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Caltech Names Thomas F. Rosenbaum as New President

To: The Caltech Community

From: Fiona Harrison, Benjamin M. Rosen Professor of Physics and Astronomy, and Chair, Faculty Search Committee; and David Lee, Chair, Board of Trustees, and Chair, Trustee Selection Committee

Today it is our great privilege to announce the appointment of Thomas F. Rosenbaum as the ninth president of the California Institute of Technology.

Dr. Rosenbaum, 58, is currently the John T. Wilson Distinguished Service Professor of Physics at the University of Chicago, where he has served as the university's provost for the past seven years. As a distinguished physicist and expert on condensed matter physics, Dr. Rosenbaum has explored the quantum mechanical nature of materials, making major contributions to the understanding of matter near absolute zero, where such quantum mechanical effects dominate. His experiments in quantum phase transitions in matter are recognized as having played a key role in placing these transitions on a theoretical level equivalent to that which has been developed for classical systems.

But Dr. Rosenbaum's scientific achievements were not solely what captured and held the attention of those involved in the presidential search. We on the search committee were impressed by Dr. Rosenbaum's deep dedication, as Chicago's provost, to both undergraduate and graduate education—both critical parts of Caltech's mission. He has had responsibility for an unusually broad range of institutions and intellectual endeavors. Among his achievements as provost was the establishment of the Institute for Molecular Engineering in 2011, the University of Chicago's very first engineering program, in collaboration with Argonne National Lab.

We also believe that Dr. Rosenbaum's focus on strengthening the intellectual ties between the University of Chicago and Argonne National Lab will serve him well in furthering the Caltech-JPL relationship.

As provost, Dr. Rosenbaum was also instrumental in establishing collaborative educational programs serving communities around Chicago's Hyde Park campus, including the university's founding of a four-campus charter school that was originally designed to further fundamental research in education but which has also achieved extraordinary college placement results for disadvantaged Chicago youths.

This successful conclusion to our eight-month presidential search was result of the hard work of the nine-member Faculty Search Committee, chaired by Fiona Harrison, and the 10-member Trustee Selection Committee, chaired by David Lee. We are grateful both to the trustees and faculty on our two committees who made our job so very easy as well as to those faculty, students, staff, and alumni who provided us with input and wisdom as we scoured the country for just the right person for our Caltech.

"Tom embodies all the qualities the faculty committee hoped to find in our next president," Harrison says. "He is a first-rate scholar and someone who understands at a deep level the commitment to fundamental inquiry that characterizes Caltech. He is also the kind of ambitious leader who will develop the faculty's ideas into the sorts of innovative ventures that will maintain Caltech's position of prominence in the next generation of science and technology."

"The combination of deep management experience and visionary leadership Tom brings will serve Caltech extremely well in the coming years," Lee adds. "The Board is excited about collaborating closely with Tom to propel the Institute to new levels of scientific leadership."

"The Caltech community's palpable and deep commitment to the Institute came through in all my conversations, and it forms the basis for Caltech's and JPL's lasting impact," Dr. Rosenbaum says. "It will be a privilege to work closely with faculty, students, staff, and trustees to explore new opportunities, building on Caltech's storied accomplishments."

Dr. Rosenbaum received his bachelor's degree in physics with honors from Harvard University in 1977, and both an MA and PhD in physics from Princeton University in 1979 and 1982, respectively. He did research at Bell Laboratories and at IBM Watson Research Center before joining the University of Chicago's faculty in 1983. Dr. Rosenbaum directed the university's Materials Research Laboratory from 1991 to 1994 and its interdisciplinary James Franck Institute from 1995 to 2001 before serving as vice president for research and for Argonne National Laboratory from 2002 to 2006. He was named the university's provost in 2007. His honors include an Alfred P. Sloan Research Fellowship, a Presidential Young Investigator Award, and the William McMillan Award for "outstanding contributions to condensed matter physics." Dr. Rosenbaum is an elected fellow of the American Physical Society, the American Association for the Advancement of Science, and the American Academy of Arts and Sciences.

