Wednesday, December 18, 2013
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Biosafety & Bloodborne Pathogens (BBP) Training

Wednesday, November 13, 2013
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Biosafety & Bloodborne Pathogens (BBP) Training

Wednesday, October 16, 2013
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Biosafety & Bloodborne Pathogens (BBP) Training

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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Kimm Fesenmaier
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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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Friday, September 27, 2013 to Sunday, September 29, 2013

Biology & Biological Engineering Annual Retreat

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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Friday, October 4, 2013

Undergraduate Teaching Assistant Orientation

A Home for the Microbiome

Caltech biologists identify, for the first time, a mechanism by which beneficial bacteria reside and thrive in the gastrointestinal tract

The human body is full of tiny microorganisms—hundreds to thousands of species of bacteria collectively called the microbiome, which are believed to contribute to a healthy existence. The gastrointestinal (GI) tract—and the colon in particular—is home to the largest concentration and highest diversity of bacterial species. But how do these organisms persist and thrive in a system that is constantly in flux due to foods and fluids moving through it? A team led by California Institute of Technology (Caltech) biologist Sarkis Mazmanian believes it has found the answer, at least in one common group of bacteria: a set of genes that promotes stable microbial colonization of the gut.

A study describing the researchers' findings was published as an advance online publication of the journal Nature on August 18.    

"By understanding how these microbes colonize, we may someday be able to devise ways to correct for abnormal changes in bacterial communities—changes that are thought to be connected to disorders like obesity, inflammatory bowel disease and autism," says Mazmanian, a professor of biology at Caltech whose work explores the link between human gut bacteria and health.

The researchers began their study by running a series of experiments to introduce a genus of microbes called Bacteriodes to sterile, or germ-free, mice. Bacteriodes, a group of bacteria that has several dozen species, was chosen because it is one of the most abundant genuses in the human microbiome, can be cultured in the lab (unlike most gut bacteria), and can be genetically modified to introduce specific mutations.

"Bacteriodes are the only genus in the microbiome that fit these three criteria," Mazmanian says.

Lead author S. Melanie Lee (PhD '13), who was an MD/PhD student in Mazmanian's lab at the time of the research, first added a few different species of the bacteria to one mouse to see if they would compete with each other to colonize the gut. They appeared to peacefully coexist. Then, Lee colonized a mouse with one particular species, Bacteroides fragilis, and inoculated the mouse with the same exact species, to see if they would co-colonize the same host. To the researchers' surprise, the newly introduced bacteria could not maintain residence in the mouse's gut, despite the fact that the animal was already populated by the identical species.

"We know that this environment can house hundreds of species, so why the competition within the same species?" Lee says. "There certainly isn't a lack of space or nutrients, but this was an extremely robust and consistent finding when we tried to essentially 'super-colonize' the mice with one species."

To explain the results, Lee and the team developed what they called the "saturable niche hypothesis." The idea is that by saturating a specific habitat, the organism will effectively exclude others of the same species from occupying that niche. It will not, however, prevent other closely related species from colonizing the gut, because they have their own particular niches. A genetic screen revealed a set of previously uncharacterized genes—a system that the researchers dubbed commensal colonization factors (CCF)—that were both required and sufficient for species-specific colonization by B. fragilis.

But what exactly is the saturable niche? The colon, after all, is filled with a flowing mass of food, fecal matter and bacteria, which doesn't offer much for organisms to grab onto and occupy.

"Melanie hypothesized that this saturable niche was part of the host tissue"—that is, of the gut itself—Mazmanian says. "When she postulated this three to four years ago, it was absolute heresy, because other researchers in the field believed that all bacteria in our intestines lived in the lumen—the center of the gut—and made zero contact with the host…our bodies. The rationale behind this thinking was if bacteria did make contact, it would cause some sort of immune response."

Nonetheless, when the researchers used advanced imaging approaches to survey colonic tissue in mice colonized with B. fragilis, they found a small population of microbes living in miniscule pockets—or crypts—in the colon. Nestled within the crypts, the bacteria are protected from the constant flow of material that passes through the GI tract. To test whether or not the CCF system regulated bacterial colonization within the crypts, the team injected mutant bacteria—without the CCF system—into the colons of sterile mice. Those bacteria were unable to colonize the crypts.

"There is something in that crypt—and we don't know what it is yet—that normal B. fragilis can use to get a foothold via the CCF system," Mazmanian explains. "Finding the crypts is a huge advance in the field because it shows that bacteria do physically contact the host. And during all of the experiments that Melanie did, homeostasis, or a steady state, was maintained. So, contrary to popular belief, there was no evidence of inflammation as a result of the bacteria contacting the host. In fact, we believe these crypts are the permanent home of Bacteroides, and perhaps other classes of microbes."

He says that by pinpointing the CCF system as a mechanism for bacterial colonization and resilience, in addition to the discovery of crypts in the colon that are species specific, the current paper has solved longstanding mysteries in the field about how microbes establish and maintain long-term colonization.

"We've studied only a handful of organisms, and though they are numerically abundant, they are clearly not representative of all the organisms in the gut," Lee says. "A lot of those other bacteria don't have CCF genes, so the question now is: Do those organisms somehow rely on interactions with Bacteroides for their own colonization, or their replication rates, or their localization?"

Suspecting that Bacteroides are keystone species—a necessary factor for building the gut ecosystem—the researchers next plan to investigate whether or not functional abnormalities, such as the inability to adhere to crypts, could affect the entire microbiome and potentially lead to a diseased state in the body.

"This research highlights the notion that we are not alone. We knew that bacteria are in our gut, but this study shows that specific microbes are very intimately associated with our bodies," Mazmanian says. "They are living in very close proximity to our tissues, and we can't ignore microbial contributions to our biology or our health. They are a part of us."

Funding for the research outlined in the Nature paper, titled "Bacterial colonization factors control specificity and stability of the gut microbiota," was provided by the National Institutes of Health and the Crohn's and Colitis Foundation of America. Additional coauthors were Gregory Donaldson and Silva Boyajian from Caltech and Zbigniew Mikulski and Klaus Ley from the La Jolla Institute for Allergy and Immunology in La Jolla, California.

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Katie Neith
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