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Bringing Silicon to Life

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Scientists persuade nature to make silicon-carbon bonds
News Writer: 
Whitney Clavin

Bringing Silicon to Life: Scientists Persuade Nature to Make Silicon-Carbon Bonds

Bringing Silicon to Life: Scientists Persuade Nature to Make Silicon-Carbon Bonds
Researchers in Frances Arnold’s lab at Caltech have persuaded living organisms to make chemical bonds not found in nature. The finding may change how medicines and other chemicals are made in the future.
Credit: Caltech

A new study is the first to show that living organisms can be persuaded to make silicon-carbon bonds—something only chemists had done before. Scientists at Caltech "bred" a bacterial protein to have the ability to make the man-made bonds—a finding that has applications in several industries.

Molecules with silicon-carbon, or organosilicon, compounds are found in pharmaceuticals as well as in many other products, including agricultural chemicals, paints, semiconductors, and computer and TV screens. Currently, these products are made synthetically, since the silicon-carbon bonds are not found in nature.

The new research, which recently won Caltech's Dow Sustainability Innovation Student Challenge Award (SISCA) grand prize, demonstrates that biology can instead be used to manufacture these bonds in ways that are more environmentally friendly and potentially much less expensive.

"We decided to get nature to do what only chemists could do—only better," says Frances Arnold, Caltech's Dick and Barbara Dickinson Professor of Chemical Engineering, Bioengineering and Biochemistry, and principal investigator of the new research, published in the Nov. 24 issue of the journal Science.

The study is also the first to show that nature can adapt to incorporate silicon into carbon-based molecules, the building blocks of life. Scientists have long wondered if life on Earth could have evolved to be based on silicon instead of carbon. Science-fiction authors likewise have imagined alien worlds with silicon-based life, like the lumpy Horta creatures portrayed in an episode of the 1960s TV series Star Trek. Carbon and silicon are chemically very similar. They both can form bonds to four atoms simultaneously, making them well suited to form the long chains of molecules found in life, such as proteins and DNA.

"No living organism is known to put silicon-carbon bonds together, even though silicon is so abundant, all around us, in rocks and all over the beach," says Jennifer Kan, a postdoctoral scholar in Arnold's lab and lead author of the new study. Silicon is the second most abundant element in Earth's crust.

The researchers used a method called directed evolution, pioneered by Arnold in the early 1990s, in which new and better enzymes are created in labs by artificial selection, similar to the way that breeders modify corn, cows, or cats. Enzymes are a class of proteins that catalyze, or facilitate, chemical reactions. The directed evolution process begins with an enzyme that scientists want to enhance. The DNA coding for the enzyme is mutated in more-or-less random ways, and the resulting enzymes are tested for a desired trait. The top-performing enzyme is then mutated again, and the process is repeated until an enzyme that performs much better than the original is created.

Directed evolution has been used for years to make enzymes for household products, like detergents; and for "green" sustainable routes to making pharmaceuticals, agricultural chemicals, and fuels.

In the new study, the goal was not just to improve an enzyme's biological function but to actually persuade it to do something that it had not done before. The researchers' first step was to find a suitable candidate, an enzyme showing potential for making the silicon-carbon bonds.

"It's like breeding a racehorse," says Arnold, who is also the director of the Donna and Benjamin M. Rosen Bioengineering Center at Caltech. "A good breeder recognizes the inherent ability of a horse to become a racer and has to bring that out in successive generations. We just do it with proteins."

The ideal candidate turned out to be a protein from a bacterium that grows in hot springs in Iceland. That protein, called cytochrome c, normally shuttles electrons to other proteins, but the researchers found that it also happens to act like an enzyme to create silicon-carbon bonds at low levels. The scientists then mutated the DNA coding for that protein within a region that specifies an iron-containing portion of the protein thought to be responsible for its silicon-carbon bond-forming activity. Next, they tested these mutant enzymes for their ability to make organosilicon compounds better than the original.

After only three rounds, they had created an enzyme that can selectively make silicon-carbon bonds 15 times more efficiently than the best catalyst invented by chemists. Furthermore, the enzyme is highly selective, which means that it makes fewer unwanted byproducts that have to be chemically separated out.

