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.

 

 

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Caltech-led WormBase Project Awarded $14.8 Million by NIH

Over the next five years, WormBase—a Caltech-led, multi-institutional effort to make genetic information about nematodes, or roundworms, freely available to the world—will receive $14.8 million in additional funding from the National Institutes of Health. As many as 1 million nematode species are thought to live on Earth, and many are pests or parasites that ravage crops and spread diseases. They also happen to share many genes that are found in humans. Therefore, the squirmy creatures are intensively researched by labs around the world.

The WormBase project began in 2000 with the original goal of creating an online clearinghouse for data related to the most widely studied nematode, the model organism Caenorhabditis elegans. The project's website (www.wormbase.org) now hosts genomic data for more than 50 nematodes as well as vast amounts of other experimental data. In fact, about 1,200 scientific papers are added to the searchable database every year. And with more than 1,000 laboratories currently registered as users, WormBase has become an invaluable tool for the biomedical and agricultural research communities.

"WormBase has made it much easier for bench researchers to access a lot of information that they need much more rapidly. That accelerates research," says Paul Sternberg, the Thomas Hunt Morgan Professor of Biology at Caltech and leader of the WormBase project. "It has enabled studies that just would not have been possible without all of this information being available in a single place."

The bioinformatics resource serves a number of different communities. One of those is the group of scientists working with less-studied nematode species. "A lot of the research comes from individual researchers studying a specific problem. They generate a lot of facts and observations along the way; that information, if you aggregate it, ends up being quite valuable and extensive," Sternberg explains. "So, WormBase collects those bits of information and stores them in one place. It ends up being more than the sum of the parts."

WormBase also serves basic biomedical researchers who have used the database to investigate everything from cancer genes and axon growth to aging and kidney disease. Finally, WormBase is helpful for those scientists who study disease-causing nematodes and those species that infect and wreak havoc on crops and livestock.

Going forward, the WormBase project hopes to help researchers understand in greater detail the mechanisms through which nematode genes work together in pathways by making certain types of data more accessible and richer. "We have the parts list," Sternberg says. "Now the question is, how do all of the parts really work together to make the intricate mechanisms?"

WormBase is also working with the organizers of similar databases for other model organisms—such as the fruit fly and the mouse—that share many genes with nematodes. They are trying to align the databases, in terms of the formats they use and their interfaces, so that researchers can easily search all of them. So, for example, researchers studying a human gene who want information about that gene's counterparts in the worm or fruit fly would be able to switch between the databases quickly and easily. "We are also sharing the development of text-mining software that allows us to extract information from papers more efficiently," Sternberg says.

WormBase is an international consortium led by Caltech. Current collaborators include the Ontario Institute for Cancer Research in Toronto, Canada, and the European Bioinformatics Institute in Cambridge, England. 

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Team Led by Caltech Wins Second $10 Million Award for Research in Molecular Programming

During the past century, programmable technologies evolved from spinning gears and vacuum tubes to transistors and microchips. Now, a group of Caltech researchers and their colleagues at the University of Washington, Harvard University, and UC San Francisco are exploring how biologically important molecules—like DNA, RNA, and proteins—could be the next generation of programmable devices.

Erik Winfree, professor of computer science, computation, and neural systems, and bioengineering, along with collaborators at Caltech and the University of Washington, began the Molecular Programming Project (MPP) in 2008, as part of an NSF Expeditions in Computing award to develop practices for programming biomolecules—much like a computer code—to perform designated functions. Over the past five years, the researchers have programmed DNA to carry out a number of tasks, from solving basic math and pattern-recognition problems to more mechanical tasks like programming RNA and DNA to selectively amplify fluorescent signals for biological microscopy. Through these initial experiments, the researchers have shown that it is possible to systematically encode specialized tasks within DNA molecules.

"Computer science gave us this idea that many tasks can actually be done with different types of devices," Winfree says. For example, a 19th-century cash register and a 21st-century computer can both be used to calculate sums, though they perform the same task very differently. At first glance, writing a computer program and programming a DNA molecule may seem like very different endeavors, but "each one provides a systematic way of implementing automated behaviors, and they are both based on similar principles of information technology," Winfree says.

