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New Method Could Improve Ultrasound Imaging

Caltech chemical engineer shows hidden potential of gas vesicles

One day while casually reading a review article, Caltech chemical engineer Mikhail Shapiro came across a mention of gas vesicles—tiny gas-filled structures used by some photosynthetic microorganisms to control buoyancy. It was a light-bulb moment. Shapiro is always on the lookout for new ways to enhance imaging techniques such as ultrasound or MRI, and the natural nanostructures seemed to be just the ticket to improve ultrasound imaging agents.

Now Shapiro and his colleagues from UC Berkeley and the University of Toronto have shown that these gas vesicles, isolated from bacteria and from archaea (a separate lineage of single-celled organisms), can indeed be used for ultrasound imaging. The vesicles could one day help track and reveal the growth, migration, and activity of a variety of cell types—from neurons to tumor cells—using noninvasive ultrasound, one of the most widely used imaging modalities in biomedicine.

A paper describing the work appears as an advance online publication in the journal Nature Nanotechnology

"People have struggled to make synthetic nanoscale imaging agents for ultrasound for many years," says Shapiro. "To me, it's quite amazing that we can borrow something that nature has evolved for a completely different purpose and use it for in vivo ultrasound imaging. It shows just how much nature has to offer us as engineers."

Ultrasound transmitters use sound waves to image biological tissue. When the emitted waves encounter something of a different density or stiffness, such as bone, some of the sound bounces back to the transducer. By measuring how long that round-trip journey takes, the system can determine how deep the object is and build up a picture of internal anatomy.

But what if you want to image something other than anatomy? Maybe you are interested in blood flow and want to see whether there are any signs of atherosclerosis, for example, in blood vessels. To make ultrasound useful in such cases, you need to introduce an imaging label that has a different density or stiffness from bodily tissue. Currently, people use microbubbles—small synthetic bubbles of gas with a lipid or protein shell—to image the vasculature. These microbubbles are less dense and more elastic than the water-based tissues of the body. As a result, they resonate and scatter sound waves, allowing ultrasound to visualize the location of the microbubbles.

Microbubbles work just fine, unless you want to image something outside the bloodstream. Because of their diameter—small, but still on the order of microns—the bubbles are too large to get out of the bloodstream and into surrounding tissue. And as Shapiro says, "Many interesting targets—such as specific types of tumors, immune cells, stem cells, or neurons—are outside the bloodstream."

A number of research teams have tried, without success, to make microbubbles smaller. There is a fundamental physical reason for their failure: bubbles are held together by surface tension. As you make them smaller, the surface tension builds, and the pressure within the bubble becomes too high in comparison to the pressure outside. That amounts to an unstable bubble that is likely to lose its gas to its surroundings.

The gas vesicles Shapiro's team worked with are at least an order of magnitude smaller than microbubbles—measuring just tens to hundreds of nanometers in diameter. And even though they look like bubbles, gas vesicles behave quite differently. Unlike bubbles, the vesicles do not trap gas molecules but allow them to pass freely in and out. Instead, they exclude water from their interior by having a hydrophobic inner surface. This results in a fundamentally stable nanoscale configuration.

 "As soon as I learned about them, I knew we had to try them," Shapiro says. 

The researchers first isolated gas vesicles from the bacterium Anabaena flos-aquae (Ana) and the archaeon Halobacterium NRC-1 (Halo), put them in an agarose gel, and used a home-built ultrasound system to image them. Vesicles from both sources produced clear ultrasound signals. Next, they injected the gas vesicles into mice and were able to follow the vesicles from the initial injection site to the liver, where blood flows to be detoxified. Shapiro and his colleagues were also able to easily attach biomolecules to the surface of the gas vesicles, suggesting that the gas vesicles could be used to label targets outside the bloodstream.

Shapiro's long-term goal is to take advantage of the fact that the gas vesicles are genetically encoded by engineering their properties at the DNA level and ultimately introducing the genes into mammalian cells to produce the structures themselves. For example, he would like to genetically label stem cells and use ultrasound to watch as they migrate to specific locations within the body and differentiate into tissues.