Joining the Caltech faculty will be Dr. Rosenbaum's spouse, Katherine T. Faber, the Walter P. Murphy Professor of Materials Science and Engineering at Northwestern University. Dr. Faber's research focuses on understanding stress fractures in ceramics, as well as on the fabrication of ceramic materials with controlled porosity, which are important as thermal and environmental barrier coatings for engine components. Dr. Faber is also the codirector of the Northwestern University-Art Institute of Chicago Center for Scientific Studies in the Arts (NU-ACCESS), which employs advanced materials science techniques for art history and restoration. Dr. Rosenbaum and Dr. Faber have two sons, Daniel, who graduated from the University of Chicago in 2012, and Michael, who is currently a junior there.

Dr. Rosenbaum will succeed Jean-Lou Chameau, who served the Institute from 2006 to 2013, and will take over the helm from interim president and provost Ed Stolper on July 1, 2014. The board, the search committee, and, indeed, the entire Institute owes Dr. Stolper a debt of gratitude for his unwavering commitment to Caltech, and for seamlessly continuing the Institute's forward momentum through his interim presidency.

As you meet Dr. Rosenbaum today and over the coming months, and learn more about his vision for Caltech's future, we believe that you will quickly come to see why he is so well suited to guide Caltech as we continue to pursue bold investigations in science and engineering, to ready the next generation of scientific and thought leaders, and to benefit humankind through research that is integrated with education.

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Programming DNA for Molecular Robots: An Interview with Lulu Qian

Embracing the idea that molecules can be programmed much like a computer, researchers can now perform remarkable feats on a very small scale. New Caltech faculty member Lulu Qian, assistant professor of bioengineering, performs research in the field of molecular programming because it allows her to design synthetic molecular systems with neural-network-like behaviors and tiny robots, both from the programmed interactions of DNA molecules. Originally from Nanjing, China, Qian received her bachelor's degree from Southeast University in 2002 and her PhD from Shanghai Jiao Tong University in 2007. After working as a postdoctoral scholar at Caltech in the laboratory of Shuki Bruck, Qian became a visiting fellow at Harvard University; she returned to Caltech and joined the faculty in July. Recently, Qian answered a few questions about her research, and how it feels to be back at Caltech.

What do you work on?

I work on rationally designing and creating molecular systems with programmable behaviors. I am interested in programming biological molecules—like DNA and RNA—to recognize molecular events from the biochemical environment, process information, make decisions, take actions, and to learn and evolve. Molecular programming is not just about using computer programs to aid the design and analysis of molecular systems; it is more about adapting the principles of computer science to create biochemical systems that can carry out instructions to perform tasks at the molecular level. For example, I develop simple and standard molecular components that can be used to perform a variety of tasks and systematic ways to configure the behavior of interacting molecules to carry out one computational or mechanical task or another. These custom-designed molecules can be ordered from a commercial supplier and mixed in a test tube to generate a "molecular program." 

Using this approach, I have designed DNA circuits that can solve basic logic problems, and I have constructed a DNA neural network that can perform simple associative memory functions—much like a network of neurons in the brain, though in a rudimentary way. In my future research, I would like to improve the speed, robustness, and complexity of these implementations and to explore the possibility of creating molecular systems with learning capabilities, while also beginning new work in the field of molecular robots—tiny, nanoscale machines made of DNA that can perform a designed task such as sorting cargo or solving a maze.

What do you find most exciting about your research?

I am driven by curiosity—outside of the lab, I like Legos and puzzles—and I view life as a program, one that is much more sophisticated than any other program that we know of so far. The sequence of nucleotides that make up DNA—As, Ts, Cs, and Gs—encodes the program within a genome, orchestrating molecules to sense, to compute, to respond, and to grow. Because of their different lengths and sequences, one genome produces a bacterium while another produces a plant, or an insect, or a mammal. The genetic program describes how to make molecules, and molecules are machines that can achieve complex tasks to regulate the behaviors of individual cells. To better appreciate the molecular programs that nature creates, I want to understand what possible behaviors a network of interacting molecules can exhibit and how we can rationally design such behaviors.

But, I am also driven by my engineering nature. I want to design and build molecular systems with increasing complexity and sophistication. For example, you could imagine using such molecular machines to make a nanoscale factory that manufactures novel chemicals in a test tube. These chemicals could become new materials or new drugs. You could also imagine embedding such molecular machines into individual cells so that you could collect information from the molecular environment and regulate the cell's behavior. Such regulation could lead to responsive biosynthesis—the production of proteins or other molecules in response to a stimulus—or localized diagnostics followed by therapeutics.

