or locked away in below-ground reservoirs. Tantalizingly, many of the Martian

debris flows seem to have originated after Mars froze. If Palucis is able to prove that the Martian meteor gullies were caused by debris flows, she would also prove that a small amount of liquid water was present in more recent times. Transient events, such as a shift in Marss orbit closer to the sun, may have unlocked enough liquid water to form a debris flow. However, Palucis says the harder questions are, What size of rainstorm is that? Do you need a torrential downpour, or could a moderate size storm form this feature? Palucis needs to prove that the amount of water required for debris flows is reasonable based on both Martian hydrology and climate. To answer these questions, Palucis laboratory experiments estimate how much water it would take to form a given debris flow feature. Instead of running after a debris flow with clipboard and lab coat flying, Palucis

Left: a flyover image of the Mars Crater; Right: a slope map of the northeast section of the crater. The formation of debris flows occurs for slopes between 15 and 20 degrees, represented as the yellow region in the map. At the center of the crater are flat sediments from an ancient lake.

250

500 meters

125 meters

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MARS CRATER IMAGES BY MARISA PALUCIS

BRIEFS Science Education

Higher Hopes
uses giant rotating drumslocated at UC Berkeleys Richmond Field Stationto create essentially a debris flow thats forced to stay in place. By varying the proportions of clay, water, sand, and soil loaded into the drum, Palucis is able to observe when the mixture transitions from something less like UC Berkeleys Strawberry Creek to something more like a raging slurry of mud and gravel. Palucis is also carrying out an extensive mapping survey at Arizonas Meteor Crater to determine the age and frequency of debris flow formation. Using cosmogenic datinga method to estimate the ages of rocks from chemical changes that occur during sun exposurePalucis determined that debris flows on Meteor Crater are not modern. They date from around 20,000 years ago, during the Pleistocene, when the American southwest was a warmer and wetter place than today. She notes that, if one [debris flow] happened a year, then a pretty average rainstorm or snowmelt event during the Pleistocene would cause it. If they happened every 100 years, then that means its a more unlikely, bigger event that happened. Paluciss ultimate goal is to use her laboratory experiments and fieldwork at Meteor Crater to integrate both geology and hydrology into a model of debris flow formation. This joint hydrologic sediment transfer model would allow her to back-calculate how much water it would take to form a given debris flow feature, both on Earth and on Mars. Contemplating this prospect, Palucis muses, If we find water, can we find life [on Mars]? However, she cautions that before taking her model to Mars, she has to prove it can accurately model phenomena on Earth. This in itself would be an enormous step toward understanding debris flow processes. For citizens of Switzerland, Taiwan, Japan, and other areas with steep terrain prone to landslides, Paluciss models could become part of an integrated storm hazard warning system. And who knows? After NASA terraforms Mars her models might be used in storm warning systems for Martian citizens living in Crater Rock City.

FOSS improves Californias science education

Ginger Jui is a graduate student in integrative biology.

As Californians, we have a keen appreciation for science, and an understanding of its importance in the classroom. At least, thats what you might assume. However, a new statewide report, conducted in part by the Research Group at UC Berkeleys Lawrence Hall of Science, exposes a frightening imbalance between these values and the reality in Californias elementary schools. In the face of these findings, a long-standing Lawrence Hall project shines as a ray of hope, providing improved access to engaging science education for the states children. Entit led High HopesFew Opportunities: The Status of Elementary Science Education in California, (High Hopes) the Lawrence Hall study asked teachers and administrators in Californias schools about sciences place in the classroom. The alarming finding was a general scarcity of quality science-education opportunities, says Dr. Rena Dorph, a researcher at the Hall. According to the report, English and mathematics are prioritized over science in the states current elementary school curriculum. As a result, less time is spent on science, leaving students with fewer chances to learn important concepts. This problem is compounded by a lack of laboratory infrastructure for inquiry-based learning, limited science-specific professional development for teachers, and ineffective assessment of science knowledge. Not surprisingly, all of these shortcomings weigh more heavily on students in low-income communities. However disappointing, these conclusions are no revelation for the scientific community at UC Berkeley, where researchers have been working for years to improve Californias science education. One particularly fruitful effort has been the Full Option Science System (FOSS), a research-based science curriculum for grades K-8 that was first developed at the Hall over 20 years ago. Rather than having students listen passively to a teachers lectures, FOSS emphasizes active learning, whereby students learn science by doing science. This inquirybased approach strikes at the heart of the shortcomings found in High Hopes, and has been demonstrated to be more engaging for students than a textbook-based curriculum.

Johann Mitchell, a 4th grade student in Lindsey Smallwoods class, compares basalt, limestone, sandstone, and marble as part of the FOSS Science Curriculum

In her FOSS Solid Earth module, Lindsey Smallwood, a 4th and 5th grade teacher at Oaklands MLK Elementary School, supervises students conducting investigations and analyses using laboratory equipment and interactive technology. Both teaching and learning are improved when activities are introduced with a lead question, she says. The Solid Earth module is made up of five sequential investigations, each of which begins with a lead question that introduces a key concept about the different types of rocks and landforms found on Earths surface. This lead question guides the students as they learn to critically approach a multifaceted problem. Most lessons within the Solid Earth module are structured around a hands-on experience with rocks and minerals. For example, to teach the processes that slowly change the Earths surface, Ms. Smallwood demonstrates chemical weathering by having the students soak limestone in vinegar and physical weathering by shaking granite in a jar. Precise scientific vocabulary is then connected to these experiences. Much like professional scientists, students collect data and record observations in a science notebook, test predictions, and eventually attempt to draw conclusions about the lead question based on strong evidence. To supplement hands-on classroom activities, the FOSS website has a vast collection of reading material, audio books, teacher preparation videos, online activities for students, and an archived Ask a scientist forum that can be accessed by anyone in
Fall 2012 Berkeley Science Review

LINDSEY SMALLWOOD

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BRIEFS Piezoelectricity

M13 viruses (in blue) can be stacked side by side on a thin film. When pressure is applied, charges generated from dipoles of viral coat proteins can power a small electronic device

Sharmistha Majumdar is a postdoc in molecular and cell biology.

Piezoelectricity is a nuanced but incredibly practical mechanism for energy conversion. In a battery, stored chemical energy can be converted into electrical potential energy, creating a voltage difference across the batterys terminals. If the battery is connected to a cell phone or car, an electric current can rapidly and efficiently carry this energy away for other uses. Similarly, piezoelectrics develop a voltage difference with the application of mechanical stress, allowing them to convert kinetic energy into electrical energy. This effect happens because ions or molecules in the material are polarized, having a separation between positive and

Lee and his team of researchers found that certain viruses have piezoelectric capabilities. Viruses are biological molecules composed of a shell of proteins (known as coat proteins) that surrounds genetic material (DNA or RNA) containing the instructions for their own replication. The three-dimensional structure of the protein shell call vary greatly from one type of virus to another. Knowing that many organized biological molecules like DNA and proteins exhibit piezoelectric properties, Lees team predicted that, based on its structure, a virus known as M13 bacteriophage might also be a piezoelectric. The team observed

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DESIGN BY NIKKI R. KONG. LIGHTBULB IMAGE: MODIFIED FROM GREG BORENSTEIN; HAND: ALL-FREE-DOWNLOAD.COM; M13 VIRUS: SEUNG-WUK LEE

the community, including other teachers, students, and their parents. These supplementary resources also help to address the access problems identified by High Hopes, as any classroom that adopts FOSS can use the website for free. To help teachers and administrators better gauge gains in understanding based on the FOSS curriculum, the Lawrence Hall staff has focused on improving the assessment of science knowledge. The FOSS curriculum encourages frequent teacher observations, science notebook reviews, and assessments at the end of investigations, followed by student self-assessments, and end-of-module exams to make sure students are on track. By all accounts, FOSS students are on track. The High Hopes report found that the best prepared teachers were those using FOSS modules in their classrooms and the most successful school districts offered professional development based on FOSS resources. Unfortunately, these categories represent only a small fraction of teachers and districts. According to the report, only about 10% of students in California are exposed to adequate science education. Though the State of California adopted FOSS as one of several recommended curricular resources for teachers in 2006, broader implementation is needed before it can reach students across the state. Moreover, once a district has adopted FOSS, teachers must be given the time to properly use it. It takes more time and work to prepare a FOSS lesson than a traditional science lesson, notes Smallwood, but the payoff is seeing students engaged in the scientific process in such a meaningful way. In the meantime, the Lawrence Hall staff continues to work with schools and districts that have already adopted FOSS. By incorporating feedback from scientists, education researchers, teachers, administrators, community members, and parents, they aim for future iterations to better engage the diversity of students in a typical California classroom. Hopefully, sooner rather than later, that typical classroom will be using tools like FOSS to provide students with the engaging science education they deserve.

Piezoelectricity goes viral


With an ever-increasing number of devices that require electricity to operate, wouldnt it be amazing to charge small electronics, like your smart phone, by the simple action of walking across campus? Scientists are exploring this approach using piezoelectrics, materials that convert the mechanical forces involved in movement to electrical energy. Recently, researchers in Lawrence Berkeley National Laboratorys Physical Biosciences Division, led by Professor Seung-Wuk Lee of the Department of Bioengineering at UC Berkeley, have found that electricity can be extracted from a surprising new piezoelectric: viruses.

Good Vibrations

negative charges. Normally, these polarized constituents cancel each other out, and the material as a whole remains unchanged. When the piezoelectric is distorted, however, the overall symmetry is lost and the internal polarization comes to the surface. Because of this, one can generate an electrical voltage in these materialsmuch like that in a batteryjust by squeezing, stretching, or twisting them. This microscopic effect makes piezoelectrics practical for a number of applications and they are currently used in a variety of common devices. For example, piezoelectric crystals in microphones convert vibrations created by sound to small electrical signals that can be amplified and projected to an audience.

BRIEFS Piezoelectricity

that M13 has polarized coat proteins and a structure that ensures the polarization does not cancel out. In the presence of an electric field, materials can be tested for their piezoelectric potential by measuring changes in shape due to the applied electric field (known as the converse piezoelectric effect). Using piezoresponse force microscopy, a high-resolution method of measuring atomic-level changes in material structure under an applied electric field, the researchers confirmed the piezoelectric properties of M13 virus. Lees team next hypothesized that they could increase the strength of the piezoelectric effect by increasing the separation of positive and negative charges in the virus coat proteins. This is where the genius of developing viruses as piezoelectric materials comes to light. Because a virus contains the very genetic material that encodes its own coat protein, genetic engineering allows one to directly tune and optimize that structural shell. To create a larger piezoelectric effect, they engineered the addition of four negatively charged amino acids, the building blocks of proteins, to the negative terminus

of the coat protein. This increased the charge separation, and ultimately the viruss piezoelectric effect. Furthermore, aligning many genetically engineered M13 viruses to form multiple layers of film strengthened the piezoelectric effect of the M13 material. Fabrication of thin films of M13 is simple and inexpensive. An overnight bacterial culture infected with M13 can create millions of copies of the virus, Lee says. While traditional piezoelectric materials are difficult to engineer, viral piezoelectric films are straightforward to synthesize: the M13 virus has an elongated shape allowing for alignment in a specific direction. The viruses then become the basic building blocks to induce electric generation, said Lee, in stark contrast to currently used piezoelectric materials that require expensive, complex, and labor-intensive procedures to assemble. In addition, virus-based piezoelectric devices provide a safer alternative to commonly used piezoelectric materials, which contain toxic compounds such as lead, nickel, and zinc oxide. The final proof-of-concept for virus piezoelectrics was to demonstrate that

multilayered films of M13 could power a small electrical device. Lining the virus films with gold electrodes, the team connected a small liquid crystal display (LCD) to the device. Pressing on the piezoelectric system with a finger generated about 400 millivolts of electricity, enough to power the LCD screen. This is the first biomaterial that has generated enough electricity to turn on and off electric devices, said Lee. While this technology cannot yet provide enough energy to power most personal electronics, it is rapidly improving. Since this study, Lee and colleagues are closer to developing viral piezoelectrics capable of powering small electronic devices; the team has already developed enhanced viral material that can provide 20 times more power than the original experiment. At this rate of progress, it may not be long before we dance to the tune of virus-powered iPods, running off the energy of our own gyrations and never plugging into a wall outlet again.

Samantha Cheung is a graduate student in molecular and cell biology

Eran Karmon Editors Award


In memory of Eran Karmon, co-founder and first Editor in Chief of the Berkeley Science Review. This award is given annually to the Editor in Chief of the BSR thanks to a generous donation from the Karmon family.

STEVE MCCONNELL / UC BERKELEY

Fall 2012

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MOFiosos
A
new class of materials called metalorganic frameworks (or MOFs) has injected a surge of energy into the scientific community. These materials are novel because they allow scientists to rationally design nanometer-scale structures and the empty spaces they define. With this control of empty space comes the ability to manipulate the chemistry of any molecules trapped inside, a powerful tool for many important applications. For this reason, chemists around the world are racing to make the newest, most exciting versions, advancing the frontier of this new field at breakneck speeds. Among scientists in Berkeley and around the world, however, the benefit of MOFs to society is up for debate. While they certainly have furthered our understanding and control of the chemical world, MOFs have yet to be applied in the real world. In particular, while MOFs are regularly touted as a potential solution for global warming, their promise as carbon dioxide (CO2) capturing materials has yet to leave the laboratory. What remains to be seen is how this balance between fundamental and applied contributions will shift in the future. At UC Berkeley, Professors Berend Smit, Jeff Long, and Omar Yaghi have devoted much of their careers to metal-organic frameworks, and each has his own perspective on the debate between the fundamental and applied benefits of the field. We are fortunate in MOF chemistry, says Yaghi. In studying MOFs, he feels he can approach chemistry from a fundamental perspective and let the applications materialize on their own. We have a responsibility as scientists to be thinking about benefiting society. In this case, weve done that. But Yaghis approach has never wavered from a purely fundamental one, despite the fact that he doesnt forget about his obligation to the greater good. We sometimes lose sight that the most difficult problems facing society are often solved by those of us who push the frontiers of knowledge, often without having a societal problem in mind. These two perspectivesfundamental science aimed at basic understanding and the develoment of viable applications for the real worlddefine the extrema of MOF research on campus. In between lies a continuum of many other researchers. But some, including Smit, prefer not to take sides. The difference between applied and fundamental is overrated, he says. The intellectual challenges in applied questions and fundamental questions can be equal. As they design, sythesize, and study fascinating new materials on a daily basis, Berkeleys MOF scientists are breaking down the barriers between these sometimes dichotomous approaches to research. And while the potentially calamitous consquences of global climate change are looming, there is no shortage of inspiration among those trying to bring MOFs to the world.