Expanding the team to include five additional faculty who bring expertise in structural and dynamic DNA nanotechnology, synthetic biology, computer-aided design, programming languages, and compilers, Winfree and his colleagues recently received a second Expeditions in Computing award to take their work in molecular programming to the next level: from proof-of-principle demonstrations to putting the technology in the hands of users in biology, chemistry, physics, and materials science.

The researchers aim to use molecular programming to establish general-purpose, reliable, and easy-to-use methods for engineering complex nanoscale systems from biomolecules. In the hands of users, these methods could be used to create novel self-assembling electronic and optical devices, powerful nanoscale tools for the study of biology, and programmable molecular circuits for the diagnosis and treatment of disease. In one application, the researchers hope to program DNA molecules to carry out recognition and logical circuitry for exquisitely targeted drug delivery, thus reducing drug side effects and increasing efficacy.

Today, the largest synthetic molecular programs—human-designed sequences of the A, T, C, and G bases that make up DNA—contain on the order of 60,000 bases. "That's comparable to the amount of RAM memory in my first computer, a 1983 Apple II+," says Winfree. Designed systems in the future will only become more complex, a challenge that MPP researchers aim to tackle by approaching biological systems with something computer scientists call the abstraction hierarchy.

"In some sense computer science is the art of managing complexity, because you design things that have billions of components, but a single person simply cannot understand all the details and interactions," he says. "Abstraction is a way of hiding a component's details while making it easy to incorporate into higher-order components—which, themselves, can also be abstracted. For example, you don't need to know the details of a multiplication circuit in order to use it to make a circuit for factoring." In the molecular world, the task might be different—like transporting a molecular cargo to a designated location—but abstraction is still essential for combining simpler systems into larger ones to perform tasks of greater complexity.

"Over the next several decades, the MPP seeks to develop the principles and practice for a new engineering discipline that will enable the function of molecules to be programmed with the ease and rigor that computers are today, while achieving the sophistication, complexity, and robustness evident in the programmable DNA, RNA, and protein machinery of biology," says Niles Pierce, professor of applied and computational mathematics and bioengineering at Caltech and member of the MPP.

To integrate these fields, the MPP has brought together an interdisciplinary team of computer scientists, chemists, electrical engineers, physicists, roboticists, mathematicians, and bioengineers—all of whom have a strong research interest in the intersection of information, biology, and the molecular world. The team will explore the potential of molecular programming from many perspectives.

"Because of the diverse expertise that is required to work on these challenges, the participating students and faculty come from an unusual array of fields," Pierce says. "It's a lot of fun to be in a room with this group of people to see where the discussions lead."

The 2013 Expeditions award was granted for the proposal "Molecular Programming Architectures, Abstractions, Algorithms, and Applications." Winfree and Pierce are joined on the project by four other collaborators at Caltech: Jehoshua (Shuki) Bruck, Gordon and Betty Moore Professor of Computation and Neural Systems and Electrical Engineering; Richard Murray, Thomas E. and Doris Everhart Professor of Control and Dynamical Systems and Bioengineering; Lulu Qian, assistant professor of bioengineering; and Paul Rothemund, senior research associate in bioengineering, computing and mathematical sciences, and computation and neural systems. Other collaborators include Eric Klavins and Georg Seelig from the University of Washington, Peng Yin and William Shih from Harvard, and Shawn Douglas from UC San Francisco.

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A New Way to Replace Damaged or Missing Cells

When certain cells in our bodies are missing or nonfunctional, the only current options are to treat the symptoms with drugs or try to acquire transplants. But what if cells in our own bodies could be transformed to take on the missing functions? What if we could convert cells from other organs to function as neurons after a stroke; cardiomyocytes to address heart disease; gland cells to address endocrine diseases, or cartilaginous cells to address joint deterioration? This may be a real possibility thanks to funding from the Caltech Innovation Initiative, a philanthropically funded internal grant program designed to provide research funds to high-risk but potentially high-reward projects that could produce disruptive technologies with practical applications in the marketplace.