How did you get into your field?

I started programming computers when I was 13 years old, and I have loved it ever since then. My dad was a philosopher, and because of his influence, I got curious about fundamental questions such as who I am and why I think the way that I do. At first, I tried to look for these answers in molecular biology, but as a programmer, biology was difficult for me to understand. Unlike in programming, you cannot just define a few logical principles to understand the behavior of an entire biological system or organism. At the time, biology was not as fun for me—or as logical—as computer programming.

But just before I went to graduate school, I discovered the first publication in DNA computing by Len Adleman at the University of Southern California. He used DNA molecules as a computing substrate to solve a hard math problem. The moment that I finished reading this paper, I felt completely excited. It was the first time that I saw a strong relationship between molecules that are traditionally only used in biology—like DNA and RNA—and computer programming. That was when I started working in my field.   

Why are you excited to be at Caltech?

After working at other institutions, Caltech has been a very special place for me. I like that Caltech is small and is an environment in which we're encouraged to pursue fundamental research and appreciate the beauty of science. I am most excited about doing great science here. There are very talented students—I am looking for the most fun and creative minds to join my lab—and I have visionary colleagues. We have an excellent molecular programming community at Caltech, including Erik Winfree in computer science, Shuki Bruck in electrical engineering, Richard Murray in control and dynamical systems, Niles Pierce and Paul Rothemund in bioengineering, and now myself. And we now have this new division, Biology and Biological Engineering, which I believe will bring fundamental engineering to biological sciences and create interdisciplinary research activities.

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Look Out Above! Experiment Explores Innate Visual Behavior in Mice

When you're a tiny mouse in the wild, spotting aerial predators—like hawks and owls—is essential to your survival. But once you see an owl, how is this visual cue processed into a behavior that helps you to avoid an attack? Using an experimental video technique, researchers at the California Institute of Technology (Caltech) have now developed a simple new stimulus with which they can spur the mouse's escape plans. This new stimulus allows the researchers to narrow down cell types in the retina that could aid in the detection of aerial predators.

"The mouse has recently become a very popular model for the study of vision," says biology graduate student Melis Yilmaz, who is also first author of the study, which will be published online in the journal Current Biology on October 10. "Our lab and other labs have done a lot of physiological, anatomical, and histological studies in the mouse retina"—a layer of light-sensitive cells in the eye that relay image information to the brain—"but the missing piece was mouse behavior: What do mice do with their vision?"

Yilmaz, under the supervision of Markus Meister, Lawrence A. Hanson, Jr. Professor of Biology, studied the behavior of 40 mice, placed one-by-one in a tiny room called a behavioral arena. After placing each mouse alone in the arena and letting it explore the new environment for a few minutes, Yilmaz played videos of different visual stimuli on a computer monitor mounted on the ceiling, the screen facing down onto the arena. The researchers then watched a video feed of the mouse's behavior, obtained with a camera located on one of the walls of the arena.

Surprisingly, all of the mice responded to one specific visual stimulus: an expanding black disk, which is meant to imitate the appearance of an approaching aerial predator.

A quarter of the mice responded to the looming disk by completely freezing in place, not moving a muscle or twitching a whisker or tail until the disk disappeared. "When I first saw this behavior, my first thought was that the video recording had stopped," Yilmaz says.

Example of mouse "freezing" upon viewing the looming disk stimulus above.

Example of mouse "freezing" upon viewing the looming disk stimulus above.
Example of mouse "freezing" upon viewing the looming disk stimulus above. Results of this study published in the paper "Rapid Innate Defensive Responses of Mice to Looming Visual Stimuli" on October 10, 2013 in Current Biology.
Credit: Melis Yilmaz and Markus Meister/California Institute of Technology


A far more common reaction to the looming disk—seen in around 75 percent of the mice—was to flee for the cover of a tent-like nest in one corner of the arena.

Example of mouse fleeing upon viewing the looming disk stimulus above.