"Now that we have our hands on the genes that encode these gas vesicles, we can engineer them to optimize their properties, to see how far they can go," Shapiro says.

In their work, the researchers found differences in the gas vesicles produced by Ana and Halo. These variations could provide insight into how the vesicle design could be optimized for other purposes. For example, unlike the Ana vesicles, the Halo vesicles produced harmonic signals—meaning that they caused the original ultrasound wave to come back, as well as waves with doubled and tripled frequencies. Harmonics can be helpful in imaging because most tissue does not produce such signals; so when they show up, researchers know that they are more likely to be coming from the imaging agent than from the tissue.

Also, the gas vesicles from the two species collapsed, and thereby became invisible to ultrasound, with the application of different levels of pressure. Halo gas vesicles, which evolved in unpressurized cells, collapsed more easily than the vesicles from Ana, which maintain a pressurized cytoplasm. The researchers used this fact to distinguish the two different populations in a mixed sample. By applying a pressure pulse sufficient to collapse only the Halo vesicles, they were able to identify the remaining gas vesicles as having come from Ana.

Shapiro notes that there is a substantial difference between the critical collapse pressures of Halo and Ana. "There's quite a good possibility that, as we start to genetically engineer these nanostructures, we would be able to make new ones with intermediate collapse pressures," he says. "That would allow you to image a greater number of cells at the same time. This sort of multiplexing is done all the time in fluorescent imaging, and now we want to do it with ultrasound."

Along with Shapiro, coauthors on the paper, "Biogenic gas nanostructures as ultrasonic molecular reporters," are Patrick Goodwill, Arkosnato Neogy, David Schaffer, and Steven Conolly of UC Berkeley, and Melissa Yin and F. Stuart Foster of the University of Toronto. The work was supported by funding from the Miller Research Institute, the Burroughs Wellcome Fund's Career Award at the Scientific Interface, the California Institute of Regenerative Medicine, the National Institutes of Health, the Canadian Institutes of Health Research, and the Terry Fox Foundation.

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Kimm Fesenmaier
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Watching the Brain Do Its Thing: An Interview with Mikhail Shapiro

To a large extent, the brain remains a black box. Taking it out of its case inside the skull and examining it—as in an autopsy—reveals some things, but not how the brain works in a living, functioning being. Assistant Professor of Chemical Engineering Mikhail Shapiro is determined to reveal the mysteries of the brain in situ, in living beings, right down to the cellular level.

Shapiro comes to Caltech from UC Berkeley, where he launched his independent research career as a Miller Fellow. Prior to that, Shapiro was a postdoctoral fellow at the University of Chicago. He received his PhD from the Massachusetts Institute of Technology. Shapiro recently sat down to discuss his research and his adjustment to his new life at Caltech.

What are you most excited about in coming to Caltech?

I'm excited for the opportunity to collaborate with the amazing faculty and students we have here across the disciplines. My first three PhD students all come from different programs, and I already have a collaboration with a colleague in electrical engineering. I can't imagine this happening so quickly and naturally anywhere else in the world.

What is the main focus of your research?

The goal of our research is to develop ways to study biological systems at the cellular level in living, breathing organisms. To do that we need ways to image and control specific molecular functions in tissues noninvasively.

Great advances have been made with dyes and fluorescent proteins to help scientists see what's happening inside living cells, but these techniques don't allow us to penetrate very deeply into larger tissues. So what we want to do is create the equivalents of dyes and fluorescent proteins for technologies like ultrasound and magnetic resonance imaging (MRI) so that we can see and label very specific things deep inside the body, and particularly in the brain.

For example, we are interested in how neural stem cells in the brain—which are regenerated even in adults—develop into different types of brain cells. What kinds of genes do they turn on and off, as they become a neuron or a glial cell in different parts of the brain? We are designing molecular reporters that will allow us to use MRI or ultrasound to monitor these cells as they migrate, express genes, and integrate into functional neural circuits.

How do you get these "molecular reporters" into the body?

The vast majority of the things we're working on are genetically encodable, which means that we can take the relevant genes, put them into a vector—for example, a nontoxic virus—and deliver them to specific cells. So not only would we be able to target a particular region of the brain, but we would be able to target specific cell types.