MOF chemistry 101


Omar Yaghi is widely known for publishing the first report of metal-organic frameworks in 1999. But he has always stated that he wasnt ever searching for the next big

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thing, and definitely not trying to create a new field of chemistry. He was simply trying to make materials that were beautiful. In the ensuing years, thousands of MOFs have been made and new bells and whistles are added to them daily. Some can bend, or stretch, or even incorporate movable parts that can be made to spin on command. Many are brightly colored and researchers have taken advantage of this by designing MOFs that will only change color in the presence of toxic molecules like cyanide. Metal-organic frameworks do their jobs by bringing order to the chaotic realm of small molecules. Ask yourself, what would it take to capture and store a gas like carbon dioxide, to stop it from entering the atmosphere, or hydrogen for use in a zeroemissions vehicle? Now imagine nano-scaled scaffolding (like at a construction site) that can catch or release these small molecules one at a time as they flow through the cages and pores. Metal-organic frameworks are exactly this: perfectly repeating cages filled

with empty spaces that are around 10 nanometers acrossjust the right size to trap a few small molecules. As a result, they represent a new era in materials chemistry in which empty space can be designed for a purpose. After the first few reports that we made on MOFs where we showed they were indeed porous, and things could be put into the pores and taken out without collapse of the framework, I think it got the attention of a lot of people, says Yaghi. MOFs are made of two types of building blocks: linkers and nodes. The long linkers are organic molecules, strings of carbon and hydrogen decorated with oxygen or nitrogen. These have at least two arms that preferentially bind to positively charged metal ions. (Metals occupy a broad swath of the periodic table, from sodium in one corner to livermorium in the other [see Elemental Christening, 4].) The metals form vertices, or nodes, between the organic linkers, making an infinite, repeating structure. Metal-organic frameworks are made by

Berkeley scientists make carbon a structure it cannot refuse


by Zoey Herm
LEAH ANDERSON

FEATURES Metal Organic Frameworks

simply adding linker and metal to a solvent (sometimes water) and heating for a couple of hours or days. During the heating process, the linkers and metals find each other and settle into the final orderly MOF structure. Then a vacuum can be used to pull out any extra solvent molecules that might be trapped inside the vacant spaces. The synthesis requires finding the perfect recipe of linker, metal, solvent, and temperature to get the thermodynamics just right to generate a MOFotherwise the resulting product can look like a knotted jumble without the pores needed for controlling the small molecules that flow inside.

periodic table and a virtually limitless number of organic linkers that can be imagined, an essentially infinite number of MOFs are waiting to be created. The shapes, sizes, and chemistry of the spaces inside metalorganic frameworks can be designed for any application where a small molecule needs to be controlled. The astronomical number of combinations begs the question: where does one begin in making new MOFs? Currently, two approachesrational modification and high-throughput chemistryspan the experimental work done by Yaghi and Long

Yaghi works on variations of MOF-5, a flavor of metal-organic framework with zinc oxide nodes and benzene-derived linkers. He has discovered that by adding subtle modifications to the linker, he can drastically alter its ability to capture CO2. All of these modifications involved adding small functionalities like hydroxyl (-OH), chloride (-Cl) or amine (-NH2) groups onto the middle of the linker. Because the linker doesnt change length or the way it binds to the metal, the skeleton stays the same but different small groups poke out

MOF design for carbon capture


After the discovery of MOFs, research efforts were quickly trained on applications for the new class of materials. One very popular application, so much that all of Berkeleys MOF scientists are now working on it, is to use MOFs to filter the carbon dioxide from the smokestack of a power plant. Most climate experts calculate that carbon capture and sequestration (CCS), as this filtration is known, will be necessary to reduce CO2 emissions to a sustainable level. If MOFs can successfully capture carbon dioxide, they could be a dream come true in the fight against global warming. Indeed, metal-organic frameworks could be the perfect answer for CCS applications. Their cages are just the right size to hold carbon dioxide molecules, and they can be modified in almost any way imaginable to take advantage of the unique behavior of CO2. If designed with this functionality, all of the other benign molecules that come out of smokestacks, like water and nitrogen, would pass straight through the MOF scaffolding, while the CO2 remained inside. Because of these promising possibilities, Professors Yaghi, Long, and Smit are all working to make metal-organic frameworks that selectively bind carbon dioxide. Using their varied expertiseYaghi and Long focus on experimental methods, while Smits group is purely computationaland taking advantage of what they already know about MOFs, their research groups are trying to build new, better MOF materials for CO2 capture. With the dozens of metals on the organic linker

Rational Modification
MOFs are cage-like structures composed of metallic nodes connected by a network of organic linkers. Single cages like the one pictured below can be repeated infinitely to create a large continuous lattice. Researchers have discovered that small modifications to chemical functional groups placed along the linkers can dramatically enhance a MOFs desired properties, like its potential for carbon capture.

metallic node

chemical modifications

and are bolstered and supplemented by the Smit groups computational Monte Carlo methods.

Designing for discovery


Like synthetic molecules, MOFs can be tweaked and altered to take a good thing and make it better. The vast majority of MOF research is in these efforts toward rational modification, rather than making brand new MOFs from scratch. For example, imagine that a MOF that is good at CO2 capture also degrades in water. Chemists would search for a way of changing the linker or changing the metal that would render the MOF more stable without sacrificing any CO2 capture performance.

into the channels and are given the chance to interact with the CO2 molecules that float through. One of his most interesting discoveries in this area of study is that by combining many of these modified linkers within the same MOF-5 framework, more CO2 can be captured than with any of the individual linkers in isolation. The underlying principles behind this discovery are not yet completely understood. Longs lab is interested in how to modify existing metal-organic frameworks to make them better materials for capturing carbon. One idea takes advantage of a very old method for capturing carbon that cant be used industrially because it is too inefficient: amine dissolved in water. An amine

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FEATURES Metal Organic Frameworks

is a small appendage to a molecule that contains a nitrogen, in addition to a few other specifications. Amines are special because they will react strongly with CO2 but have no interaction with any other component of air. In practice, these dissolved amines are hugely wasteful because heating and cooling water is energy-intensive. Metal-organic frameworks are a much more promising approach because the gaseous mixture of CO2 and air can flow through the empty space as opposed to bubbling through a mixture of water. To mimic this, the Long

carbon but bad at releasing it. Industrially, many such criteria must be met for a material to be able to withstand the harsh conditions of a power plant, and near-perfect efficiency of holding CO2 and releasing it at just the right conditions is needed. Because a viable MOF doesnt exist, asyet-unimagined MOFs need to be created and tested. Making new MOFs is a completely different type of chemistry from the rational modification and detailed study of existing MOFs discussed above, and much less developed. Chemists dont have a good way

High-Throughput Chemistry
So many combinations, so little time... It can be hard to predict how a new combination of linkers and nodes will look or behave. So when scientists search for MOFs with interesting cage geometries, or with the resilience to excel in real-world industrial conditions, they want to try as many combinations as possible. Computational chemists armed with simulations, and experimental chemists armed with robots, can create and test thousands of new MOF variations. Each MOF is screened for desirable properties, and the results are compared to find trends among MOFs with similar building blocks.

thousands of new MOFs in a week. The Long lab takes this a step further by using a streamlined approach to quickly test dozens of MOFs for their ability to capture CO2. To accomplish this, they couple characterization tools to the high-throughput combinatorial syntheses discussed above. After a large number of new MOFs are made, they are all tested for CO2 capture and the results are entered into a database. Information about promising materials can then be data-mined to distill useful information about what kind of linkers, metals and solvents are effective. This feedback can then guide further synthesis, progressively increasing the likelihood of finding viable new MOFs.

Computational methods
Smits lab evaluates the carbon dioxide capture potential of these tailored metalorganic frameworks theoretically, using a computational method called Grand Canonical Monte Carlo simulation. In this method, simulated gas molecules are allowed to flow freely through the structure of a particular MOF and interact with its chemical environment (see Toolbox, 53). By running such a simulation, Smit can see exactly where CO2 molecules go and how many can fit within the structure of interest. Its like developing a flight simulator for molecules, he says. These computational efforts can free the high-throughput approach to MOF design from the confines of synthetic methods. In fact, theoretical studies can calculate structures for hundreds of times more materials than could possibly be done synthetically. The Smit lab recently published a study that used Monte Carlo simulations to compare the CO2 capacity of hundreds of thousands of metal-organic frameworks. Using these vast amounts of data, they were able to identify patterns and important hallmarks of what might make the best carbon capture material.

lab has installed amines that dangle into the pores of metal-organic frameworks and are perfect for picking up CO2 before it is emitted into the atmosphere. The reversibility of CO2 capture inside metal-organic frameworks is one of the most promising aspects of the technology. With a little bit of extra heat, the CO2 will float out of the channels as a pure gas that can be sequestered underground, leaving the MOF ready for another cycle.
GRAPHICS: LEAH ANDERSON

Casting a wide net


None of the thousands of existing metalorganic frameworks are a perfect carbon capture material yet. For example, there are many MOFs that are great at capturing

of designing a structure and then picking linkers and metals that will arrange to create it. Similarly, it is often impossible to predict what the final structure will look like when a new metal-linker combination is reacted for the first time. Chemists have found a way to make new MOFs even though they are essentially feeling their way through the dark: try everything. This approach is called high-throughput chemistry. The first step involves combinatorial chemistry: reacting dozens of existing metals with dozens or hundreds of linkers, and trying each reaction in many different solvents. To facilitate this approach, both the Yaghi and Long labs use robots, allowing them to make hundreds or

The role of funding


The US Department of Energy (DOE) is funding all facets of MOF research at UC Berkeley and Lawrence Berkeley National Laboratory (LBL). In addition to funding a new applied research center at the Molecular
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FEATURES Metal Organic Frameworks

This crystal is smaller than your fingernail, but it contains at least a billion nanoscale cages! The crystal is made of a MOF called MOF-5, which is composed of phenylene linkers connected by zinc oxide nodes and is a specialty of Yaghis lab. Experiments on crystals like this demonstrated that MOFs containing many different functional groups can be more than the sum of their parts. Yaghi is still not sure why some mixed MOFs outperform any pure MOF that could be made out of just one of the mixed MOFs many constituent linkers.

1 mm

Foundry, LBLs nanoscience facility, the DOE has also funded two multi-lab, multi-year CO2 capture projects. One of them is the Energy Frontier Research Center (EFRC), which funds basic science with the hope that a good carbon capture material will be discovered if scientists are given the freedom to explore the unknown. Thus, while still focused on a particular application, EFRC grants have only limited constraints: researchers are asked to pursue work that is interesting to them, follow up on exciting leads, and test any new materials they make for their ability to capture CO2. This allows them to find new mechanisms of catching CO2 and investigate them thoroughly, without worrying about the commercial viability of their results. Professors Smit, Long, and Yaghi all work together on one EFRC grant that funds most of their work on rationally designed and tailored materials. As Smit explains, the approach encouraged by the EFRC is very fundamental research, but in addition you make the effort that its actually useful in the end. Its positioning yourself within the field of fundamental research rather than compromising fundamental research. In contrast, the Advanced Research Projects Agency-Energy (ARPA-E) is a special funding agency created to take academic technologies and quickly make them industrially viable. Both Long and Smit are part of an ARPA-E funded project that is designed to use robotics and computation to find the perfect MOF for carbon capture. In contrast to a more fundamental approach, materials

are tested for CO2 capture before anything is known about their structure, and the funds dont cover any detailed understanding of what makes one material better than the other. The work for this project entails monitoring and maintaining the robots and organizing the data that they generate. While both the DOE and EFRC funds ideally will be used to find new MOFs for CO2 capture, the methods of arriving at this endpoint are surprisingly different. Eric Bloch, a chemistry graduate student in the Long group, has contributed to both the EFRC and the ARPA-E projects, and prefers the

company, BASF, has recently begun making MOFs in large quantities with the intent of selling them to industry. From a basic science perspective, MOFs already have made an invaluable contribution to science and will continue to do so. Their intrinsic beauty lies in their ability to tailor the walls around empty pores so they can finely control small molecules. And they have pushed the boundaries of what materials can do and can be. MOFs present a whole new field of chemistry that young people can be dabbling at for the next generation at least, says Yaghi. To that end, Yaghi has created a laboratory in Vietnam, which he considers one of his most important projects so far. To him, MOFs are so special because their hierarchical structure allows MOF scientists to have an idea and make a new material that will match the structure that was imagined. He wanted to share that with universities that dont necessarily have thriving research centers, so that students anywhere could begin to learn how to conduct world-class research. From this vantage point, Yaghi has a unique perspective when it comes to the most useful applications of MOFs, one he says hes never mentioned publicly before. When discussing one new material recently published

. . . it stands for young people as an example of some achievement that was thought impossible but now is possible. That to me should always be part of working in science.
EFRC. I came to grad school to do basic science. If its ultimately used for an application its a bonus. He sees ARPA-Es rigid focus on applications as a major drawback since it doesnt always leave room for curiositydriven experiments. There are basic science questions that we have to ignore, Bloch says. in the journal Science, one that Yaghi had been told could never be made, he said it was maybe a useless compound in the sense that its not going to be put in every power plant to capture carbon dioxide, but it stands for young people as an example of some achievement that was thought impossible but now is possible. That to me should always be part of working in scienceto inspire young people. Its an important application.

Outlook
MOFs have yet to be used for CO2 capture and are years away from being a viable technology in that regard. But that doesnt mean they arent close: a large chemical

Zoey Herm is a graduate student in chemistry.

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FOXSI fires up
Sounding rocket mission looks at solar flares
by Lindsay Glesener

FEATURES FOXSI

n the Tularosa desert basin in New Mexico, not far from the White Sands National Monument, a fireball occasionally lights up the sky, climbing higher and higher until it is lost to the observers eye. Out of sight, the rocket climbs to a height of 300 kilometers, over 30 times higher than a passenger airplane, and escapes the atmosphere before plummeting back to the grounds of the White Sands Missile Range roughly 15 minutes after its launch. There, a team of scientists eagerly awaits its return. This story has played out in the New Mexico desert hundreds of times over the last half-century, and quite often the waiting scientists are from Berkeley. This will be the case for an upcoming launch in November 2012, when researchers from UC Berkeleys Space Science Laboratory will fly an experiment called the Focusing Optics X-ray Solar Imager (FOXSI) onboard a sounding (i.e. exploratory) rocket from White Sands. FOXSI will attempt to produce the most sensitive X-ray observations ever made of the Sun using on-board telescopes and cameras. As a graduate student on the FOXSI project, it will be my job not only to perform several scientific tasks, but also to chronicle the preparations and flight for posterity. This article will offer a look at the history of Berkeley rocket science and show what it takes to get an experiment into space.

A better vantage point


Almost five years of instrument design, assembly, and testing will culminate in FOXSIs 15-minute rocket flighta significant investment for just a few minutes of data. Yet, for scientists intent on highaltitude experiments, sounding rocket flights are highly sought-after. For astrophysicists, many useful tools are simply not available at ground level. The earths atmosphere blocks radiation in many parts of the electromagnetic spectrum, including gamma rays, X-rays, infrared, and some ultraviolet wavelengths. (This is crucial for the presence of life on Earth, as much of this radiation would cause tissue damage.) For highsensitivity solar X-ray studies, for example, astrophysicists must send their experiments high above the atmosphere to find an unobstructed view of the Sun.