Example of mouse fleeing upon viewing the looming disk stimulus above.
Example of mouse fleeing upon viewing the looming disk stimulus above. Results of this study published in the paper "Rapid Innate Defensive Responses of Mice to Looming Visual Stimuli" on October 10, 2013 in Current Biology.
Credit: Melis Yilmaz and Markus Meister/California Institute of Technology


"For each mouse, this was the very first time that the animal was put into this arena, and it was the very first time that it saw that stimulus, and yet it has this sort of immediate reflex-like response…beginning to flee in less than a quarter of a second," Meister says. "What's attractive about this behavior is that it's incredibly robust, so we can rely on it, and it's quite specific to this particular visual stimulus. If the same disk was presented on a monitor at the bottom of the arena, the animals don't respond to that at all. And a looming white disk is also much less effective," he adds.

Although their study wasn't designed to evaluate the purpose of the two responses, Yilmaz and Meister suspect that, in the wild, different environmental conditions could lead to different visual behaviors.

"If you were out in nature, maybe freezing is a good reaction to a predatory bird that is very far away because it would allow you to blend into the surroundings," Meister says. This would confound the bird's visual system, which uses movement to track targets. Furthermore, he adds, "If the bird is within hearing distance, freezing so completely would help it avoid making a rustling noise."

The behaviors these researchers observed in this experiment are not uncommon among other animals in the wild, as Meister discovered one evening after giving a presentation about the fleeing and freezing results. "When I came home that evening, my son said, 'Papi, you won't believe what happened when we were at the park today. This squirrel was running across a wall, and suddenly it just froze! And then some guy yelled, 'Hey look!' and there was a hawk circling around.' So he had just that day seen it in real life," Meister says.

Freezing might be the best game plan for an animal trying to avoid predators that are far away, but, Meister says, when the threat is closer "and there is a protective place nearby, then escape might be a better strategy."

When Yilmaz and Meister began connecting these specific behavioral observations with other information about the mouse visual system, they were able to make predictions about the types of neurons and circuits involved in this rapid response. "We tested four different speeds of the expanding disk video, and we found that only one of those speeds caused this behavior robustly," Meister says. "That also gives us clues about what types of cells in the retina might be involved, because we know that one type responds to high-speed motion and one type responds to low-speed motions. The cells that detect low-speed motion are probably not involved in this behavior."

"It's really striking to me to watch the animal completely ignore one stimulus—like an expanding white disk—whereas they have such a robust reaction to the other type of stimulus," Yilmaz says. Her next experiments will be focused on manipulating these candidate cell types to pinpoint exactly which types of neurons and circuits are involved in this visual behavior.

In addition to its specific implications for visual behaviors, the work also helps to validate the mouse model for the study of visual processing, Meister says. Mice used in research have been bred for dozens of generations in laboratories—where they never would have seen an aerial predator—and yet the instinctual behavior still exists. "Lab mice never had to learn that a dark object from above was bad news," he says. "In fact, in our experiments, there was never any kind of punishment or ill effect from a visual display, so they didn't have any chance to learn the meaning. We believe it's kind of built into their genetic constitution."

Although humans don't have to escape the threat of predatory birds, Meister says that the results from this research could eventually provide information about human visual behaviors. "The mouse and human retinas are really very similar, so many of the circuits that are important for the mouse have analogous circuits in the human retina," he says. "Humans also react instinctively to approaching objects, but, obviously, we don't freeze. So, how did nature change a circuit that helps one animal escape from predators so that it serves a different function in another animal?"

This work was published in a paper titled "Rapid Innate Defensive Responses of Mice to Looming Visual Stimuli." The research was funded by the National Institutes of Health.

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Minding the Gaps in the Genome: An Interview with Mitch Guttman

Mitchell Guttman is a new assistant professor of biology on campus. He just arrived last month, having recently completed a fellowship at the Broad Institute of MIT and Harvard. Originally from Brooklyn, New York, Guttman received both his BS and MS degrees in 2006 from the University of Pennsylvania and completed his PhD at MIT in 2012. Since then, he has received an NIH Early Independence Award and was included on Forbes magazine's 30 Under 30: Science and Healthcare list.