Will the technologies you're developing be useful in exploring other systems in the body?

Yes. Our main raison d'etre is to develop ways to probe the nervous system, but the technologies we develop could be used in a variety of biological contexts and in synthetic biology. In addition, we are fascinated by the basic science involved with connecting various forms of energy—magnetic fields, sound waves, temperature—with biological molecules and cells. This interface is relatively unexplored, and we hope to contribute to its fundamental understanding.

What do you like about Caltech?

I've always thought of Caltech as a scientific paradise. The density of high-quality research here is second to none. It's an environment that encourages the pursuit of big, bold ideas across disciplines. That's why I went into academia, so this is the place to be.

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Caltech Appoints Diana Jergovic to Newly Created Position of Vice President for Strategy Implementation

Caltech has named Diana Jergovic as its vice president for strategy implementation. In the newly created position, Jergovic will collaborate closely with the president and provost, and with the division chairs, faculty, and senior leadership on campus and at the Jet Propulsion Laboratory, to execute and integrate Caltech's strategic initiatives and projects and ensure that they complement and support the overall education and research missions of the campus and JPL. This appointment returns the number of vice presidents at the Institute to six.

"Supporting the faculty is Caltech's highest priority," says Edward Stolper, provost and interim president, "and as we pursue complex interdisciplinary and institutional initiatives, we do so with the expectation that they will evolve over a long time horizon. The VP for strategy implementation will help the Institute ensure long-term success for our most important new activities."

In her present role as associate provost for academic and budgetary initiatives at the University of Chicago, Jergovic serves as a liaison between the Office of the Provost and the other academic and administrative offices on campus, and advances campus-wide strategic initiatives. She engages in efforts spanning every university function, including development, major construction, and budgeting, as well as with faculty governance and stewardship matters. Jergovic also serves as chief of staff to University of Chicago provost Thomas F. Rosenbaum, Caltech's president-elect.

"In order to continue Caltech's leadership role and to define new areas of eminence, we will inevitably have to forge new partnerships and collaborations—some internal, some external, some both," Rosenbaum says. "The VP for strategy implementation is intended to provide support for the faculty and faculty leaders in realizing their goals for the most ambitious projects and collaborations, implementing ideas and helping create the structures that make them possible. I was looking for a person who had experience in delivering large-scale projects, understood deeply the culture of a top-tier research university, and could think creatively about a national treasure like JPL."

"My career has evolved in an environment where faculty governance is paramount," Jergovic says. "Over the years, I have cultivated a collaborative approach working alongside a very dedicated faculty leadership. My hope is to bring this experience to Caltech and to integrate it into the existing leadership team in a manner that simultaneously leverages my strengths and allows us together to ensure that the Institute continues to flourish, to retain its position as the world's leading research university, and to retain its recognition as such."

Prior to her position as associate provost, Jergovic was the University of Chicago's assistant vice president for research and education, responsible for the financial management and oversight of all administrative aspects of the Office of the Vice President for Research and Argonne National Laboratory. She engaged in research-related programmatic planning with a special emphasis on the interface between the university and Argonne National Laboratory. This ranged from the development of the university's Science and Technology Outreach and Mentoring Program (STOMP), a weekly outreach program administered by university faculty, staff, and students in low-income neighborhood schools on the South Side of Chicago, to extensive responsibilities with the university's successful bid to retain management of Argonne National Laboratory.

From 1994 to 2001, Jergovic was a research scientist with the university-affiliated National Opinion Research Center (NORC) and, in 2001, served as project director for NORC's Florida Ballot Project, an initiative that examined, classified, and created an archive of the markings on Florida's 175,000 uncertified ballots from its contested 2000 presidential election.

Jergovic earned a BS in psychology and an MA and PhD in developmental psychology, all from Loyola University Chicago, and an MBA from the Booth School of Business at the University of Chicago.

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Resourceful Computing Advances Chemistry at Caltech

In the 21st century, it seems impossible to imagine a group of researchers sharing just one computer. However, several decades ago—when computers required big budgets and lots of space—this hypothetical scenario was just the day-to-day reality of research. In the early 1970s, Caltech researcher Aron Kuppermann—seeking an alternative to this often-crowded arrangement—found additional computer resources in an unlikely place: a local religious organization. In the same spirit of creativity, Caltech researchers today have also found ways to practice resourceful computing.