Compared to building a spacecraft, rockets offer a faster and cheaper way to put an experiment into space, albeit for a shorter length of observation time. Scientific rockets are funded by the National Aeronotics and Space Administration (NASA) LowCost Access to Space program, which offers the opportunity to f ly a suborbital project with a construction time of only a few years, at a fraction of the cost of a spacecraft. NASA describes the program as a low-cost testbed for new scientific techniques, scientific instrumentation, and spacecraft technology that may eventually end up on satellite missions. Many astrophysics experiments do indeed use rocket flights as stepping stones to spacecraft status. To win a NASA spacecraft proposal, investigators must prove that all the parts of their hypothetical instrument will work. In some cases this means proving an entirely new concept; in others it means demonstrating that an established technology can withstand the tough physical environment of space. One way to demonstrate that technology is space-ready is to send it there, if only for a few minutes. Rocket-tested technology has formed the basis for hundreds of NASA satellites, past and present. Sometimes spacecrafts and rockets fly simultaneously: for example, after the Solar Dynamics Observatory spacecraft was launched in 2010, several rockets were flown to improve the calibration of one of its instruments. But not all science experiments on rockets gaze at otherworldly objects. Atmospheric and plasma physicists use rocket f lights for in situ measurements of the ionosphere and thermosphere plasma, data that is not available to either a groundbased observatory or to a spacecraft. Microgravity experimenters also make use of the rockets freefall to measure the behavior of physical and biological systems in a low-acceleration environment. Finally, another important scientific component developed by means of rocket experiments is the scientists themselves. Rocket f lights have typically been used to train students as physicists and engineers. The short time scale of a rocket project, as well as its greater risk tolerance, allows a PhD student to see a project through from

beginning to end and be involved in all aspects of the project, including the design phase, building and testing of the instrument, the f light itself, and data analysis.

The story of science rockets


Rockets certainly werent invented just to suit the whims of scientists who wanted to get their experiments into space. The evolution of space rocketry is intertwined with that of military rocketry. Rudimentary military rockets were built almost as soon as gunpowder was discovered, and solid-fuel rockets were used in battles throughout the 1800s. But by the early 20th century, rockets began to excite the human imagination as a way of turning science fiction into reality, by exploring space. In the 1920s, Hermann Olberth, a German physicist, proposed that rockets could be used to either place artificial satellites around the Earth or to escape the Earths gravitational field entirely, and thus could serve as a useful tool for space exploration. Around the same time in the United States, Robert H. Goddard experimented with liquid fuels, stabilizing systems, and multiple stages, the building blocks of space-capable rockets. For this work, Goddard would later become known as the father of modern rocketry. It didnt take long for military personnel to realize that these principles would also be useful for building powerful weapons of war. Throughout the 1930s, aggressive rocket development programs took place in several countries, particularly in Germany. A large and well-funded team of rocket scientists led by Werner von Braun developed the V-2, a liquid-fuel, singlestage military rocket. The V-2 was used against several Allied targets in World War II, and in 1944 became the first man made object to f ly into space. The end of the war marked an important turning point for space rocketry. The United States competed with other Allied forces for custody of captured V-2 rockets, along with their creators. German rocket experts, having surrendered to the Allies, immigrated to the United States and continued development of rocket systems (the United States secret effort to recruit German rocketeers was known as Operation Paperclip). Von Braun himself remained the leader of this team,
Fall 2012 Berkeley Science Review

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NASA

FEATURES FOXSI

working first in White Sands, and later in Huntsville, Alabama. In 1960 the newlyformed NASA established the Marshall Space Flight Center in Huntsville, with von Braun as director. This facility designed and built the rockets that powered the American side of the space race, culminating in the development of the Saturn V rocket, which would eventually be used to launch the Apollo Moon missions. Along with human spacef light, the newly formed space agency recognized the value of sending scientific instruments to make measurements in space. At birth, NASA inherited hundreds of retired Army rockets and immediately put them to use, putting out calls for academic physicists to propose rocket experiments. Thus, NASAs sounding rocket program was born. The term sounding rocket comes from nautical use, in which sounding is a method to gauge distance. In this sense, to sound via a rocket is to explore an unknown realm. These flights are also known as suborbital flights, since the rockets enter space but do not stay there for an entire orbit of the earth. Early NASA sounding rockets carried instruments designed to study cosmic rays, atmospheric composition, the Sun, the aurora borealis (northern lights), and X-ray and UV-emitting astronomical sources, among many others. Experiments not only made new measurements, but also tested out groundbreaking new technology. Later on, the best of this technology would be used to build spaceborne astronomical observatories. University professors and their students carried out many of the experiments, and typically a student was given the main responsibility for the project. In this way, rockets were not only a platform to develop new technology and science, but also one to develop new scientists for the space age. UC Berkeleys involvement in sounding rocket expeditions goes back to the very beginnings of the field. In 1958, Berkeley faculty recognized the opportunities for research offered by newly available rockets and satellites, and proposed a new research center called the Space Sciences Laboratory (SSL). SSL began operations in 1960, constructing experiments for flight on rockets, high-altitude balloons, and spacecraft.

Rockets in history. (top left) Robert H. Goddard stands with one of his experimental rockets in 1926. Goddards work in developing liquid fuel rockets earned him a legacy as one of the fathers of modern rocketry. NASAs Goddard Space Flight Center in Greenbelt, Maryland is named in his honor. (top right) In the 1950s and 1960s, Werner von Braun and his team of rocket scientists built increasingly larger rockets at the Marshall Space Flight Center in Huntsville, Alabama. The capstone of this work was the Saturn V rocket, pictured here, which launched the Apollo moon missions. (bottom) A V-2 rocket in transport. Built by the Germans, a V-2 was the first manmade object to enter space. After WWII, German scientists and rockets played a vital role in the start of the US space program.

Over the last 58 years, almost 400 PhDs have been awarded for experiments f lown on NASA sounding rockets, with 40 of them from Berkeley. Michael Lampton, a retired physicist at Lawrence Berkeley Laboratory (LBL) and a former NASA payload specialist, was one of the first Berkeley students to fly a rocket. In the late 1960s he and his advisor, physics professor Kinsey Anderson, won a proposal to do daytime studies of the aurora. They built and launched four Nike rockets with Apache stages from Fort Churchill, Canada into Hudson Bay and found the first evidence of auroral activity during the daytime. After graduating in 1969, Lampton flew several X-ray astronomy rockets from White Sands, where, he said, the projects would amass a large crew. We called them rocket roadies. Other students, girlfriends, friends, dogs, everyone would pile into campers and trucks and make the drive out to the desert, he recalled. The rocket roadies would help out with manual labor and moral support, and were rewarded

The FOXSI mission


Berkeleys participation in sounding rocket programs lagged in the new century: the last Berkeley rocket was an auroral experiment

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CLOCKWISE FROM TOP LEFT: NASA; NASA; IMPERIAL WAR MUSEUM

with the chance to help with and witness an exciting rocket launch. By the 1980s, when LBL physicist Pat Jelinsky was a PhD student, SSL had become an assembly line of both rockets and students. Berkeley rockets were flown almost every year, and each new student was trained by the previous one. Jelinsky flew three rockets (two Aries and one Black Brant) to perform extreme-ultraviolet astrophysical studies. The earliest of these rockets suffered problems with the alignment system and the pressure environment and were unsuccessful. Later f lights were able to fix these problems and produced the first extreme-ultraviolet studies of the local interstellar medium. In this way, rockets were used to successively iron out problems, culminating in a tested instrument capable of groundbreaking new science.

FEATURES FOXSI

flown from Alaska in 2000. That will change this year, however, with the November launch of the FOXSI mission, which continues the long tradition of building rocket experiments at the Space Sciences Laboratory. FOXSI promises to reveal a new view of the quieter parts of the Sun at elusive high X-ray frequencies. X-ray telescopes are notoriously difficult to engineer because traditional telescope configurations wont work. X-rays do not reflect or refract as easily as visible light does, so traditional telescopes with large reflecting mirrors or refracting lenses cant be used. In the past, to image highenergy X-rays from astronomical objects, scientists had to resort to indirect imaging techniques that are limited in sensitivity and dynamic range. But producing focused X-ray images is not an impossible task, though the technological requirements are high. X-rays need to ref lect on a mirror at a very small angle (less than half a degree). The mirror also needs to be carefully shaped and needs to be smooth down to the scale of a few atoms. Recent advances at NASAs Marshall Space Flight Center (NASA/Marshall), among others, have produced telescopes that can focus high-energy X-rays. One of the fields that could benefit most from such a telescope is the study of solar f lares. Solar f lares, or giant explosions on the Sun, occur frequently and
Paraboloid

are the most powerful accelerators in the solar system. Radiation and high-energy particles released during flares often reach the Earth, affecting communications and power systems and placing satellites at risk. Understanding how solar f lares happen and what triggers them is an important goal of solar physics. Because X-rays are emitted from high-energy charged particles traveling through the solar plasma, they give us important clues into the underlying processes of solar f lares. FOXSI was born five years ago in a proposal to NASA by UC Berkeley scientists that aimed to study f lares in the quietest regions of the Sun. Since it is so far impossible to predict large solar flares and time a rocket accordingly, the team chose instead to focus on small flares theorized to occur frequently. FOXSI combines focusing X-ray telescopes made by NASA/Marshall with X-ray cameras from Japanese collaborators to be able to image faint solar X-ray sources. Sm Krucker, the principal investigator of FOXSI and a senior physicist at the Space Sciences Laboratory, emphasizes that this science can only be done from a rocket or a spacecraft. He also underscores the importance of rockets as a training tool. With their quick turnaround times, rockets are a great low-cost way to try out new instrumentation and train students. To accomplish this, SSLs heritage in building rocket experiments is essential. We rely

on scientists and engineers with decades of experience in building space projects. New students tasked with building and testing rocket payloads can draw from this wealth of institutional knowledge to help them build instruments that will work in space. After about four years of work, FOXSI is ready for its first flight. But the populous, crowded Bay Area is no place to fly a rocket that requires an isolated area where a rocket can launch and land without posing a danger to anyone. So the FOXSI team will take their experiment to one of the birthplaces of US rocketry: White Sands.

FOXSI in the desert


The White Sands Missile Range is geographically the largest active military base in the country, covering over 3000 square miles of New Mexico desert. Located an hour north of El Paso, TX, and a half hour east of Las Cruces, NM, the range is like a small town in itself. Families of active military personnel live there, and a tour of the base reveals houses, schools, playgrounds, and a golf course. Theres even a bowling alley, which is a good place to take a break from work for a burger and a chocolate shakeimportant for scientists working around the clock to put the finishing touches on their experiment. White Sands is a military and scientific facility with an illustrious history. It was here that the first atomic bomb was

Hyperboloid

DIAGRAM: ESA/XMM-NEW TON; SUN: SAO, NASA, JAXA, AND NAOJ

DOUB

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FOCAL SURFACE

750

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AYS X-R AYS X-R

(left) In order to focus X-rays, a telescope must be carefully positioned so that photons enter it at an angle of half a degree or less. X-rays reflect at shallow angles from two surfaces inside the telescope before focusing to an image. Typically, many mirrors are nested together as shown in this diagram to capture a greater number of photons. (right) An X-ray image of the Sun taken by the Hinode spacecraft. Hinode has found small bright X-ray spots all over the Sun that may be tiny solar flares. The FOXSI rocket will examine the Sun at higher energies to find out whether these are indeed flares and whether they can play a role in heating the outer solar atmosphere.
Fall 2012 Berkeley Science Review

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FEATURES FOXSI

exploded in 1945 at the Trinity Site. It was here that the Operation Paperclip rocket scientists arrived along with truckloads of V-2 rockets after the end of World War II. And it hosts a facility used by NASA for launching scientific rockets for the last 50 years. Launching a rocket at White Sands now is a different story than it was 50 years ago. Security regulations do not allow for non-essential personnel; rocket roadies are no longer permitted. During the launch, scientists, engineers, and observers will be located in a sturdy block house near the launch rail or else a viewing location miles away; outdoor viewing bleachers right next to the rail are a thing of the past. Anyone wishing to attend the launch should get there early; a few hours before the launch, the nearby highway as well as the adjacent national park will be closed to traffic and visitors. Though FOXSI will have its first shot at space in late 2012, it has already been

introduced to the range. In March of 2012, FOXSI was brought to White Sands for a first f light attempt, but the f light was delayed due to unexpected problems with the experiment. The time on the missile range was instead used as a dry run of the flight preparation, in which each essential step leading up to the launch was practiced. One of the first steps in preparing the rocket was to line up the telescopes with the X-ray cameras. To get the needed precision, this had to be done using a high-power X-ray generator located 60 feet away from the instrument. Since X-rays are undetectable to the naked eye and can be harmful in high doses, this was done in a carefully controlled environment so that no personnel could be exposed to the X-ray beam. The next step was integration, meaning that all rocket components, including the instrument, were attached together for the first time. This was followed by a sequence test of the entire instrument. In this test, events during the countdown,

launch, and flight of the rocket were simulated. Power and communications systems were switched on at the appropriate times. The shutter door that will expose the telescopes to the Sun was opened. Members of the FOXSI team in a control room practiced receiving the experimental data and making command decisions based on it. The appropriate times for the parachute to open and for the payload to hit the ground were called out. Next was an important milestone: the vibration test. When the rocket fires, the entire structure will be subject to strong vibrations, with amplitudes up to 10 times the force of gravity. Naturally, it is necessary to make sure the experiment and all the rocket parts can hold up under this extreme stress. To check this, the rocket was placed on a special vibrating table that simulated the launch environment. Over the loud rumble of the vibrating table, a high-pitched squeal could be heard from the telescope, caused by resonances in the

Putting FOXSI in space


Be sure to check the Berkeley Science Review blog for an update on how the FOXSI mission fared in November!
RHESSI spacecraft launched.
230 cm

First launch attempt cut short by equipment malfunction.

A cooling system run awry resulted in a few broken detectors, delaying the launch while the experiment was repaired.

The Reuven Ramaty High Energy Solar Spectroscopic Imager (RHESSI) is the current standard in high-energy solar observing. Built at Berkeley, RHESSI's results provided the motivation for the FOXSI rocket. Pictured is a model of the spacecraft in orbit.

FOXSI design commenced.


370 cm

130 cm

12 cm

30 cm

30 cm

170 cm

While researchers and engineers at Berkeley began to design the payload structure, teams in Japan and Alabama started construction of the detectors and optics. Pictured here is a diagram from early in the design phase of the structure that supports and aligns FOXSI.

Jun, 2011 Mar, 2008

Jan, 2012

Mar, 2012

Oct, 2007 Feb, 2002

FOXSI proposal accepted by NASA.

Optics system completed.

The FOXSI proposal was rejected by NASA twice before being approved in late 2007. Funding for scienti c rockets and highaltitude balloons comes from the Low Cost Access to Space program, which selects a few projects to be built and own each year.

The heart of the instrument is a set of grazing-angle X-ray re ecting optics, which were made at NASA's Marshall Space Flight Center in Huntsville, Alabama. Each of the six modules shown here contains seven carefully shaped and aligned mirrors.