While still a graduate student at the Broad Institute, Guttman led the team that first described a special class of genes called lncRNAs (large noncoding RNAs, pronounced "link RNAs"). These pieces of genetic material fall between the genes that code for proteins, and therefore had been largely overlooked previously. However, researchers are now finding that these lncRNAs are important players in genome regulation and cellular organization. Guttman's lab at Caltech will continue to study lncRNAs—how they work, why they are needed, and what makes them special. A recent paper in Science Express shares the latest.

Guttman recently took a break from setting up his lab to answer a few questions.

Do you remember how you first became interested in science?

I've always kind of been interested in science, ever since high school. I had a really great chemistry teacher who recognized my love of chemistry and biology and introduced me to some researchers at Mount Sinai in New York. I started doing research there at the end of my sophomore year of high school and worked there through my senior year. It was cancer research—mostly looking at breast cancer, and migration and adhesion patterns. I was doing very basic molecular biology, and I learned a ton.

When I was an undergraduate at Penn, the person I had worked with back in high school introduced me to one of his colleagues—a pathologist at Penn who was starting to do a lot of work on cancer genomics, which I knew nothing about but which sounded very fascinating. I started working with her my freshman year. During that time, it became very clear to me that to understand this work, I had to delve into the quantitative and computational aspects. I eventually helped develop computational methods to look at cancer mutation patterns and identify the "driver" mutations in the cancer genome versus the passengers—things that just come along for the ride but don't really have a direct effect in causing cancer. At the time, there weren't any methods to do that.

When I started graduate school, I wanted to work on cancer. That's how I met Eric Lander, the director of the Broad Institute, who was my graduate advisor.

How did you end up working on lncRNAs?

At the time I joined Eric's lab, there was kind of a revolution going on in genomics. Next-generation sequencing—ultrahigh-throughput, massively parallel sequencing—was starting to come online. There were very few institutions in the world that had instruments to do this—the Broad was one, Caltech was one. These were the first instruments that allowed us to sequence DNA at unparalleled depth. Eric's lab was using these instruments to look at chromatin modifications—how DNA wraps around different proteins, or histones, in the nucleus—and they had all of this new data. It hadn't been published. So Eric said, "I bet there's something here to be found. You're a computational guy; why don't you play around with it?"

The first thing I did, as a good computational guy, was to try to figure out a good algorithm to make sense of it. Once I did, it kind of hit me in the face.

What did you find?

Until then, we hadn't been able to look at anything but genes. But when we were able to look at the whole genome, we saw all of these regions of intergenic space—things that were between genes—that looked like genes. They had chromatin modifications with patterns that looked identical to genes. That suggested that there were thousands of unannotated genes. What became clear immediately was that although they had the same patterns as protein-coding genes, they didn't code for proteins. They did not have evolutionary signatures that looked like proteins. They were very different. We called them lncRNAs.

That finding basically led me on what has now been a seven-year stretch of trying to figure out what they are, what they do, and how they work.

Had no one previously looked at histone modifications?

They had, but they were mostly looking at very specialized regions—they were looking at promoters, which are regions that control transcription, or they were looking at proteins, or they were looking at the genes themselves. But only 1 percent of the genome encodes proteins, so 99 percent is really a no-man's-land, if you will. There had been no methods to pick out and classify these patterns across the entire genome, because there had been no data.

We wrote a computer program to search for these regions. We never named the original program, but its successor was called Scripture.

Why was all of this so exciting?

It made me realize that there were in fact thousands of these large noncoding RNAs that looked like proteins but didn't act like proteins—they did something else. What that something else was, I didn't know, but it was new and unexplored and was clearly important. The potential was huge.

And as a scientist, you can't just turn away when you find something like this. You've got to figure it out. The idea was exciting: there were all these thousands of genes that had previously been missed and unappreciated that could play really important roles in ways that we didn't understand. I wanted to know how they work. What are they doing? We're still figuring it out. Every time we find something, it is more exciting than I would have anticipated. That's what I love about this: it's never been obvious; it's never been dull.

Why did you choose to come to Caltech?

Caltech's an amazing place. I love the faculty. I love the small size. I love how interactive and not overlapping but collaborative it is. No other place that I had been to was like this—this seamless—and in no place did I feel as comfortable talking with chemists and engineers as I did with biologists. The breadth of the institution and the vision and the interactions were pretty unique and exciting.