"This iron-based, genetically encoded catalyst is nontoxic, cheaper, and easier to modify compared to other catalysts used in chemical synthesis," says Kan. "The new reaction can also be done at room temperature and in water."

The synthetic process for making silicon-carbon bonds often uses precious metals and toxic solvents, and requires extra processing to remove unwanted byproducts, all of which add to the cost of making these compounds.

As to the question of whether life can evolve to use silicon on its own, Arnold says that is up to nature. "This study shows how quickly nature can adapt to new challenges," she says. "The DNA-encoded catalytic machinery of the cell can rapidly learn to promote new chemical reactions when we provide new reagents and the appropriate incentive in the form of artificial selection. Nature could have done this herself if she cared to."

The Science paper, titled "Directed Evolution of Cytochrome c for Carbon-Silicon Bond Formation: Bringing Silicon to Life," is also authored by Russell Lewis and Kai Chen of Caltech. The research is funded by the National Science Foundation, the Caltech Innovation Initiative program, and the Jacobs Institute for Molecular Engineering for Medicine at Caltech.


Programmable Disorder

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Random Algorithms at the Molecular Scale
News Writer: 
Lori Dajose
image of self-assembled random tree structures on the surface of DNA tile arrays
Colored atomic force microscope image of self-assembled random tree structures on the surface of DNA tile arrays. Each tree has a single loop as the “root”.
Credit: Caltech / Grigory Tikhomirov, Philip Petersen and Lulu Qian

Many self-organized systems in nature exploit a sophisticated blend of deterministic and random processes. No two trees are exactly alike because growth is random, but a Redwood can be readily distinguished from a Jacaranda as the two species follow different genetic programs. The value of randomness in biological organisms is not fully understood, but it has been hypothesized that it allows for smaller genome sizes—because not every detail must be encoded. Randomness also provides the variation underlying adaptive evolution.

In contrast to biology, engineering seldom takes advantage of the power of randomness for fabricating complex structures. Now, a group of Caltech scientists has demonstrated that randomness in molecular self-assembly can be combined with deterministic rules to produce complex nanostructures out of DNA.

The work, done in the laboratory of Assistant Professor of Bioengineering Lulu Qian, appears in the November 28 issue of the journal Nature Nanotechnology.

Living things use DNA to store genetic information, but DNA can also be used as a robust chemical building block for molecular engineering. The four complementary molecules that make up DNA, called nucleotides, bind together only in specific ways: A's bind with T's, and G's bind with C's. In 2006, Paul Rothemund (BS '94), research professor of bioengineering, computing and mathematical sciences, and computation and neural systems at Caltech, invented a technique called DNA origami that takes advantage of the matching between long strands of DNA nucleotides, folding them into everything from nanoscale artwork to drug-delivery devices. The self-assembled structures formed through DNA origami may be functional by themselves or they may be used as templates to organize other functional molecules—such as carbon nanotubes, proteins, metal nanoparticles, and organic dyes—with unprecedented programmability and spatial precision.

Using DNA origami as a building block, researchers have made larger DNA nanostructures, such as periodic arrays of origami tiles. However, because the building block is just repeated everywhere, the complexity of patterns that can be formed on these larger structures is quite limited. Entirely deterministic assembly processes—controlling the design of each individual tile and its distinct position in the array—can give rise to complex patterns, but these processes do not scale up well. Conversely, if only random processes are involved and the global features of the array are not controlled by design rules, it is impossible to create complex patterns with desired properties without simultaneously generating a large fraction of undesired molecules that are wasted. Until the work by Qian and her colleagues, combining deterministic processes with random ones had never been systematically explored to create complex DNA nanostructures.

"We were looking for molecular self-assembly principles that embrace both deterministic and random aspects," says Qian. "We developed a simple set of rules that allow DNA tiles to bind randomly but only into specific controlled patterns."

The approach involves designing patterns on individual tiles, modulating the ratios of different tiles, and determining which tiles can bind together during self-assembly. This leads to large-scale emergent features with tunable statistical properties—a phenomenon the authors dub "programmable disorder."