DESIGN: HELENE MOORMAN

FEATURES FOXSI

telescope shells. At many times, it was difficult not to anthropomorphize the experiment, and hearing FOXSI scream on the vibration table was one of those times. Everyone held their breath in hopes that the instrument was unharmed, and it was. With a little luck and a lot of hard work, FOXSI will be back in the desert in October of this year for its first launch attempt. The experiment will be launched via a Black Brant Mark II rocket and will fly for a total of 15 minutes. For five of these minutes, the telescope will be in space with an unhindered view of the Sun. FOXSI will aim at two targets: first, it will record the hot, active part of the Sun where most flares arise, as a check of the instruments capabilities. Then the telescope will switch to a less active area, searching for neverbefore-seen X-rays from the quiet regions of the Sun. While most of the excitement lies in the preparation and launch of the instrument, the work does not end there. Launched

FEB 2002: RHESSI TEAM; NOV 2012 & NOV 2014: NASA; REMAIING: FOXSI TEAM

at an almost vertical angle, FOXSI will return to earth within about 60 miles of its launch site. A parachute will slow its descent once it re-enters the atmosphere and a metal crush bumper beneath the telescope will take the brunt of the impact with the ground. Members of the science team will travel by helicopter to recover the rocket and check the instrument for damage. With any luck, the instrument will be recovered in good shape, intact and ready to f ly again.

The future of FOXSI


One of the reasons to hope for a good recovery is that FOXSI is just beginning its life as a solar observer. FOXSIs second flight has been funded and will take place in two years. Sounding rocket experiments can typically be flown several times, with each flight gathering more data or making improvements and upgrades to the instrument. After this adolescence, it is hoped that FOXSI will mature into an orbiting observatory, with

several rocket flights having provided the proof that it is space-worthy. As a spacecraft, FOXSI could study the Sun with a far better sensitivity than any current instrument, and could help us understand how the giant explosions seen in solar flares come about. Evolving FOXSI into a spacecraft is one of the main goals of Krucker and his team. The motivation and idea for FOXSI came from studying data from a previous solar X-ray observing spacecraft, named RHESSI, which greatly advanced our knowledge of solar flares and gave clues about what to look for next. Once FOXSI, now a temporary flame in the sky, has matured into a spacecraft, its results will surely spark new ideas, which will be tested on rockets and balloons. With each of these, young scientists will be trained to build and run a mission. In this way, the cycle of space science continues.

Lindsay Glesener is a graduate student in physics.

Though a rocket mission goes from the drawing board to flight in a few years, it first takes years of work to propose and win a mission. And the work wont end with the launch in November; efforts to put FOXSI on a spacecraft will continue for many years.
Detector system rebuild nished. FOXSI launches.

A completely new detector system (as well as backups) were built and tested in Berkeley, with help from colleagues in Japan. Some additional improvements were added to the payload.

The designated launch date is November 2, 2012, though delays could result from high winds on launch day or failure of any tests prior to the launch. During the ight, the team will watch the instrument data in real time and can send commands to the experiment if any ne-tuning is needed.

2018

Nov, 2014 Aug, 2012 Oct, 2012 Nov, 2012

Potential launch of a FOXSI spacecraft. Testing performed on instrument and rocket.

Alignment and vibration tests ensure that every piece of the experiment and rocket is ight ready. Here, a laser is used to roughly align the optics; the image shown is the laser pattern formed by the optics on a piece of paper.

Eventually, Berkeley researchers hope to build a spacecraft based on the FOXSI experiment. With a sensitivity greater than any current instrument, a "Super FOXSI" could help answer fundamental questions about solar ares and the hot outer atmosphere of the Sun.

Detector system completed.

Planned second launch.

FOXSI's X-ray detectors came from the ISAS institute in Japan, with the readout system and testing done here at Berkeley. A detector is like an X-ray camera that takes pictures of the X-rays that are focused by the optics. Shown here is a board with a detector in the middle surrounded by readout electronics.

FOXSI will y again to gather more solar X-ray data with some upgrades to both the optics and detector systems. Data from the rst ight will provide important feedback on how to optimize the instrument for future ights.

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Manipulative microbes
The invisible invaders that influence guts, brains, and decision making
by Teresa Lee

e all know how complicated our behavior can be. Despite many psychiatric and biological advances in the past century, humans have never completely understood how external or internal forces influence our behaviorour upbringing, diet, parents, and genes have all been implicated in making us do what we do. Recent studies into the millions of microbes that share our bodies may add several (thousand) more culprits to the list. And even though microbes live inside us animals, only some of them are on our side.

Perfectly tailored manipulation


Take the aberrant behavior of an infected ant in the Thai jungle. Normally, a worker ant forages for materials along chemicallydetermined trails in its colonys territory. But when spores of the Cordyceps fungus infiltrate an ants exoskeleton, the fungus begins to take root, feeding on the ants nonessential organs. After a few days, Cordyceps filaments will have grown into the ants brain, driving the ant to commit its last act. It will stagger from its nest, climb a nearby

shrub, and clamp its mandibles onto a leafs vein. This zombie-like behavior is very precise: most infected ants will bite the underside of a leaf about 25 centimeters from the ground on the northwestern side of a planta fortunate thing for Cordyceps, because the conditions in this environment are perfect for the formation and release of spores. The fungus will spread through the ants corpse to fortify its new home by strengthening the ants exoskeleton and producing antibiotics to keep other microbes at bay. Within a few days, a stalk will erupt from the ants head to rain spores upon the rest of the ants former colony members. This gruesome interaction is so sophisticated that it seems precisely tailored for these two organisms. And indeed it is: parasites often alter host behavior in ways that might be benign in other organisms, but are particularly detrimental to the hostusually causing the animals death. Ants infected by roundworms parade in a way that makes them more likely to be eaten by birds. Infection by wasp larvae alters the patterns a spider will spin into its web. Crickets are driven to watery deaths after becoming host to hairworms. The rabies virus increases aggression and salivation in dogs and other mammals before
Fall 2012 Berkeley Science Review

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AMY ORSBORN

FEATURES Microbes

paralyzing their jaws. In all of these examples, the behavioral changes induced in the host ensure the continued survival of the parasite. Michael Eisen, a professor of molecular and cell biology at UC Berkeley, is fascinated by the ubiquity of microbial manipulation. We see examples of parasite manipulation across all taxainsects, shellfish, even llamas can be infected. But whats still lacking is an understanding of how microbes can accomplish some pretty sophisticated things. Some of these parasites are only one single cell, he said. Everyone agrees that behavior manipulation is both fascinating and gruesome, but Eisen believes the most interesting part of these interactions is how finely-tuned each microbes response must be to its host. Along with two graduate students in his lab, Eisen uses molecular techniques to uncover the biological underpinnings of microbial manipulation. One of the labs projects uses familiar laboratory organisms, while the other addresses the role of Toxoplasma gondii, a parasite thats received quite a bit of media attention for its putative role in human behavior.

Do yeast cells lure fruit flies?


The fruit fly Drosophila melanogaster and budding yeast Saccharomyces cerevisiae are two of the most widely studied organisms in biologythey are easy to maintain in the lab, reproduce quickly, and are eminently suited for genetic manipulation. Eisen and his graduate student Kelly Schiabor believe this scientific popularity will make it easier

to discover the mechanisms behind behavioral manipulation. In nature, fruit flies are often found near spoiled or fermenting fruit covered in yeast, which is mysterious because they prefer to eat fresh fruit. Schiabor has shown that laboratory flies have a similar preference for yeast cultures taken late in the fermentation cycle. These late cultures have few nutrients left for either yeast or fly larvae, so there is no apparent reason for flies to be attracted to these late cultures. Schiabor suspects that yeast may secrete chemicals to attract flies under false pretenses. S. cerevisiae cells are particularly sticky. The only hope they have for leaving a nutrient-poor piece of fruit are as stowaways on other animals. But what makes flies land on fruit when its nutrients have already been depleted? Schiabor explains that these microbes cant do too much theyre limited to what chemicals they produce. And it just so happens that late-fermentation cultures tend to give off many aromatic, fruity smells. Flies are lured by the promise behind the scent. Once they land, they realize its not a hospitable environment for larvae. By this point, the flies will be covered in yeast cells, which they can deposit elsewhere in the rest of their travels. The timing of this attraction is particularly interesting: yeast cultures tend to secrete these molecules just before the culture is about to run out of food in its current environment. Since many molecular details are understood in both flies and yeast, Schiabor believes they represent a perfect system

Budding yeast cells are very sticky, latching onto anything that moves their culture. Here, an adult fruit fly is covered in yeast cells expressing green fluorescent protein, after exposure to the cultures in its food plates.

for understanding how behavior can be manipulated. Behavior is one of the last frontiers, she said. I do believe that theres biology behind behavior thats the same from individual to individual. But there are many other factors that can affect even the simplest behavioral circuitthe variation can seem endless and therefore hopeless to untangle. This is what excites Schiabor about her system. If we can figure out how or why a yeast cell can manipulate a fly, think of what that might mean for our understanding of interactions between other species.

Making mice forget their fears


One of the challenges Schiabor faces is finding out whether yeast cells intentionally attract flies. Do they produce fruitysmelling molecules because they want the flies to investigate their culture, or are these simply by-products of their natural processes? Evidence of potential manipulation becomes more apparent when the desires of the parasite are directly at odds with those of its host. Wendy Ingram, another

When the Cordyceps fungus first infects an ant, it sends filaments to feed on the ants organs. After infiltrating the ants brain, this parasitic fungus creates a zombie ant that leaves its colony to climb a shrub and clamp onto a leaf. Here, Cordyceps has spread to cover the ants exoskeleton and extended a stalk from the ants head, which can release spores onto the forest floor below.

FROM RIGHT: PENNSYLVANIA STATE UNIVERSIT Y; KELLY SCHIABOR

FEATURES Microbes

graduate student in Eisens group, is studying a system in which this is exactly what happens. Toxoplasma gondii (Toxo for short) is a parasite that reproduces in the gut of its primary host, the cat. Infected cats shed fertilized Toxo eggs in their feces, which can infect mammals or birds that accidentally eat an egg. Toxo can spend years in a host, hidden in a latent stage, but it will eventually head to the brain of its host. There, it enters neurons and waits. Toxo can only sexually reproduce in cat intestines, so it needs to wait until its host is eaten by a cat. But it is not at the mercy of fateby lodging itself in the brain, Toxo may be able to encourage the premature predation of its host. This seems like a long shot, but researchers have discovered this actually does occur when Toxo infects rodents. In theory, said Ingram, Toxo can get a rodent to walk right up to a cat and essentially deliver its next meal. Uninfected rats have a strong and innate fear of cat smells. When rats are infected with Toxo, they seem to lose their natural caution around predators. In the 1990s, Professor Joanne Webster, an epidemiologist at Imperial College London, was the first to scientifically characterize this behavior. She found that not only did infected rats lose their natural aversion to cat odor, but they may even be attracted to the smell of cat urine. Ingram studies the effects of Toxo infection in mice, which have the benefit of a sequenced genome in addition to wellunderstood behavioral assays. She first demonstrated that infected mice act the same as infected rats. Using urine from an assortment of felines (bobcat, tiger, mountain lion) and other animals (rabbit, hyena), she quantified the different behaviors of infected and uninfected mice. In a cage with a cup of any type of feline urine at one end, an uninfected mouse spends most of its time cowering at the farthest edge of the cage. But infected mice will roam over the entire cage, completely disregarding the presence of cat urine. This is the same response that all miceinfected and uninfectedhave to rabbit or hyena urine, as these animals do not generally eat mice. Combining the many genetic tools available to mouse researchers with some newly developed genetic assays in Toxo,

The Toxo Life Cycle


1 2

After mating in the primary host, Toxo forms these cysts, which are thick-walled spores able to survive outside the host. Cysts are excreted in cat feces and can infect intermediate hosts.

After infecting a host, each Toxo cell will divide asexually into tachyozoites, its motile form. Here, Toxo uses a conoid (the pointed tip at the left) to invade other cells in its host.

Primary host (sexual reproduction)

1 2
Intermediate hosts (asexual reproduction) Unintended hosts (asexual reproduction)

DESIGN: AMY ORSBORN, PHOTOS - 1: CDC, 2: JOHN BOOTHROYD, 3: CAROLINA CAFFARO, 4: YALE ROSEN

In intermediate hosts, Toxo divides asexually to form large cysts in brain, muscle, and liver tissue. Its presence in the brain may allow it to manipulate the behavior of its hosts. Pictured is a Toxo cyst in a mouse brain.

Toxo also infects unintended hosts, like humans. These infections also result in cysts, like those shown here in lung tissue. Humans are exposed to Toxo cysts through undercooked meat or contaminated soil.

FEATURES Microbes

Ingram hopes to uncover how Toxo can negate a mouses potent aversion to predators. There are clearly things about biology that Toxo understands better than we do, she said. Toxo has already proven to be a wily parasiteit can trick the immune system to slip past its hosts blood-brain barrier, which is usually impenetrable to most infecting agents. Last year, Webster and Glenn McConkey, a parasitologist at the University of Leeds, discovered that Toxo has several genes that affect the production of dopamine, a common neurotransmitter involved in signaling pleasure, motivation, and fear. Toxo may also be able to inject molecules into the nuclei of its hosts cells, which could allow it to hijack whether certain genes are turned on or off in those cells.

Does Toxo affect us?


Its natural to wonder whether humans are subject to this eerie manipulation. Many of us have been exposed to Toxoin some countries, more than half the population has been infected, primarily from eating undercooked meat. Although humans

Nasal Oral

The Human Microbiome Project


Dermal

Gastrointestinal

Urogenital

The Human Microbiome Project studies microbial communities found in a variety of sites on the human body.

are not a natural part of Toxos life cycle, we share many genes and molecular pathways with rodents. This makes them useful models for human disease, but it may also leave us susceptible to accidental manipulation by the parasite. If Toxo does affect dopamine production, it could very well play a role in our behavior. Dopamine signaling is involved in many processes, including the powerful neural circuits of fear, pleasure, anxiety, and arousal. Jaroslav Flegr, an evolutionary biologist at Charles University in Prague, believes hes found evidence of Toxo infection affecting human behavior. He conducted personality studies linking infection in humans to an unlikely variety of behavioral traitsintroversion in men, image-consciousness in women, aggression, likelihood of committing suicide, and even attractiveness to the other sex. In 2011, he published a separate study that linked brain damage in schizophrenia patients to Toxo infection. Using MRI machines to scan patients brains, he found that those infected with Toxo had more reduction in brain tissue than uninfected patients. Non-schizophrenics had no significant difference in brain tissue, regardless of their infection status. Of course, many environmental and genetic factors have been associated with schizophrenia, which complicates any role that infection might play in understanding the causes of this disorder. Another of Flegrs studies from 2002 found that people infected by Toxo are at least two times more likely to be involved in a traffic accident. When I asked Ingram about the possibility of Toxo manipulating human behavior, she rolled her eyes and smiled. What people dont mention is that Flegrs study didnt consider whether the infected person was driving the car, or just a passenger, she pointed out. Most of Flegrs studies have only correlated Toxo infection with behavioral changes and correlation, as the mantra goes, does not equal causation. Ingram notes that many of the behaviors associated with infection might actually make someone more likely to be infected by Toxo, rather than being caused by infection itself. We are so far from understanding how behavior works in infected rodents, which are a pretty well-understood system, let alone

even beginning to comprehend what happens in infected humans. She believes that her work on the mechanism behind Toxos manipulation of mouse behavior may help to uncover whether it affects human behavior, but doesnt think the changes will be as straightforward as Flegrs studies claim. I respect the fact that there are microbes that want to use us for their own benefit, she said. It is very possible that this may involve changes in our behavior. The interactions between microbes, our immune system, and our brain are so complex. Theres a lot going on we dont even realize.