Kimm Fesenmaier
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Caltech Named World's Top University in Times Higher Education Global Ranking

For the third year in a row, the California Institute of Technology has been rated the world's number one university in the Times Higher Education global ranking of the top 200 universities.

Harvard University, Oxford University, Stanford University, and the Massachusetts Institute of Technology round out the top five schools in the 2013–2014 rankings.

Times Higher Education compiled the listing using the same methodology as in the 2011–2012 and 2012–2013 surveys. Thirteen performance indicators representing research (worth 30 percent of a school's overall ranking score), teaching (30 percent), citations (30 percent), international outlook (which includes the total numbers of international students and faculty and the ratio of scholarly papers with international collaborators, 7.5 percent), and industry income (a measure of innovation, 2.5 percent) make up the data. The data were collected, analyzed, and verified by Thomson Reuters.

The Times Higher Education site has the full list of the world's top 400 schools and all of the performance indicators.

Kathy Svitil
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NIH Director's Awards Granted to Two Caltech Scientists

Two researchers from the California Institute of Technology (Caltech) have received Director's Awards from the National Institutes of Health (NIH) High Risk-High Reward research program. The awards, funded by the NIH Common Fund, are intended to support scientists proposing highly innovative approaches to major contemporary challenges in biomedical research.

The awards are intended to support "visionary" investigators, at all career stages, "pursuing science with the potential to transform scientific fields and accelerate the translation of scientific research into improved health," said NIH director Francis S. Collins in announcing the awards on September 30. The High Risk-High Reward Research program, he added, "allows researchers to propose highly creative research projects across a broad range of biomedical research areas that involve inherent risk but have the potential for high rewards."

NIH New Innovator Award

An NIH New Innovator Award, which is given to investigators who are within 10 years of receiving their terminal degree, was granted to assistant professor of biology Viviana Gradinaru (BS '05) for her research involving the neuronal effects of deep brain stimulation (DBS)—a therapy in which electrical impulses are applied to the brain to treat symptoms of Parkinson's disease.

"Deep brain stimulation has been used to ameliorate the symptoms of Parkinson's, however, very little is known about what DBS does to affect the course of the disease and to the cells themselves. The goal of the award is to look at the effect of this type of stimulation treatment on cellular health in a model organism," Gradinaru says. With the award, Gradinaru will also investigate the protective role of growth factors—substances made by the body that regulate cell division and cell survival—on neurons in the brain. The results of these studies could provide insights about measures to slow down the progression of neurodegenerative disease, she says.

Gradinaru received her bachelor's from Caltech in 2005 and her doctorate from Stanford University in 2010. After also completing a postdoctoral fellowship at Stanford, she joined the Caltech faculty in 2012.

NIH Early Independence Award

Elaine Hsiao (PhD '13), a postdoctoral scholar in biology and chemistry and chemical engineering, received an NIH Early Independence Award to support her work in identifying the role of microbes in the release of neurotransmitters—chemicals that relay signals from neurons in the brain and peripheral nervous system. The award is granted to exceptional junior scientists to allow them to move immediately into independent research positions and skip the time traditionally spent in postdoctoral training. With this award, Hsiao will pursue her research independently as a senior research fellow at Caltech.

"There's an increasing appreciation that microbes fundamentally regulate a number of normal biological processes," explains Hsiao, "and one aspect of this area of research is the finding that microbes in other areas of the body can affect the nervous system and behavior. A lot of research has been done on what responses are modulated by these microbes, but little is known about how. My area of research is to explore the biological mechanisms underlying these relationships, to pinpoint the particular communities involved, and to study them in the context of health and disease."

Hsiao received her bachelor's from UCLA in 2006 and her doctorate from Caltech in 2013, under the direction of Paul Patterson, Anne P. and Benjamin F. Biaggini professor of biological sciences. She is currently a joint postdoctoral scholar in the laboratories of Sarkis Mazmanian, professor of biology, and Rustem Ismagilov, Ethel Wilson Bowles and Robert Bowles professor of chemistry and chemical engineering, and director of the Jacobs Institute for Molecular Engineering for Medicine.