Kuppermann's work focused on understanding how chemical reactions are influenced by quantum effects—the physics that governs the behavior of matter at the atomic (and subatomic) scale. Such quantum effects can now be studied in parallel with the Newtonian physics of a reaction using so-called "multiscale models," the development of which earned Caltech alum Martin Karplus (PhD '54) a share of the 2013 Nobel Prize in Chemistry. However, four decades ago, this "shortcut" wasn't available to Kuppermann, who passed away in 2011.

"In the late 1960s and early 1970s, the quantum effects of these reactions were unknown territory," says George Schatz (PhD, '76), professor of chemistry at Northwestern University and a former student of Kuppermann's. "And in order to do these studies, one needed to do large, computationally expensive calculations that would simulate the chemical reaction using quantum mechanics."

Although Caltech had a computer center at the time and Kuppermann's group also had access to the supercomputer at Lawrence Berkeley National Laboratory via ARPANET, a precursor to the Internet, the shared equipment was in high demand, and individual research groups had limited time available for their calculations. "We were also limited as to how much we could accomplish because we were charged hundreds of dollars per hour to use a computer—and Kuppermann's research grant didn't have enough money to pay for what we needed," Schatz says.

Kuppermann and his colleagues knew that these computer resources would not be sufficient for their project, so they actively started looking for solutions. The answer was provided by a postdoctoral scholar who uncovered a wealth of unused computer time at a Pasadena religious organization called the Worldwide Church of God. The church and its associated religious school, Ambassador College, used an IBM 360 computer to record information about their donors —the same type of machine that Kuppermann's group was using at the Caltech's computer center. Such machines required that each line of computer code be physically "punched" out on a card, which would then be fed into and read by the computer.

The computer at Ambassador College was only used for church business during the week, so Kuppermann's lab group got permission to use the computer for research purposes on the weekends. "We would take these boxes of computer cards and either drive or ride our bicycles to Ambassador College," Schatz recalls. "When it started, we were doing this on Fridays—we'd prepare these cards, deliver them on Friday afternoon, and then go back on Monday to pick up the results. And since the computers were sitting idle over the weekend except for our work, we were actually able to accomplish a huge amount."

In fact, this unorthodox collaboration between a religious organization and a group of scientists enabled the Kuppermann group to resolve several important issues about the importance of quantum effects in chemical reactions. "These calculations allowed us to to solve the Schrödinger equation—in other words, to use quantum mechanics to describe the reaction of a hydrogen atom and a hydrogen molecule (H2)," he says. "And it was the first time that the Schrödinger equation was solved for this reaction," a highlight of Kuppermann's career, Schatz says.

Despite the importance of the computing time, the staff at Ambassador College "had no idea that their computer was basically the center of the universe for doing computations of reaction dynamics," says Schatz. "We acknowledged Ambassador College in our papers at the time, but they never charged us for anything; they just seemed to be interested in the fact that we could do fundamental science with computer resources that they just were never using.

Eventually, advances in technology and increased funding for research computer centers spelled the end for this unusual collaboration, and today computers can be found in every nook and cranny on campus. However, that doesn't mean Caltech scientists have stopped finding resourceful, creative solutions to their computing and research problems.

For example, last fall, Professor of Chemistry Thomas Miller used an event called a "hackathon"—an all-hands-on-deck marathon of continuous computer programming—to make the most of another resource: the human mind. Miller's research at Caltech, similar to Kuppermann's, focuses on developing new computational methods to better predict and understand chemical reactions. With the help of the two-day programming event, Miller and his research group were able to quickly make progress on the development of a new computational method for quantum chemistry that had previously only existed on paper.

"If I had asked only a single person in my group to program the new method, it would have taken a couple of weeks," says Miller. "But after two solid days and nights of programming as a group—and a lot of pizza and bagels—we had a working implementation of the new method, we had gained valuable insight into its advantages and limitations, and we had an improved understanding of how best to implement the new method in its final version."