What lies within


Although we lack conclusive evidence that Toxo infection affects our behavior, there are still many other likely manipulators that live much closer to home. Humans are host to a huge collection of bacteria and other microbes that are completely integrated into our bodys functions: our microbiome. We like to think of ourselves as ourselves, but we could accurately be described as a mobile scaffold for our microbiome, which technically outnumbers us. Collectively, our microbiome has ten times more cells than our bodies, with perhaps a hundred times more genes than exist in our genome. In the past few decades, researchers have come to believe the relationship between our microbiome and our bodies doesnt just benefit the microbes: it is mutually beneficial, and vital to our health. The bacteria in our intestines make our digestion more efficient, help develop our immune systems, manufacture vitamins, assist in fat storage, and prevent the growth of pathogenic bacteria. Recent work also suggests that our gut microbiome can influence us in more subtle ways, affecting neural development, normal brain function, and even our emotional state. Its easy to dismiss how essential microbes are to our health. Theyre too small to see, and many of the bacteria that live on our bodies have not been cultured or observed in a laboratory. We pay much more attention to the pathogens that harm us than to the beneficial microbes that help us. To better understand our coexistence with this community of microbes, the National Institutes of Health launched the Human Microbiome Project, a five-year

AMY ORSBORN

FEATURES Microbes

The evolving microbiome The ever-evolving gut microbiome


Day 5 Day 10 Day 15 Day 20

The guts of human infants are colonized by microbes during birth, but the community of microbes can change drastically over time. Shown is a graphical representation of the microbial community in the gut of an infant girl studied by the Banfield group. Each square represents a sample taken on the specified day, with colors denoting the twenty most dominant bacterial groups. Researchers noticed periods of relative stability in the microbial community, where one or two groups would be present at much higher numbers than other groups. These were punctuated by abrupt transitions, in which another bacterial group would assume dominance. Its interesting to note that changes to the infants diet after days 9 and 14 were followed by changes to the population of her gut microbiome.

effort to characterize the microorganisms in healthy and diseased humans. Jillian Banfield, a professor of earth and planetary science who studies geological microbiomes (see Germ Warfare, 38), has become interested in the process of bacterial colonization of the human gut. Unlike our genomes, which we inherit from our parents, we do not come with a predetermined gut microbiome. As infants, we accumulate bacteria from our mothers during birth and acquire more diversity in the first year of our lives. Our gut bacteria play an important role in the development of our immune system, helping it learn which bacteria are friendly and which are harmful. In the past decade, drastic advances in DNA sequencing have allowed us to take a closer look at our microbiome. Because its diversity is so complex, it would be impractical to examine bacteria on a speciesby-species basis. Banfields group takes a metagenomic approach to circumvent this difficulty. Metagenomics allows researchers to identify bacterial species in a sample without knowing beforehand which species were present. Researchers can sequence DNA isolated directly from its environmentin this case, infant fecesinstead of relying on bacterial cultures grown in a lab. Itai Sharon, a postdoctoral researcher in the Banfield lab, explained how this works. We isolated the genomes of the entire bacterial population from infant guts and sequenced the same gene16S ribosomal RNA, which is present in all speciesto see how many differences exist in the population. By comparing these

DNA sequences to the ribosomal RNA of known species, the researchers can infer how many types of bacteria are present in the microbial population. Using the number and extent of differences in DNA sequence, they can also identify whether different strains of the same species are present. This is an important distinction: while one strain of bacteria might be helpful, another strain of the same species could be pathogenic. The Banfield group has now examined the microbiome of two infants, taking fecal samples daily during the first few weeks of the infants lives. The interactions between different microbes have proven to be more interdependent and dynamic than they previously thought. A strain of bacteria will achieve dominance in the population only to cede it to a different strain a few days later. Their work, along with other studies reported by the Human Microbiome Project, has enumerated the sheer diversity of our microbial passengers. Our guts carry many beneficial strains, but researchers also found a significant amount of pathogenic bacteria in healthy human guts. Our bodies are just another complex ecological system, Sharon says. As in any ecological environment, he believes that the diversity in our microbiomes will be important for our overall health, rather than which species is dominant at a given time. The Banfield group and others involved in the Human Microbiome Project would like to classify which bacterial species make up a normal microbiome in healthy humans. Knowing what a healthy microbiome looks like may help us understand how

variation in bacterial populations could lead to poor health, both physical and mental.

Ads for your gut ora products tout Thingsyogurt or kombucha do for you: the benefits of probiotic supplements, Ferment and absorb carbs so its fairly common knowledge that the contents repress growth of harmful bacteria of our gut microbiome factor into daily in uencemammals depend on a healthy health. But immune system developme microbiome for and funtion normal development long before they begin eating solid foods. A study preventing allergies (over-reaction of performed in infant mice at the Karolinska immune system) demonstrated that Institute in Sweden has metabolism: synthesis of requires mammalian brain development vitamins, exposure to of ions at crucial stages. absorptongut bacteria(e.g. iron) Mice raised in completely sterile conditions are more active and react differently Diseasesstimuli than control mice,to envilinked to gut: ronmental which cancer--bacteria specific gut microbes. grow researchers exposed to linked to tumor rates differences dwindle when germ-free These mouse pups are bowl to gut bacteria, but in amatory exposeddisease only if they obesity receive this exposure within a certain period in their lives. By the time germ-free mice reach adulthood, exposure to gut bacteria cannot make them act more like the control mice. It seems that microbial interaction has been important for so much of mammalian evolution that even the proper wiring of a mouse brain has come to rely on bacterial colonization of the gut. Gut bacteria can also affect the brains of fully developed animals. In 2011, researchers led by Professor John Cyran at University College Cork in Ireland found that mice that ate Lactobacillusa common bacteria found in yogurtdisplayed fewer behaviors associated with anxiety and depression. As
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How deep does this interaction go?

AMY ORSBORN

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FEATURES Microbes

The multi-purpose microbiome


Our gut microbiome does many things for us:
Digests a tenth of our daily calories. If humans relied only on enzymes produced

by our genomes, many carbohydrates from plant material would be indigestible. Fortunately, enzymes encoded in the genomes of our microbiome are able to break down these complex sugars into nutrients our native enzymes can process.

Trains our immune system. Receiving the correct complement of

microbes during infancy helps our immune system fully mature into the complicated set of organs and cells that can recognize invading pathogens. While the links between our microbiome and autoimmune diseases remain unclear, it seems likely that an unbalanced microbiome may be part of the reason our immune systems turn on the bodys healthy cells.

The cells that line our guts have thousands of protrusions called microvilli, which increases the surface area of our gut lining and absorb nutrients.

by humans. Our microbiome is a valuable source of folic acid (which we can also get from leafy greens) and vitamins B2 and B12 (which we can get from eggs or meat). Because these are water-soluble vitamins they can easily be excreted, so we need to acquire them on a consistent basis.

Provides a source of vitamins. Vitamins are nutrients that cannot by synthesized

opposed to the artificially reared germ-free mice (like those in the Karolinska study), these mice were normal healthy adults that came with a full complement of their own gut microbiome. Lactobacillus ingestion caused these mice to have lower levels of stress hormones in stressful situations and higher levels of GABA, a neurotransmitter involved in anxiety and stress responses. But how can bacteria residing in the gut generate relatively immediate changes in brain chemistry? Cryans group suspected that a likely conduit was the vagus nerve, a meandering nerve that carries information to the brain from the intestine and other internal organs. And in the intestines, only a thin layer of epithelial cells separates nerve endings from bacteria and whatever molecules they produce. As they theorized, when Cyrans group severed the vagus nerve in mice, these animals no longer displayed the anxiety-reducing effects of eating Lactobacillus. If bacteria are involved in determining our mental state, any changes to our microbiomes would have profound ramifications. Pathogens make their presence felt, often in unpleasant ways, and we have developed effective antibiotics to fight them. But these antibiotics also decimate thousands of helpful bacteria in our bodies. One of the infants studied in the Banfield lab took a round of antibiotics during sample collection. There

Not complete puppets


In nature, many examples of behavior modification by microbes are nefarious, causing zombification or death of the host animal. For humans, the data dont support these drastic effects, but research into microbes may uncover some mysterious influences

Teresa Lee is a graduate student in molecular and cell biology.

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LEFT: THE JOURNAL OF CELL BIOLOGY; RIGHT: AMY ORSBORN

were substantial changes in the composition of her gut microbiome, which is similar to what has been observed in adults. After antibiotics, your microbiome never returns to the way it was before, Sharon explained. We cant say yet whether it is necessarily better or worse than before antibiotics, but it is definitely changed forever. Probiotics claim to replenish our gut microbiome, but these consist of only a few bacterial species, which cannot replace the previously thriving and complex ecosystem of our microbiome. One of the hopes of the Human Microbiome Project is to understand how to harness our microbial ecosystem to fight disease. This approach might be able to target pathogens and reduce the side-effects of broad spectrum antibiotics, which are usually a crude solution to specific and identifiable problems. Since beginning this research, Sharon has assumed a different outlook on the role that bacteria play in our lives. Im not really worried anymore when my kids play in dirt, he said.

behind our behavior. We like to think that we control our environment, but in truth, we are as much at the mercy of our environment as any other creature. Although its easy to forget, our environment consists of untold numbers of microbes. It seems like a stretch to blame our behaviors on their influence, but it isnt implausible to think they affect our brain chemistry. At the end of the day, were made up of a bunch of cells, responding in pretty predictable ways, said Schiabor. Signaling pathways are often shared between living things, and molecules produced by bacteria can, and do, interact with our cells. Every animal exists in an ecological context, and humans are no exception: we have evolved along with our microbiome, and these bacteria have become essential to our functioning, while eking out a cozier place for themselves. The environment shapes our development as much as our genes do, and as the Human Microbiome Project makes clear, the influence of the environment might be more proximal than we previously thought. Maybe it helps to think of it as Ingram does: Were not complete puppets, but we do have some strings that microbes can use to pull us in different directions.

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GERM
WARFARE
Bacteria and viruses adapt for battle
by Sam Sternberg

FEATURES Germ Warfare

here is an oft-repeated statistic that the human body is made up of ten times more bacterial cells than actual human cells. Indeed, we live in a world dominated by invisible microbes. Perhaps less well known is the fact that viruses are even more abundant than bacteria in almost every ecological setting on this planet, posing a constant threat to survival of cellular life. As a result, organisms have evolved countless strategies to protect themselves from infection as part of an effective immune response. Just seeing an image of a cell being attacked by dozens of virus particles is enough to appreciate the powerful role that these ancient life forms have played in shaping evolutionary processes. Viruses are biological entities comprising two components possessed by all forms of life: genetic material made from either deoxyribonucleic acid (DNA) or ribonucleic acid (RNA), and proteins that form a surrounding shell to encase and protect the genetic material. By most definitions, however, viruses

Bacteria, natures simplest living organisms, have also evolved a robust innate immune system, an impressive feat given that bacterial viruses, or bacteriophages (meaning eaters of bacteria), represent one of the most common biological entities on Earth. One liter of seawater, for example, contains an average of almost one billion distinct bacteriophage particles. Most bacterial immune defense strategies are fairly well understood and have more sophisticated equivalents in the innate immune systems of higher organisms. Five years ago, however, the scientific community was shocked by reports suggesting bacteria might also possess a highly sophisticated adaptive immune system, one that looked nothing like the immune responses of other organisms. Since then, ambitious research efforts at UC Berkeley and elsewhere have revealed how bacteria maintain rapidly evolving molecular vaccination cards by preserving small chunks of viral DNA in their own chromosomes.

Bacterial viruses, or bacteriophages, represent one of the most common biological entities on earth
are not alive because they cannot replicate on their own. Rather, viruses have been finetuned to hijack the cellular environment of other living organisms in order to access the biomolecules necessary for their survival and propagation. Influenza virus (cause of the common flu), for example, adheres to specific attachment points on the cell surface and, after becoming internalized, transports its genetic material into the cells nucleus. Host enzymes are then co-opted to generate all of the proteins that ultimately lead to viral replication and propagation. Luckily, humans have evolved multiple immune responses to ward off infection. Among these, the innate immune system is the first line of defense, acting non-specifically to recognize and respond to interfering pathogens. The adaptive immune system is far more complex: specific pathogens are remembered so that subsequent infections can be combated with even stronger defenses.

The birth of a field


The central dogma of molecular biology describes the flow of information inside the cell and can be summarized in its simplest form as DNA makes RNA makes protein. DNA is the genetic blueprint of the cell, but because cells usually contain only a single precious copy of DNA, important regions that encode proteins (genes) are first copied into short-lived RNA molecules that are chemically similar to DNA but disposable. Using the genetic code, the sequence information in these RNA molecules is then translated into proteins that ultimately carry out most of the cells functions. Because DNA contains all the instructions that govern cellular physiology, it has been commonly assumed that knowing the entire sequence of a cells DNAits genomewould readily reveal all its inner workings. In reality, genomes are far more enigmatic than originally thought. Many genes

encode proteins whose functions cannot be straightforwardly predicted or experimentally revealed, and certain regions of the genome do not encode proteins at all and have completely unknown functions (See Reading Between the Genes, BSR Spring 2011). The discovery of bacterial adaptive immunity finds its origin in precisely such a region. As early as 1987, scientists first described highly repetitive sequence elements in the genome of the model bacterium Escherichia coli. After a number of independent studies documented similar repetitive sequence elements in diverse species of bacteria, researchers eventually recognized a common theme to these genomic regions and grouped them under an all-encompassing term: clustered regularly interspaced short palindromic repeats, or CRISPRs. As the name suggests, these regions contain long arrays of identical DNA sequences, or repeats, interrupted at regular intervals by intervening sequences, known as spacers. Yet the functional role of CRISPRs remained a source of confusion and speculation for more than a decade. Finally, in 2005, three labs independently discovered that many spacers were in fact identical in sequence to the genomic regions of known phages. This finding suggested the novel possibility that CRISPRs might be the molecular memory of a previously unknown bacterial immune system. Yogurt-producing bacteria held the key. Researchers at Danisco, a prominent food ingredients company, were investigating viral defense strategies employed by the bacterium Streptococcus thermophilus, in the hopes of developing phage-resistant strains that would be less susceptible to infection in large-scale industrial food processes. Working in the laboratory, they discovered something remarkable: after infecting S. thermophilus cultures with one kind of phage, some cell strains developed robust immunity after integrating and thereby preserving a piece of the viral DNA in the CRISPR region of their own genome. A second distinct virus could still kill most of these cells, but again some cells persisted, and invariably, these phage-resistant strains had also inserted a new piece of viral DNA into the CRISPR. Somehow, sequence information provided by these repetitive genomic regions allowed

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TITLE PAGE COPYRIGHT: LEE D. SIMON

FEATURES Germ Warfare

Viral infection begins with a bacteriophage attaching to the outer surface of the cell and injecting its DNA.

ath

Ba
l ria cte

ct er

ial

De

The phage hijacks the cells resources to produce more copies of its own DNA and proteins.