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New Gut Bacterium Discovered in Termite's Digestion of Wood

Caltech researchers find new species of microbe responsible for acetogenesis, an important process in termite nutrition.

When termites munch on wood, the small bits are delivered to feed a community of unique microbes living in their guts, and in a complex process involving multiple steps, these microbes turn the hard, fibrous material into a nutritious meal for the termite host. One key step uses hydrogen to convert carbon dioxide into organic carbon—a process called acetogenesis—but little is known about which gut bacteria play specific roles in the process. Utilizing a variety of experimental techniques, researchers from the California Institute of Technology (Caltech) have now discovered a previously unidentified bacterium—living on the surface of a larger microorganism in the termite gut—that may be responsible for most gut acetogenesis.

"In the termite gut, you have several hundred different species of microbes that live within a millimeter of one another. We know certain microbes are present in the gut, and we know microbes are responsible for certain functions, but until now, we didn't have a good way of knowing which microbes are doing what," says Jared Leadbetter, professor of environmental microbiology at Caltech, in whose laboratory much of the research was performed. He is also an author of a paper about the work published the week of September 16 in the online issue of the Proceedings of the National Academy of Sciences (PNAS).

Acetogenesis is the production of acetate (a source of nutrition for termites) from the carbon dioxide and hydrogen generated by gut protozoa as they break down decaying wood. In their study of "who is doing what and where," Leadbetter and his colleagues searched the entire pool of termite gut microbes to identify specific genes from organisms responsible for acetogenesis.

The researchers began by sifting through the microbes' RNA—genetic information that can provide a snapshot of the genes active at a certain point in time. Using RNA from the total pool of termite gut microbes, they searched for actively transcribed formate dehydrogenase (FDH) genes, known to encode a protein necessary for acetogenesis. Next, using a method called multiplex microfluidic digital polymerase chain reaction (digital PCR), the researchers sequestered the previously unstudied individual microbes into tiny compartments to identify the actual microbial species carrying each of the FDH genes. Some of the FDH genes were found in types of bacteria known as spirochetes—a previously predicted source of acetogenesis. Yet it appeared that these spirochetes alone could not account for all of the acetate produced in the termite gut.

Initially, the Caltech researchers were unable to identify the microorganism expressing the single most active FDH gene in the gut. However, the first authors on the study, Adam Rosenthal, a postdoctoral scholar in biology at Caltech, and Xinning Zhang (PhD '10, Environmental Science and Engineering), noticed that this gene was more abundant in the portion of the gut extract containing wood chunks and larger microbes, like protozoans. After analyzing the chunkier gut extract, they discovered that the single most active FDH gene was encoded by a previously unstudied species from a group of microbes known as the deltaproteobacteria. This was the first evidence that a substantial amount of acetate in the gut may be produced by a non-spirochete.

Because the genes from this deltaproteobacterium were found in the chunky particulate matter of the termite gut, the researchers thought that perhaps the newly identified microbe attaches to the surface of one of the chunks. To test this hypothesis, the researchers used a color-coded visualization method called hybridization chain reaction-fluorescent in situ hybridization, or HCR-FISH.

The technique—developed in the laboratory of Niles Pierce, professor of applied and computational mathematics and bioengineering at Caltech, and a coauthor on the PNAS study—allowed the researchers to simultaneously "paint" cells expressing both the active FDH gene and a gene identifying the deltoproteobacterium with different fluorescent colors simultaneously. "The microfluidics experiment suggested that the two colors should be expressed in the same location and in the same tiny cell," Leadbetter says. And, indeed, they were. "Through this approach, we were able to actually see where the new deltaproteobacterium resided. As it turns out, the cells live on the surface of a very particular hydrogen-producing protozoan."

This association between the two organisms makes sense based on what is known about the complex food web of the termite gut, Leadbetter says. "Here you have a large eukaryotic single cell—a protozoan—which is making hydrogen as it degrades wood, and you have these much smaller hydrogen-consuming deltaproteobacteria attached to its surface," he says. "So, this new acetogenic bacterium is snuggled up to its source of hydrogen just as close as it can get."