Working with Caltech colleague Isabelle Peter and Yong Zhu of the start-up Vivoscript, Caltech biologist Eric Davidson applied seed funds from the Caltech Innovation Initiative to test experimentally a new theory of cell-fate transformation that he and Peter codeveloped. The theory posits that cells in a living patient can be converted to work as completely different types of cells. Davidson and colleagues have transformed liver cells into cells that function like pancreatic cells, at least to the extent that they produce insulin.

The work, inspired by the group's studies of gene regulatory networks in sea urchin embryos, begins with putting suites of protein molecules called transcription factors near the cells targeted for transformation. These proteins have been engineered in a proprietary way, in collaboration with Vivoscript, so that they will be taken up by cells and will travel into the nuclei. The new proteins control cellular activity by regulating gene expression. Researchers want to be able to predict the complete suite of proteins needed to durably reproduce the gene expression — and resulting normal functions — of one kind of cell in a different original cell.

These new possibilities for therapies based on cell transformation avoid the expense and hazards associated with use of genetically transformed cells or in vitro differentiated stem cells.

If the approach is generalizable and predictable, it could answer the urgent need for a safe, inexpensive way to replace damaged or missing cells. Caltech has applied for patent protection. Davidson's next step is to demonstrate the degree to which the conversion of liver cells into pancreatic cells works.  

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Caltech to Offer Online Courses through edX

To expand its involvement in online learning, the California Institute of Technology will offer courses through the online education platform edX beginning this October.

The edX course platform is an online learning initiative launched in 2012 by founding partners Harvard University and the Massachusetts Institute of Technology (MIT). Caltech's rigorous online course offerings will join those of 28 other prestigious colleges and universities in the edX platform's "xConsortium."

This new partnership with edX comes one year after Caltech offered three courses through the online learning platform Coursera in fall 2012. The Institute will now offer courses through both platforms.

"Coursera and edX have some foundational differences which are of interest to the faculty," says Cassandra Horii, director of teaching and learning programs at Caltech. Both organizations offer their courses at no cost to participating students; edX, however, operates as a nonprofit and plans to partner with only a small number of institutions, whereas Coursera—a for-profit, self-described "social entrepreneurship company"—partners with many institutions and state university systems.

The two platforms also emphasize different learning strategies, says Horii. "Coursera has a strong organizational principle built around lectures, so a lot of the interactivity is tied right into the video," she says. Though edX still enables the use of video lectures, a student can customize when he or she would like to take quizzes and use learning resources. In addition, edX allows faculty to embed a variety of learning materials—like textbook chapters, discussions, diagrams, and tables—directly into the platform's layout.

In the future, data collected from both platforms could provide valuable information about how students best learn certain material, especially in the sciences. "Caltech occupies this advanced, really rigorous scientific education space, and in general our interest in these online courses is to maintain that rigor and quality," Horii says. "So, with these learning data, we have some potential contributions to make to the general understanding of learning in this niche that we occupy."

Even before joining edX and Coursera, Caltech had already become an example in the growing trend of Massive Open Online Courses (MOOCs). Yaser Abu-Mostafa, professor of electrical engineering and computer science, developed his own MOOC on machine learning, called "Learning from Data," and offered it on YouTube and iTunes U beginning in April 2012.

Since its debut, Abu-Mostafa's MOOC has reached more than 200,000 participants, and it received mention in the NMC Horizon Report: 2013 Higher Education Edition—the latest edition of an annual report highlighting important trends in higher education. The course will be offered again in fall 2013 on iTunes U, and is now also open for enrollment in edX.

Although Caltech is now actively exploring several outlets for online learning, the Institute's commitment to educational outreach is not a recent phenomenon. In the early 1960s, Caltech physicist Richard Feynman reorganized the Institute's introductory physics course, incorporating contemporary research topics and making the course more engaging for students. His lectures were recorded and eventually incorporated into a widely popular physics book, The Feynman Lectures on Physics, which has sold millions of copies in a dozen languages.

Continuing in the tradition set by Feynman, the MOOCs at Caltech seek to provide a high-quality learning environment that is rigorous but accessible. "No dumbing down of courses for popular consumption . . . no talking over people's heads either; at Caltech, we explain things well because we understand them well," adds Abu-Mostafa.

More information on Caltech's online learning opportunities is available on the Online Education website.

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