Ba

Im

un ity

Viral infection is blocked through a successful CRISPR/Cas immune response.

Phage particles reassemble and cause the cell to break open during a step called lysis, releasing more viruses into the environment.

repeats

spacers (from viral DNA)

CRISPR-associated (Cas) genes

CRISPR

Cas proteins

CRISPR RNA

the bacteria to both recognize and evade foreign transgressors that they had previously encountered. But the CRISPR alone was not sufficient for this immune response; numerous proximal CRISPR-associated (Cas) genes were also required, indicating that proteins encoded by these genes might act together with the CRISPR to defend the bacteria against infection. Indeed, a second pioneering study published a year later revealed that CRISPRs are actually copied into RNA inside the cell, and that Cas proteins use these RNA molecules to target the destruction of any matching phage DNA. The implication of RNA in this process immediately suggested a plausible

mechanism for CRISPR/Cas function. Since RNA can associate with complementary DNA sequences just as in the two strands of a DNA double helix, CRISPR-derived RNA molecules could be used to identify DNA sequences indicative of an infecting phage and then trigger its destruction. Remarkably, bacteria had achieved an elegant solution to the problem of pathogen detection that relied on nucleic acids instead of proteins, like the antibodies employed by the human adaptive immune system. As with most breakthroughs, these seminal findings provoked more questions than answers and spawned an exciting new area of research in which UC Berkeley has figured

ASAKO MIYAKAWA AND SAM STERNBERG

prominently. In addition to hosting annual, international CRISPR conferences over the last five years, UC Berkeley Professors Jillian Banfield and Jennifer Doudna and their teams of researchers have been at the forefront of the blossoming CRISPR/Cas field. Working in such a nascent field is not an opportunity afforded many scientists, and the potential for discoveries has been vast.

CRISPRs highlight virus-host evolutionary dynamics


Much of what we know about bacteriaphage interactions has been learned from carefully controlled studies in laboratory settings. While invaluable, these experiments
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FEATURES Germ Warfare

Professor Jillian Banfield on-site collecting samples in the Richmond mine at Iron Mountain in northern California. Sequencing the genetic material extracted from this natural environment enabled her and her colleagues to learn how CRISPRs and phages co-evolve.

do not accurately reflect natural ecological habitats and so have limited relevance to real ecosystems, where a single strain of bacteria would never encounter a single type of phage as in the S. thermophilus experiment. In nature, innumerable microbial species are constantly battling diverse mixtures of infectious viruses. As CRISPRs were identified in laboratory strains of bacteria, researchers began wondering how CRISPRs and phages function and evolve in the wild. Banfield (see also, Manipulative Microbes, 30), a faculty member in the Departments of Earth & Planetary Science and Environmental Science, Policy, & Management, has made substantial contributions to the field of geomicrobiology, the study of how natural environments and microorganisms interact. In the early 2000s, Banfield began pioneering a new approach in the study of microbial diversity in ecological niches. Traditional methods were limited by the requirement for laboratory isolation of genetically identical strains from natural environments, but Banfield and her team of researchers recognized that the advent of inexpensive and robust DNA sequencing technologies offered a powerful alternative. By recovering all genetic material contained in environmental samples and sequencing hundreds of thousands of random DNA fragments from this heterogeneous mixture,

the genomes of numerous microorganisms and phages from the sample could be reconstructed in parallel with the help of powerful computer algorithms, an approach called metagenomics. In addition to shedding light on the species diversity in these samples, this technique could also reveal highly mutable regions within a single species since the sequenced pieces of DNA originate from non-identical strains. Examining microbial populations rather than single isolates is particularly critical since CRISPR regions can be extremely diverse within a population, explains Christine Sun, a PhD student in the Banfield laboratory. In some cases, different cells from the same bacterial species have acquired completely unique sets of spacers to mediate CRISPR immunity. The ecological importance of CRISPR/ Cas immune systems in shaping virus-host dynamics was immediately revealed by Banfields work. On the host side, bacterial CRISPR regions evolved on extremely short time scales, even faster than the natural accumulation of mutations that invariably occurs during DNA replication. By rapidly integrating new fragments of viral DNA into the CRISPR, bacteria were able to continuously mount an effective immune response against phages in their environment. Just as surprising was the finding that viruses similarly evolved an effective strategy to evade the

CRISPR immune system. Through a process called homologous recombination, phages had shuffled large chunks of their genomes with other phages in the community to effectively rid themselves of the very sequences matching spacers in the CRISPR regions, enabling them to still trigger a successful infection. Collecting samples from different time points further enabled Banfield and her colleagues to observein real timehow both virus and host evolved over the course of months and years. When asked about the relative advantages of her work as compared to more controlled laboratory experiments, Banfield stresses that the phage-host interactions that rapidly generate diverse populations make sense in the context of complex natural systems. This diversity is ultimately required for the long-term survival of both populations. More recently, Banfield has teamed up with Professor Wayne Getz of the Department of Environmental Science, Policy, & Management, to build a more complete picture of the evolutionary dynamics shaping CRISPRs using a combination of metagenomics and population-scale mathematical modeling. Taken together with other work, this study helps to explain the long-term advantages of maintaining such an elaborate immunological memory in microbial CRISPR regions.

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ERIC RAMAHATRA

FEATURES Germ Warfare

Inner workings of CRISPR/Cas immune systems


The work of Banfield and others established that CRISPRs evolve rapidly in natural ecosystems, and that these genomic regions also require CRISPR-associated genes to confer viral immunity. But Doudna, a joint appointee in the Departments of Chemistry and Molecular and Cell Biology, wanted to know what molecular mechanisms achieve this objective inside the cell. What biomolecules are involved, what do they do, and how do they work together to efficiently recognize and mount an immune response against infecting phages? Such questions are left to the domain of biochemists and molecular biologists, who rely on purified systems studied in vitro (literally in glass, i.e. test tube experiments) to tease out the biochemical steps that underlie a biological outcome. Doudna has spent her career investigating the molecular structures and functions of various kinds of cellular RNA molecules. With early reports documenting a critical role for RNA in CRISPR/Cas immune systems, her lab was an ideal setting for studying

the molecular details of this pathway, though Doudna credits Banfield for initially setting her on this path. Jill brought the system to my attention six years ago, before there was any evidence for the molecular mechanisms involved. She suggested that my lab would be able to conduct biochemical and structural biology experiments to dissect the function of CRISPRs, and weve been having fun doing this ever since. To appreciate the contributions made by Doudna and her team of researchers (including this author), one must first be familiar with the three stages of CRISPR/ Cas immune system function (see illustration below). In stage oneadaptationan infected bacterium, faced with imminent death, pilfers a small piece of the phage DNA and integrates it into one end of the CRISPR region in order to quickly mount an immune response before its too late. During stage twoCRISPR RNA biogenesisthe entire CRISPR region is copied into long RNA molecules, which are precisely chopped into smaller pieces by an enzyme called a ribonuclease; each mature, processed CRISPR RNA molecule contains one unique spacer

sequence encoded by the CRISPR. Finally, during stage threeinterferenceadditional Cas proteins interact with each CRISPR RNA molecule to form large surveillance complexes that search for DNA sequences in the cell that are complementary to the CRISPR RNA. If such sequences are detected in foreign DNA such as that originating from a phage (the CRISPR DNA is excluded during this step), Cas enzymes degrade the targeted DNA and the phage is disabled. Having previously made significant advances in our understanding of ribonucleases involved in a process known as RNA interference, Doudna was naturally drawn to analogous Cas ribonucleases involved in CRISPR RNA biogenesis. In particular, she wanted to better understand how a single enzyme could selectively cut the long CRISPR-derived RNA into smaller pieces, at a defined location, while leaving other cellular RNA molecules untouched. To answer this question, her team needed to visualize the biomolecules at high resolution, and because proteins and RNA are too small to see by light microscopy, they turned to a technique known as X-ray crystallography.

Viral DNA

2. CRISPR RNA Biogenesis 1. Adaptation 3. Interference

The CRISPR/Cas immune response proceeds in three stages: fragments of viral DNA are inserted into CRISPR regions during adaptation, CRISPR RNAs are produced and processed during biogenesis, and complementary viral DNA sequences are targeted and destroyed during interference.

ASAKO MIYAKAWA AND SAM STERNBERG

CRISPR RNA

CRISPR-associated (Cas) genes

CRISPR

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FEATURES Germ Warfare

Doudna and her team were the first to visualize detailed interactions between a Cas ribonuclease and CRISPR RNA by determining atomic-resolution, three-dimensional images of the protein-RNA complex. These images revealed that each repeat sequence of the long CRISPR RNA molecule folds into a characteristic hairpin shape that is perfectly complemented by the shape of the Cas ribonuclease, allowing the two biomolecules to form a tight binary complex. Furthermore, their data revealed that specificity for the correct RNA sequence is provided by a set of energetically favorable hydrogen bonds between the two molecules, ensuring that only this RNA sequence is cut by the ribonuclease. Subsequent work from Doudna and her colleagues revealed that similar strategies of RNA recognition are conserved in numerous other bacterial CRISPR/Cas immune systems, demonstrating the evolutionary importance of this proteinRNA interaction. The work leading up to a high-resolution structure determined using X-ray crystallography is challenging and time-consuming, so a successful result often leads to considerable excitement. It has been fantastic to see the three-dimensional structures of these biomolecules for the first time, says Doudna. I still get chills down my spine each time a discovery like this is made. The first objective of the approach is to grow well-ordered, microscopic crystals of the biomolecule(s) of interest, something that occurs serendipitously and only through trial and error. After countless rounds of optimization, the crystals are exposed to high-energy X-ray beams such as those produced at the Advanced Light Source synchrotron at Lawrence Berkeley Laboratory, and interactions between the X-rays and electrons from the biomolecule lead to diffraction patterns that are collected by a camera. Finally, the three-dimensional position of each atom in the biomolecule is calculated from the raw data using advanced mathematics, producing the final model that describes the precise shape of the molecule. To the frustration of many researchers, however, some biomolecules are simply intransigent to X-ray crystallography. Blake Wiedenheft, a former post-doctoral fellow in the Doudna laboratory who is now an assistant professor at Montana State University, found himself with this problem. When

I first started in the Doudna lab, one of my primary objectives was to get a highresolution structure of the protein-RNA complex that mediates the interference stage of the CRISPR/Cas pathway. I threw everything but the kitchen sink into this project, but five years later we still have not found crystallization conditions suitable for generating well-behaved crystals. So Wiedenheft took advantage of two other powerful techniques at his disposal in the Berkeley community that do not require crystal growth: small-angle X-ray scattering (SAXS) and electron microscopy (EM). Like X-ray crystallography, these approaches can provide three-dimensional images of biomolecules, though the lower resolution renders atomic-level detail invisible. I initially determined the first three-dimensional structures of the protein-RNA complex using SAXS, explained Wiedenheft. Later, I teamed up with Gabe Lander, a post-doctoral fellow in the laboratory of Eva Nogales [also at UC Berkeley], and we froze these complexes in ice and analyzed them using cryogenic EM. The first images of the complex with this approach were stunning. In addition to revealing how each protein component of the complex interacts with the CRISPR RNA, these structures, in conjunction with other experiments, showed how matching DNA sequences are recognized and marked for destruction by other Cas enzymes.

Collaboration is a must
Speaking of his research on CRISPR/ Cas immune systems while at UC Berkeley, Wiedenheft is quick to stress the importance and influence of his colleagues. The atmosphere of the Doudna lab was enthusiastic, intense, and stimulating, and my collaborations both within and outside of the lab were critical to my success. Wiedenheft added that the rapid progress in the CRISPR field is largely due to intellectual contributions from research groups with diverse backgrounds. In fact, if youve spoken with anyone studying CRISPR/Cas immune systems, then youve undoubtedly heard about the importance of collaborative research. Evidently the stereotype about scientists working in isolation does not apply here. David Pez, a post-doctoral fellow in the Banfield lab, couldnt agree more. It is very important to collaborate in our field. Combining information from bacterial isolates, metagenomics, mechanistic studies, and computational models is critical to future discovery. Having arrived at UC Berkeley with a background in molecular biology, Pez challenged himself to switch gears and develop the skills necessary for metagenomic research. But instead of working only with natural ecosystems, Pez teamed up with some of the lead authors on the groundbreaking S. thermophilus study to apply a metagenomic approach to isolated cultures challenged with phage. Rather than focusing on species diversity, millions of DNA sequencing reads from individual S. thermophilus cells were instead used to learn about what regions from the phage genome are chosen for insertion into the bacterial CRISPR during an infection. We are able to recover the CRISPR content of hundreds of thousands of cells with different immune system potentials on a daily basis using time-series experiments, to reveal underlying trends in spacer acquisition patterns, explains Pez. By blending experimental approaches used by the Banfield lab and Danisco (now DuPont), Pez and his colleagues are deciphering the mechanistic details of the adaptation stage in living bacteria. Although collaborations can and do happen between scientists separated by large distances, it certainly helps to have

The three-dimensional structure of a Cas ribonuclease bound to a piece of CRISPR RNA was determined using X-ray crystallography and revealed the atomic-level interactions that confer specificity. Hydrogen bonding interactions between the protein and RNA are indicated by dashed lines.

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SAM STERNBERG

FEATURES Germ Warfare

The protein-RNA complex involved in the interference stage of CRISPR/Cas immunity was imaged with this electron microscope (center), which enables 100,000x magnification of cryogenically frozen samples. Involved in the research collaboration were, from left to right, Blake Wiedenheft, Eva Nogales, Gabe Lander, and Jennifer Doudna.

an international meeting to bring everyone together once a year. Rachel Haurwitz, a recently graduated PhD student from the Doudna laboratory, has a unique perspective on the topic; she is one of the few individuals who has attended all of the five annual CRISPR conferences at UC Berkeley to date. It has been quite exciting to watch the CRISPR field grow rapidly over the past five years, says Haurwitz. Despite its growth, though, the field has remained cordial and tight-knit. It seems that nearly everyone is collaborating with someone else, and the CRISPR conferences have been an integral part of making those personal connections. I hope they will continue for many years to come.
ROY KALTSCHMIDT

What the future holds


Far from peaking in interest, CRISPR/ Cas immune systems continue to attract

new scientists and students. Its easy to get excited about a field when its so young, says Megan Hochstrasser, a new graduate student in the Doudna lab. There are always fresh questions to ask, novel mechanisms to elucidate, and new techniques to try. Our understanding of CRISPR systems advances almost daily, and its great to feel like youve gotten in on the ground floor. A brief survey of the literature also attests to the steady increase in academic research efforts, as the number of CRISPR-related publications has risen exponentially ever since its initial discovery. The coming years will undoubtedly bring a deeper understanding of the CRISPR/ Cas bacterial immune system, both in how it plays out in natural environments and in the molecular details of its function. But slowly, new initiatives are surfacing that aim to develop the knowledge from basic research

for completely distinct purposes. I think the field has naturally split in two directions, says Haurwitz, focusing in parallel on basic aspects of the biology underlying CRISPRs and on potential applications of the CRISPR/Cas system. As to the kinds of applications we can expect, Pez has some ideas. Information from model systems will be used towards improving industrial processes [such as dairy cultures or microbial biofuel production], bacterial strain identification, and most probably in synthetic biology, he says. An illuminating example of a promising synthetic biology application can be found in a recent study published in the journal Science by Doudnas group and colleagues at Ume University in Sweden. While characterizing the CRISPR interference stage in a subset of bacteria, they stumbled upon a Cas enzyme that could be engineered to generate precise cuts in both strands of a DNA double helix at any desired position, as specified by the CRISPR RNA sequence. Scientists hoping to cure genetic diseases through site-specific genome editing have long sought designer enzymes with this functionality, but until now, every new gene target has required a complete re-engineering of the enzyme, an arduous task. In the case of the Cas enzyme, though, only the RNA sequence needs to be modified, an adjustment that can be made practically overnight. Time will tell if the full potential of this enzyme in genome editing is realized, but one thing is certain: no amount of foresight could have predicted that a bacterial immune system might offer so much biomedical potential. Perhaps hereat the intersection of pure science unadulterated by utility, and engineering pursuits motivated by everyday problemsdo we find research at its most exciting. As Haurwitz puts it, neither of these research directions happens in a vacuum. Basic research feeds into the applications, and knowledge learned from the applications feeds back into the basic research. Both ventures will surely keep UC Berkeley scientists engaged in this microbial battle for years to come.