This intimate relationship, Leadbetter says, might never have been discovered relying on phylogenetic inference—the standard method for matching a function to a specific organism. "Using phylogenetic inference, we say, 'We know a lot about this hypothetical organism's relatives, so without ever seeing the organism, we're going to make guesses about who it is related to," he says. "But with the techniques in this study, we found that our initial prediction was wrong. Importantly, we have been able to determine the specific organism responsible and a location of the mystery organism, both of which appear to be extremely important in the consumption of hydrogen and turning it into a product the insect can use." These results not only identify a new source for acetogenesis in the termite gut—they also reveal the limitations of making predictions based exclusively on phylogenetic relationships.

Other Caltech coauthors on the paper titled "Localizing transcripts to single cells suggests an important role of uncultured deltaproteobacteria in the termite gut hydrogen economy," are graduate student Kaitlyn S. Lucey (environmental science and engineering), Elizabeth A. Ottesen (PhD '08, biology), graduate student Vikas Trivedi (bioengineering), and research scientist Harry M. T. Choi (PhD '10, bioengineering). This work was funded by the U.S. Department of Energy, the National Science Foundation, the National Institutes of Health, the Programmable Molecular Technology Center within the Beckman Institute at Caltech, a Donna and Benjamin M. Rosen Center Bioengineering scholarship, and the Center for Environmental Microbial Interactions at Caltech.

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Caltech Establishes New Division of Biology and Biological Engineering

The California Institute of Technology, in a move that creates an academic division unlike any other among its peer institutions, has combined the disciplines of biology and biological engineering into a new Division of Biology and Biological Engineering (BBE). The division, formally approved by the Caltech Board of Trustees in April, expands Caltech's Division of Biology, which was founded in 1928 by Nobel Prize–winning geneticist Thomas Hunt Morgan. Biological engineering focuses on using a "bottom up" approach to manipulate biological substrates, such as genes, proteins, and cells, to produce a given outcome or to encourage fundamental discovery—as opposed to the "top down" engineering of chips, medical implants, or other macroscopic devices.

"Biological engineering represents an engineering discipline that is based on the fundamental science of biology, and the formation of BBE further highlights Caltech's distinctive nature, as we tend to be extremely quantitative in our approach," says Stephen Mayo, William K. Bowes Jr. Foundation Chair of the division and Bren Professor of Biology and Chemistry. "Although other schools have biological engineering programs within their schools of engineering, none have a college or school in which biological engineering is integrated directly with biology, so they can enhance each other—allowing those people who are doing engineering to interact more closely with those who are doing fundamental work and obtaining basic knowledge. The potential synergy is powerful and important."

"The creation of BBE is a critical part of an effort at Caltech to enhance bioengineering and biological sciences and to continue Caltech's position at the forefront of these fields," says Edward M. Stolper, Caltech's provost and interim president.

As part of this change, a total of 11 professors have been added to BBE from other Caltech divisions; they represent research areas spanning genetic engineering, translational medicine, synthetic biology, molecular programming, and more. The restructured division will consist of three administrative groupings: biology, biological engineering, and neurobiology. Caltech's undergraduate program in bioengineering, previously administered by the Division of Engineering and Applied Sciences (EAS), will be managed by BBE, and the existing bioengineering graduate program also will move to BBE.

The division will manage the existing biology graduate and undergraduate options; a newly established neurobiology graduate option; the biochemistry and molecular biophysics (BMB) graduate option in collaboration with the Division of Chemistry and Chemical Engineering (CCE); and the computation and neural systems (CNS) graduate option in collaboration with EAS. Caltech's Donna and Benjamin M. Rosen Bioengineering Center, founded in 2008 through an $18 million gift from the Benjamin M. Rosen Family Foundation, will remain the campus hub for bioengineering activities and will continue to be jointly administered by BBE, EAS, and CCE.

"The formation of BBE is a reflection of the diversity and breadth of the activities in biological sciences and engineering at Caltech—from the structure and function of proteins at the atomic level to developing nanoprobe electrodes that can simultaneously measure the activity of thousands of neurons in the brain," says Mayo. "Putting these activities into one division increases the potential and the pace for providing transformative solutions to some of the biggest problems in science, medicine, and health."

The last time a division at Caltech changed its name was in 1970, when the Division of Geological Sciences became the Division of Geological and Planetary Sciences.



Kathy Svitil
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Wednesday, December 18, 2013

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