Although nonstop programming sounds like a stressful way to spend 48 hours, Miller says that he was impressed with the success of the hackathon and how well his students and postdocs rose to the challenge. "Everyone in the group has a million things to get done for their own research projects and degree requirements, so a programming exercise that benefits the group more than any one individual could easily have been viewed as a burden," he says. "But everyone—myself included—seemed to enjoy the urgency of the tight deadline and the responsibility of delivering essential components for a larger mission."

The computers used by Miller's lab at Caltech today are much more powerful than those available at the Caltech computer center of Kuppermann's day, but the computations now performed by researchers have also rapidly increased in complexity. This means that sourcing computer time—in Miller's case, about 30 million computer hours per year—from a variety of different computational resources is still common practice. In addition to on-campus computing, Miller and many other researchers apply for large amounts of computer time from agencies like the National Science Foundation or the Department of Energy.

But while the availability of computer resources is an important piece of the puzzle, Miller says the real challenge is in obtaining the physical insight—and enough good ideas—to do the right calculation. "As any theorist will tell you, a big computer is no replacement for scientific insight and creativity," both of which are found in abundance at Caltech, he says.

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National Inventors Hall of Fame to Induct Frances Arnold

Frances H. Arnold, the Dick and Barbara Dickinson Professor of Chemical Engineering, Bioengineering and Biochemistry, and director of the Donna and Benjamin M. Rosen Bioengineering Center at Caltech, is one of five living innovators chosen to be inducted into the National Inventors Hall of Fame (NIHF) in 2014.

The NIHF, in partnership with the United States Patent and Trademark Office (USPTO), announced the names of this year's inductees on March 4. A ceremony honoring the inductees will be held on the USPTO campus in Alexandria, Virginia, on May 21, 2014.

According to the NIHF announcement, inductees are inventors who hold a United States patent and "who have made extraordinary contributions to their respective fields, and in many cases, changed the world forever." A selection committee made up of representatives from science, technology, and patent organizations makes recommendations on who should be inducted, and the NIHF board ratifies each year's class of inventors.

Arnold heads a research group at Caltech that has pioneered methods of "directed evolution" that are now widely used to create biological catalysts for use in industrial processes, including the production of fuels and chemicals from renewable resources. In a process akin to breeding by artificial selection, directed evolution uses mutation and screening to optimize the amino-acid sequence of a protein and give it new capabilities or improve its performance.

Arnold's research group develops evolutionary design strategies and uses them to generate novel and useful proteins for applications in medicine, neurobiology, chemical synthesis, and alternative energy. Arnold is a member of the Resnick Sustainability Institute's Faculty Board of Directors. She holds 39 registered U.S. patents.

The National Inventors Hall of Fame inducted its first honoree, Thomas Edison, in 1973.  Previous inductees with a Caltech connection (either faculty or alumni) include Arnold Beckman, Robert Bower (MS, '63), Robert Hall (BS, '42; PhD, '48), Lee Hood (BS, '60; PhD, '68), Carver Mead (BS, '56; MS, '57; Phd, '60), Gordon Moore (PhD, '54), Bernard Oliver, Harold Rosen (MS, '48; PhD, '51), William Shockley, and Theodore von Kármán.

"Recognition by the National Inventors Hall of Fame is a huge honor," says Arnold. "It is also a testament to Caltech's culture of interdisciplinary science and innovation which encourages us to invent new ways to explore the unknown."

Arnold is a recipient of the 2011 National Medal of Technology and Innovation and the 2011 Charles Stark Draper Prize, among other prizes. She holds the rare distinction of having been elected to all three branches of the National Academies—the National Academy of Engineering (2000), the Institute of Medicine (2004), and the National Academy of Sciences.

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Brian Bell
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Monday, March 31, 2014
Center for Student Services 360 (Workshop Space)

Unleashing Collaborative Learning through Technology: A Study of Tablet-Mediated Student Learning

Monday, April 7, 2014
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Planning Session for the Fall 2014 Teaching Conference

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The Art of Scientific Presentations

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Beckman Institute Auditorium

Juggling Teaching at a Community College and Research at Caltech

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