Sam Sternberg is a graduate student in chemistry.


Fall 2012 Berkeley Science Review

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f aculty profile
T
he work of a scientist can be a bit of a random walk. We are always moving in some general direction, but we need to allow for turns of events, to be able to react when suddenly an opportunity appears, says Carlos Bustamante, professor in molecular and cell biology, physics, and chemistry at UC Berkeley. Bustamante has experienced many of those turns in the course of his career. Born in Peru, he initially went to medical school, but then decided to pursue an academic research career. After obtaining a masters degree in biochemistry from San Marcos University in Lima, Peru, he moved to UC Berkeley to pursue graduate studies in biophysics under Professor Ignacio Tinoco. Bustamante is best known for his work in the single-molecule field, using optical and magnetic tweezers to manipulate molecules such as DNA and proteins, one at a time, and measure the forces they generate. In the Bustamante lab, single-molecule methods have been used to follow the step-by-step movements of molecular motors as well as the folding and unfolding events of single proteins. More recently, the Bustamante lab has entered the field of synthetic biology and is working towards creating a living organism by furnishing mitochondria with the genes that might make them independent from their host cells. Mitochondria are energygenerating organelles that are found inside the cells of all eukaryotic organisms such as plants, animals, and humans. They are thought to be descendants of a bacterium that was engulfed by another cell at some point during the evolution of life. Since then, mitochondria have lost most of their genes and cannot live independently anymore, but rely on their host cell for survival. Research in the Bustamante lab aims at reintroducing the essential genes into mitochondria that will make them independent once again, to gain a better understanding of the minimal set of genes that constitutes life. Here, Bustamante discusses the motivation for his research, his efforts to promote cutting-edge science in South America, as well as the implications of seeking to create life in the lab. SK : What got you interested in science? CB: I was interested in science very early on. When I was only 11 years old, I was already playing with rockets with my friends, and I also had a chemistry set and fell in love with the microscope. When I was about 12, I happened to open one of my fathers books, an autobiography of Ramon y Cajal, the Spanish neuroscientist. I was fascinated that he had developed a staining method for neurons [the Cajal stain], and that motivated me to develop a Carlos stain for onion skin. By playing with my chemistry set, I was able to develop a stain for the nuclei of the cells. I was very proud that I had launched my career in this fashion! But, although I was interested in science early on, I knew my parents expected me to become a physician, and I wanted them to be happy. SK : How did your parents react when you decided to do something else and not study medicine? CB: I did go to medical school initially, but then I took biochemistry in my third year, and this really changed my life. It was exactly what I wanted to doto understand how things work at the molecular level. Of course I realized that if I were going to be a physician, I would have to stop thinking that way and instead solve the patients problems. At the end of the third year, when my friends started working in hospitals, I decided to stay in a biochemistry laboratory for the summer, and that experience convinced me that what I really wanted was to do science. My parents were very understanding, and it just happened that at the moment I was quitting medical school, the university in Lima introduced a masters degree in biochemistry. I was able to validate all my credits, take some more courses, complete a bachelors degree in biology, and then enter the masters degree program in biochemistry. It was quite an unusual student career. SK : You have been involved a lot in science outreach, particularly in Latin America. Could you tell us more about that? CB: Its not likely that either myself or my colleagues who left Peru will return, now that we have already established our lives and careers in the United States or Europe. But I thought that what we could do is to create laboratories similar to our ownI call them twin labsin Peru, and maintain an umbilical cord to the original laboratory here in Berkeley through collaborations. Right now, I have eight students at the university in Lima. They have an atomic force microscope and an optical tweezers instrument. People sometimes wonder why single-molecule studies, which are a very advanced technology even for the first world, should all of a sudden be done in Peru. But thats the whole point! By establishing a twin laboratory in Peru, I am creating conditions in which things that

Mitochondria are energy-generating organelles that rely on their host cell for survival. Researchers in the Bustamante lab work towards making them independent once again by introducing the genes they may have lost during evolution.

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MITOCHONDRIA: LOUISA HOWARD; PORTRAIT: MAREK JAKUBOWSKI

Carlos Bustamante
Re-creating life in the lab
by Susanne Kassube

FACULTY PROFILE Carlos Bustamante

I dont think we are playing God. I think we are playing scientists. We are just doing what a scientist is supposed to do, which is to ask questions.
could not happen otherwise are beginning to happen. I am doing a pilot experiment to see if we can create first-rate science in South America. I am lucky in having funding from different sources, but without that, it is a lot harder. I hope that the [Peruvian] government will contact selected scientists abroad and create a program to help them establish a laboratory in Peru at a university of their choosing to train people in their area of expertise. Within five or 10 years, we might be able to change the nature of research and technology in Peru completely. The country invested a lot in my education, and I would like to pay back something to that society. SK : You are considered a pioneer of single-molecule biophysics. How did the single-molecule field come about and what motivated you to go into that direction? CB: In 1981, John Hearst, professor in chemistry here at Berkeley at the time, attended a Cold Spring Harbor [Laboratory] symposium where a Japanese researcher showed that it was possible to see molecules of DNA with a fluorescence microscope by staining with ethidium bromide, a dye that becomes more fluorescent when it binds to DNA. When he came back to Berkeley, he told us all about it. I was incredibly fascinated by these experiments, but by the time the conference proceedings were published in 1982, I was leaving for New Mexico to start my own lab. All I did was photocopy the article and throw it into the trunk of my car. For the next two or three years, every time I opened the trunk, the paper reminded me of what I really wanted to do. But I was busy with many other things at the time: I was trying to get tenure, building my laboratory, getting new graduate students, building the machines, and teaching for the first time as a professor. However, when I received the Searle scholarship in 1984, I was able to buy a fluorescence microscope, and since the department was putting me up for tenure early, I decided that I could now concentrate on something that would be fun to do. When we repeated the previously published experiment, we could actually see the molecules of DNA dancing around. We were filming all of this, and while I was watching the movies, it became clear to me that I wanted to study the mobility of molecules in a gel during electrophoresis, and try to understand how DNA molecules separate when they move through a gel. During these experiments, we could see that DNA molecules were enormously elastic. From here, the next idea was just a very short jump: how about grabbing one of these molecules at the end and pulling it to determine how much force we have to apply in order to stretch the molecule? In order to do this, we attached one end of the DNA molecule to the coverslip and then a bead of glass to the other end, and used its weight to test the elasticity of the DNA. This is essentially the classical spring experiment, except that in our case the spring was a molecule of DNA and the weight was a microscopic bead of glass. We obtained the first curve of the elastic behavior of DNA that showed that the molecule of DNA was a non-linear spring. It soon became clear that we could manipulate single molecules to learn about their properties. SK : What are the advantages of singlemolecule over bulk studies? What information can be obtained that is not accessible through other methods?

CB: In a way it is a little unfair to knock down bulk methods. Most of what we have learned in chemistry and biochemistry has been done in bulk, by averaging everything that is going on in a solution over the entire population of molecules. Theres nothing wrong with that approach, except that the average may not always be a well-behaved entity. There is probably no molecule in the solution that is behaving exactly according to the average: some molecules react early, others late. Therefore, what you record when you follow a chemical reaction in bulk is a deceitfully clean signal, which chemists have agreed to call kinetics. By using bulk methods, you study the movement of the mean of the population, and therefore a lot of information is lost. You can easily see that in a population of chimpanzees, on average, each member of that population has one testicle and one ovary. This is mathematically correct, but biologically, physiologically, and experimentally, empirically incorrect. In other words, an average can lead to errors, and those errors in interpretation may hide information that is crucial. It is essentially the same with molecules. A lot of insight can be gained by observing the actual trajectory of a molecule undergoing a chemical reaction: how does a single molecule go from A to B, how does it react, and how does it interact with other molecules? SK : As the single-molecule field matures, what are the challenges and big unanswered questions? CB: I think the challenges are that we have to learn how to study ever more complex systems. As a biophysical technique, single-molecule studies are always better done in vitro: we want to make quantitative measurements, and in order to do so

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Fall 2012

FROM TOP; MAREK JAKUBOWSKI; KELLY CLANCY

FACULTY PROFILE Carlos Bustamante

we have to have control over the variables that determine the behavior of the system. The ultimate hope is that one day, we will learn to manipulate biological molecules inside the cell. That poses a lot of problems and challenges because the cell is not a very controlled environment. You have 5,000 different chemical compounds inside a cell surrounding your molecule, so part of the problem is to figure out how to make quantitative measurements when we do not have control over 4,999 variables. SK : More recently, you established a research focus in synthetic biology. What got you initially interested in doing that? CB: I think that bio-scientists never get away from the awe of the living phenomenonor at least, we shouldnt. And I think that this is probably ultimately the most central question of biology: what leads to the living state? What makes matter organize itself to the point that it can reproduce and be capable of control and growth and obtain memory? I think it would be wonderful to be able to build a cell from scratch, but this is a very long shot. Therefore, the idea I had was to start halfway, by using a mitochondrion and re-engineering it in such a way that it re-gains the functions

that it presumably lost throughout evolution. We are using the mitochondrion as a chassis, and putting genes back into it. It is not easy to do that, as we have learned during the last three or four years. It is a big idea, but it is also a tough idea, like all big ideas. SK : So you think it will be possible to create life in the lab in the limited sense of the expression? CB: Yes, I think so. I dont know in how many years, and I dont want to make a prediction, but I think that maybe in a hundred years, two biologists will meet here in Berkeley and one will tell the other, Weve recently been working with a new system we just put together, and it actually has very funny properties. And they will not be talking about what exists in nature. They will be talking about what they have made in the laboratory. And that would make biology truly synthetic. SK : Many people are skeptical about the idea of playing God for either ethical or biosafety reasons. How do you address these concerns? CB: I am perfectly in agreement with the need to be careful from the point of

biosafety. We do not want to be Dr. Frankenstein. However, I dont share those ethical concerns because I dont think we are playing God. I think we are just playing scientists. We are just doing what a scientist is supposed to do, which is to ask questions and try to understand. There was a point in chemistry where scientists stopped studying molecules that already existed in nature, and started making molecules that never existed before. Were they playing God? SK : Most people would probably say no. CB: No, they were just being chemists. And the same is true with biological systemswe are only trying to understand how they work. I think the issue of God and the issue of religion should be very personal and individual, but under no circumstances is it acceptable that we say that we do not want to know. That is against human nature. As long as we take care of the safety aspects of our experiments and observations, we are always better off knowing than not knowing.

Susanne Kassube is a graduate student in biophysics.

your click your pick.


Readers Choice Award
FEATURES FOXSI

MOFiosos
new class of material called metalorganic frameworks has injected a surge of energy into the scientific community. These materials are novel because they allow scientists to rationally design of nanometer-scale environments, and with this control of empty space comes the ability to control chemistry of any molecules trapped inside. Chemists around the world are racing to make the newest, most powerful versions, often with the goal of using them to end greenhouse gas emissions. Among metal-organic framework (or MOF) scientists in Berkeley and around the world, however, the benefit of MOFs to society is up for debate. While they certainly have furthered our understanding and control of the chemical world, MOFs have yet to be used to fix outstanding global issues, for example by curbing the release of greenhouse gases. What remains to be seen is how this balance between fundamental and applied contributions will shift in the future. At UC Berkeley, professors Berend Smit, Jeff Long, and Omar Yaghi have devoted

thing, and definitely not trying to create a new field of chemistry. He was simply trying to make materials that were beautiful. In the ensuing years, thousands of MOFs have been made and new bells and whistles are added to them daily. Some can bend or stretch or even incorporate movable parts that can be made to spin on command. Many are highly colored and researchers have taken advantage of this by designing MOFs that will only change color in the presence of toxic molecules like cyanide. Metal-organic frameworks do their jobs by bringing order to the chaotic realm of small molecules. Ask yourself, what would it take to capture and store a gas like carbon dioxide, to stop it from entering the atmosphere, or hydrogen for use in a zero-emissions vehicle? Now imagine a nano-scaled scaffolding (like at a construction site) that can catch, or release, these small molecules one at a time as they flow through the cages and pores. Metal-organic frameworks are exactly this: perfectly repeating cages

filled with empty spaces that are around 10 nanometers acrossjust the right size to trap a few small molecules. As a result, they represent a new era in materials chemistry in which empty space can be designed for a purpose, applied or fundamental. After the first few reports that we made on MOFs where we showed they were indeed porous, and things could be put into the pores and taken out without collapse of the framework, I think it got the attention of a lot of people, says Yaghi. MOFs are made of two types of building blocks, linkers and nodes. The long linkers are organic molecules, strings of carbon and hydrogen decorated with oxygen or nitrogen. These have at least two arms that preferentially bind to positively charged metal ions. (Metals occupy a broad swath of the periodic table, from sodium in one corner to livermorium in the other [see livermorium labscope].) The metals form vertices, or nodes, between the organic linkers, making an infinite, repeating structure.

FOXSI fires up
Sounding rocket mission looks at solar flares
by Lindsay Glesener

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Spring 2012

Berkeley Science Review

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NASA

much of their careers to metal-organic frameworks, and each has his own perspective on the debate between the fundamental and applied benefits of the field. We are fortunate in MOF chemistry, says Yaghi. In studying MOFs, he feels he can approach chemistry from a fundamental perspective, let the applications materialize on their own, and then pursue these applications. We have a responsibility as scientists to be thinking about benefiting society. In this case, weve done that. But his approach has never wavered from a purely fundamental one, despite the fact that he doesnt forget about his obligation to the greater good. We sometimes lose sight that the most difficult problems facing society are often solved by those of us who push the frontiers of knowledge, often without having a societal problem in mind. In contrast to Yaghis primary approach to MOF research, he directs the chemists who work with him in many different directions. Dr. David Britt, a staff scientist working on a new project of Yaghis, explains that since

2008 there has been a surge of research in [greenhouse gas capture], but no single group has all of the resources necessary to find a solution. It is my goal to make [my] MOF program a hub for addressing this type of complex problem. These two perspectives, Yaghi focusing on fundamentals and Britt on applications, represent examples of two extremes. In between lie many other researchers. For example, Berend Smits drive in research is toward problem solving. Smit feels that the difference between applied and fundamental is overrated. The intellectual challenges in applied questions and fundamental questions can be equal. Due to these varying approaches, MOFs can be used as a lens to examine the role of fundamental and applied chemistry research in academic laboratories.

Berkeley scientists make carbon a structure it cannot refuse


by Zoey Herm
LEAH ANDERSON

n the Tularosa desert basin in New Mexico, not far from the White Sands National Monument, a fireball occasionally lights up the sky, climbing higher and higher until it is lost to the observers eye. Out of sight, the rocket climbs to a height of 300 kilometers, over 30 times higher than a passenger airplane, and escapes the atmosphere before plummeting back to the grounds of the White Sands Missile Range roughly 15 minutes after its launch. There, a team of scientists eagerly awaits its return. This story has played out in the New Mexico desert hundreds of times over the last half-century, and quite often the waiting scientists are from Berkeley. This will be the case for an upcoming launch in November 2012, when researchers from UC Berkeleys Space Science Laboratory will fly an experiment called the Focusing Optics X-ray Solar Imager (FOXSI) onboard a sounding (meaning, exploratory) rocket from White Sands. FOXSI will attempt to produce the most sensitive X-ray observations ever made of the Sun using onboard telescopes and cameras. As a graduate student on the FOXSI project, it will be my job not only to perform several scientific tasks, but also to chronicle the preparations and f light for posterity. This article will offer a look at the history of Berkeley rocket science and show what it takes to get an experiment into space.

A better vantage point


Almost five years of instrument design, assembly, and testing will culminate in FOXSIs 15-minute rocket flighta significant investment for just a few minutes of data. Yet, for scientists intent on highaltitude experiments, sounding rocket flights are highly sought-after. For astrophysicists, many useful tools are simply not available at ground level. The earths atmosphere blocks radiation in many parts of the electromagnetic spectrum, including gamma rays, X-rays, infrared, and some ultraviolet wavelengths. (This is crucial for the presence of life on Earth, since much of this radiation would cause tissue damage.) For highsensitivity solar X-ray studies, for example, astrophysicists must send their experiments high above the atmosphere to find an unobstructed view of the Sun.

MOF Chemistry 101


Omar Yaghi is widely known for publishing the first report of metal-organic frameworks in 1999. But he has always stated that he wasnt ever searching for the next big

Compared to building a spacecraft, rockets offer a faster and cheaper way to put an experiment into space, albeit for a shorter length of observing time. Scientific rockets are funded by NASAs Low Cost Access to Space program, which offers the opportunity to f ly a suborbital project with a construction time of only a few years, at a fraction of the cost of a spacecraft. NASA describes the program as a lowcost testbed for new scientific techniques, scientific instrumentation, and spacecraft technology that may eventually end up on satellite missions. Many astrophysics experiments do indeed use rocket flights as stepping stones to spacecraft status. In order to win a NASA spacecraft proposal, investigators must prove that all the parts of their hypothetical instrument will work. In some cases this means proving an entirely new concept, in others it means demonstrating that an established technology can withstand the tough physical environment of space. One way to demonstrate that technology is space-ready is to send it there, if only for a few minutes. Rocket-tested technology has formed the basis for hundreds of NASA satellites, past and present. Sometimes spacecrafts and rockets fly simultaneously: for example, after the Solar Dynamics Observatory spacecraft was launched in 2010 several rockets were f lown to improve the calibration of one of its instruments. (Videos of these rocket launches, including footage from an onboard video camera, can be found at http:// lasp.colorado.edu/home/eve/2010/05/03/ nasa-36-258-sdo-eve-calibration-rocket/.) But not all science experiments on rockets gaze at otherworldly objects. Atmospheric and plasma physicists use rocket f lights for in-situ measurements of the ionosphere and thermosphere plasma, data that is not available to either a ground-based observatory or a spacecraft. Microgravity experimenters also make use of the rockets freefall to measure the behavior of physical and biological systems in a low-acceleration environment. Finally, another important scientific component developed by means of rocket experiments is the scientists themselves. Rocket f lights have typically been used to

train students as physicists and engineers. The short time scale of a rocket project, as well as its greater risk tolerance, allows a PhD student to see a project through from beginning to end and be involved in all aspects of the project, including the design phase, building and testing of the instrument, the f light itself, and data analysis.

The story of science rockets


Rockets certainly werent invented just to suit the whims of scientists who wanted to get their experiments into space. The evolution of space rocketry is intertwined with that of military rocketry. Rudimentary military rockets were built almost as soon as gunpowder was discovered, and solid-fuel rockets were used in battles throughout the 1800s. But by the early 20th century, rockets began to excite the human imagination as a way of turning science fiction into reality, by exploring space. In the 1920s Hermann Olberth, a German physicist, proposed that rockets could be used to either place artificial satellites around the Earth or to escape the Earths gravitational field entirely, and thus could serve as a useful tool for space exploration. Around the same time in the U.S., Robert H. Goddard experimented with liquid fuels, stabilizing systems, and multiple stages, the building blocks of space-capable rockets. For this work, Goddard would later become known as the father of modern rocketry. It didnt take long for military personnel to realize that these principles would also be useful for building powerful weapons of war. Throughout the 1930s, aggressive rocket development programs took place in several countries, particularly in Germany. A large and well-funded team of rocket scientists led by Werner von Braun developed the V-2, a liquid-fuel, singlestage military rocket. The V-2 was used against several Allied targets in World War II and in 1944 became the first manmade object to f ly into space. The end of the war marked an important turning point for space rocketry. The U.S. competed with other Allied forces for custody of captured V-2 rockets, along with their creators. German rocket experts, having surrendered to the Allies, immigrated to the U.S. and continued development of rocket systems (the U.S.s secret
Spring 2012 Berkeley Science Review

Manipulative microbes
The invisible invaders that influence guts, brains, and decision making
by Teresa Lee

!"#$%
&'#('#"%
Bacteria and viruses adapt for battle
AMY ORSBORN

e all know how complicated our behavior can be. Despite many psychiatric and biological advances in the past century, humans have never completely understood how external or internal forces influence our behavior our upbringing, diet, parents, and genes have all been implicated in making us do what we do. Recent studies into the millions of microbes that share our bodies may add several (thousand) more culprits to the list. And even though microbes live inside us animals, only some of them are on our side.

Perfectly tailored manipulation


Take the aberrant behavior of an infected ant in the Thai jungle. Normally, a worker ant forages for materials along chemicallydetermined trails in its colonys territory. But when spores of the Cordyceps fungus infiltrate an ants exoskeleton, the fungus begins to take root, feeding on the ants nonessential organs. After a few days, Cordyceps filaments will have grown into the ants brain, driving the ant

to commit its last act. It will stagger from its nest, climb a nearby shrub, and clamp its mandibles onto a leafs vein. This zombie-like behavior is very precise: most infected ants will bite the underside of a leaf about 25 centimeters from the ground on the northwestern side of a plant a fortunate thing for Cordyceps, because the conditions in this environment are perfect for the formation and release of spores. The fungus will spread through the ants corpse to fortify its new home by strengthening the ants exoskeleton and producing antibiotics to keep other microbes at bay. Within a few days, a stalk will erupt from the ants head to rain spores upon the rest of the ants former colony members. This gruesome interaction is so sophisticated that it seems precisely tailored for these two organisms. And indeed it is: parasites often alter host behavior in ways that might be benign in other organisms, but are particularly detrimental to the host usually causing the animals death. Ants infected by roundworm parade in a way that makes them more likely to be eaten by birds. Infection by wasp larvae alters the patterns a spider will spin into its web. Crickets are
Spring 2012 Berkeley Science Review

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book review
Heisenberg in the Atomic Age:
by Cathryn Carson Cambridge University Press 558 pages, $92.00

Science and the Public Sphere

rom Isaac Newtons formulation of classical mechanics to the early 20th century, it was believed that all physical quantities of a given system could be known simultaneously to complete precision. However in 1926, a 25-year-old physicist named Werner Heisenberg proved that there were naturally imposed limits on the accuracy to which related variables such as position and velocity could be measured, and no matter how hard a diligent scientist might try, a more accurate measurement of one of these variables would increase the uncertainty of the other. Today, Heisenbergs uncertainty principle remains one of the most famous and revolutionary concepts in all of science. Appearing at the center of Heisenbergs revolutionary science, uncertainty was a theme that extended to many other aspects of his life. The nature and underlying motives for Heisenbergs choice to remain in Germany during and after World War II and work in the National Socialist State remain a source of open debate among scientists and historians. Was he biding his time to take part in the reconstruction of Germany after the war? Or was he an active resister undermining the Third Reichs nuclear fission research? There has been no shortage of speculation. In her book Heisenberg in the Atomic Age: Science and the Public Sphere, UC Berkeley science historian Cathryn Carson sheds light on these questions by contextualizing Heisenberg within the political and cultural atmosphere of post-war West Germany. Carson explains these historical nuances by pointing out the difficulties in interpreting Heisenbergs words and their relation to the overall guarded language within the evolving

public sphere of West Germany following the war. According to Carson, Heisenberg struggled to speak directly and convincingly about National Socialism and often instead relied on gestures and allusions. This included his depictions of his own work in the Third Reich, which tended likewise toward understatement, stopping short of both self-critique and claims of resistance. Carsons approach is insightful and detailed, drawing from a vast number of Heisenbergs publications, lecture transcripts, and personal correspondences with family, friends, and colleagues. However, this abundance of information, coupled with highly detailed discussions of culture and politics in West Germany, weighed the book down for me at times and took some dedication to read. Aside from Heisenbergs war work, the book also centers on the instrumental role he played in re-developing science in Germany after World War II. German science had taken a major blow, with countless worldclass scientists emigrating as Hitler rose to power. Heisenberg was essential to picking up the pieces, from his development and administration of the prestigious Max Planck Institute for Physics and the Alexander von Humboldt foundation, to his role in securing West Germanys involvement with the multi-national European Organization for Nuclear Research (CERN). The latter was of particular importance not only for the scientific benefits it offered but also in reestablishing Germanys relations with its European neighbors. Heisenbergs involvement in the founding of CERN utilized his unique assets, including his esteem as a Nobel Laureate, influence in his government, and many close contacts in the physics community. Heisenberg also pushed for largescale design of an accelerator laboratory and presented West Germanys desire for it to be located in Geneva (the eventual site of the accelerator). Heisenberg went on to be elected to chair the inaugural Scientific Policy Committee and is credited as one of CERNs co-founders.

Aaron Harrison is a graduate student in chemistry.

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Berkeley Science Review

Fall 2012

CAMBRIDGE UNIVERSIT Y PRESS

The book is very light on Heisenbergs contributions to science and is better suited for someone who enjoys reading about postwar political and social history. If Heisenbergs physics and his role in the advent of quantum mechanics are what youre looking for, this book wont be satisfying. But if youve already read a more traditional biography of Heisenberg and would like to delve further into his political and social circumstances, this book would certainly be of interest. Heisenberg was, as one friend put it, a master of the art of leaving things open, and in the end Carsons book isnt pushing any moral interpretation of Heisenberg. She instead lays out a thorough depiction of post-war Heisenberg, bringing the man into better focus and showing the decidedly beneficial role he played in rebuilding Germany following the war. While Carsons book is engaging and well written, the book is still somewhat inaccessible to the motivated novice and might be best appreciated by her fellow historians of science.

toolbox
ur physical world feels deterministic. A billiards player depends on this when she carefully lines up complex shots across several cushions. Make the billiard balls ten thousand times smaller and play underwater, however, and she would have a much tougher time predicting the shots outcome (let alone finding a very tiny pool cue). Indeed, the behavior of molecularscale systems, especially molecules in liquid solvents, is often best represented as a series of random events called a random process. The modern study of molecular random processes began in the late 19th century, when Austrian scientist Ludwig Boltzmann discovered his famous equation that connects the laws of physics to the laws of probability. Studying random processes with equations can be fiendishly tricky, however, and this approach has limits like any other research tool. Would it be possible to take the same mathematical model and simulate its random behavior on a computer? Such was the thinking at Los Alamos National Laboratory among the scientists that were in charge of nuclear weapons development during and after World War II (better known as the Manhattan Project). In the method they devised, random numbers generated on a computer are used to choose new positions for a simulated set of molecules. These new positions are either accepted or rejected based on Boltzmanns equation. As this process repeats, the model traces out molecular configurations according to the laws of thermal physics. Mathematical physicist John von Neumann code-named this method Monte Carlo, in reference to the town along the French Riviera where games of chance are played in casinos. Intriguingly, when the method was first published in 1953, the papers final author was Edward Teller, the father of the hydrogen bomb,making the Monte Carlo technique, somewhat awkwardly, the bombs more benign older sibling. The Monte Carlo method has been an invaluable tool throughout the physical sciences ever since. Where non-computational

methods might require approximations, Monte Carlo techniques can provide a way to attain exact numerical calculations for the various properties of a given theoretical model. In 1970 it was shown that the method could be generalized to probabilistic models far beyond those used in physics. Since then the application of this method has spread throughout the fields of economics, genomics, sociology, and more. Indeed, its power lies in its flexibility. Researchers can use any computational move (i.e., a way to generate the next step in the random process) that they can dream up, as long as the move obeys Boltzmanns equation or similar criteria. New types of Monte Carlo moves can help computational scientists study research
Traditional Monte Carlo
calculate random particle movements

Grand-Canonical Monte Carlo


calculate random particle movements + likelihood of particles being inserted/deleted

MOF insertion

Carbon

deletion

problems with ease that would be impossible, or at least prohibitively slow, using straightforward Monte Carlo moves. Berend Smit and coworkers at UC Berkeley and LBL develop and apply Monte Carlo techniques to study porous materials like zeolites and metal-organic frameworks (MOFs). These materials can capture gases like carbon dioxide (CO2) before they are released into the atmosphere (see From Air to Zeolites and MOFiosos, 5 and 16) and are thus a promising clean energy technology. However, they are very challenging to study experimentally. Monte Carlo techniques have therefore provided an especially valuable way to understand their characteristics. How would you design a simulation to study how CO2 molecules are absorbed by a MOF? Perhaps you would run a Monte Carlo simulation where the gas molecules start outside a block of material and gradually wander insidebut these simulations take far too long to run. To circumvent this problem, Smit and coworkers had to develop new, physically-justified moves that would allow gas molecules to be inserted or deleted throughout the structure based on their interactions with the surrounding MOF environment, all in a computationally efficient way. These so-called grand canonical moves give the same answer as the simple diffusion-based simulations would, and they can get there much faster. James Bond, the fictional master of myriad specialized gadgets, was also inspired by the seaside casino that von Neumann had in mind. One could argue however, that Monte Carlo techniques empower you to be more cunning than even a secret agent. You are often the maker of the tools as well as the master, deftly addressing each perhapsunexpected, apparently-insurmountable challenge in your path. Not bad for the sibling of a nuclear weapon.

AMY ORSBORN

Christopher Ryan is a graduate student in biophysics.


Fall 2012 Berkeley Science Review

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