"The structures that we can build have programmably random aspects," says Grigory Tikhomirov, a senior postdoctoral scholar in biology and biological engineering, and lead author on the paper. "For example, we can make structures that have lines that take seemingly random paths, but we can ensure that they never intersect and always eventually close up into loops."

In addition to loops, the team chose two other examples, mazes and trees, to demonstrate that many nontrivial properties of these structures can be controlled by simple local rules. They found these examples interesting because loop, maze, and tree structures widely exist in nature across multiple scales. For example, lungs are tree structures at the millimeter to centimeter scale, and neural dendrites are tree structures at the micrometer to millimeter scale. The controlled properties that they showed include the branching rules, the growth directions, the proximity between adjacent networks, and the size distribution.

The group was first inspired by the classic Truchet tiles, which are square tiles with two diagonally symmetrical arcs of DNA on the surface. There are two rotationally asymmetrical orientations of the arc pattern (see image below). Allowing a random choice of the two tile orientations at each location in the array, the pattern will continue through neighboring tiles, either becoming loops of various sizes or exiting from an edge of the array.

ALT Left, Truchet tiles have two arcs that are rotationally asymmetrical. Right, popular board games inspired by Truchet tiles. (credit: Courtesy of L. Qian)

To create Truchet arrays at the molecular scale, the team used the DNA origami technique to fold DNA into square tiles and then designed the interactions between these tiles to encourage them to self-assemble into large two-dimensional arrays.

"Because all molecules bump into each other while floating around in a test tube during the process of self-assembly, the interactions should be weak enough to allow the tiles to rearrange themselves and avoid being trapped at any undesired configurations," says Philip Petersen, a graduate student in the Qian laboratory and co-first author on the paper. "On the other hand, the interactions should be specific enough so the desired interactions are always much preferred over undesired, spurious interactions."

Different types of global patterns emerge when tiles are marked with different local patterns. For example, if each randomly oriented tile carries a "T" rather than two arcs, the global pattern is a maze with branches and loops rather than only loops (see images below). If the self-assembly rules constrain the possible relative orientation of neighboring "T" tiles, it is possible to ensure that other than a single "root," the branches in the mazes never close into loops—producing trees. To explore the full generality of these principles, Qian's team developed a programming language for random DNA origami tilings.

ALT Self-assembled loop, maze, and tree structures on the surface of DNA tile arrays. Top row, random mazes with three-way and four-way junctions of varying distances between adjacent junctions versus only three-way junctions of a fixed distance between adjacent junctions. Middle row, random trees (each tree has a single loop as the "root") with longer branches of varying lengths versus shorter branches of fixed lengths. Bottom row, random loops with tunable lengths and number of crossings. (credit: Courtesy of L. Qian)

"With this programming language, the design process starts with a high-level description of the tiles and arrays, which can be automatically translated to abstract array diagrams and numerical simulations, then moves to DNA origami tile design including how the tiles interact with each other on their edges. Finally, we design DNA sequences," Qian says. "With these DNA sequences, it is straightforward for researchers to order the DNA strands, mix them in a test tube, wait for the molecules to self-assemble into the designed structures overnight, and obtain images of the structures using an atomic force microscope."

The group's method of programmable disorder has diverse future applications. For example, it could be used to build complex testing environments for ever-more-sophisticated molecular robots—DNA-based nanoscale machines that can move on a surface, pick up or drop off proteins or other kinds of molecules as cargos, and make decisions about navigation and actions.

"The potential applications are much broader," Qian adds. Since the 1990s, random one-dimensional chains of polymers have been used to revolutionize chemical and material synthesis, drug delivery, and nucleic acid chemistry by creating vast combinatorial libraries of candidate molecules and then selecting or evolving the best ones in the laboratory. "Our work extends the same principle to two-dimensional networks of molecules and now creates new opportunities for fabricating more complex molecular devices organized by DNA nanostructures," she says.

The paper is titled "Programmable disorder in random DNA tilings." This work was funded by the National Science Foundation, a National Institutes of Health National Research Service Award, and the Burroughs Wellcome Fund.

Parkinson's Disease Linked to Microbiome

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News Writer: 
Lori Dajose
microglia
Gut microbes can initiate activation of microglia (brain-resident immune cells, shown in green), which leads to the neuroinflammation that is characteristic of Parkinson’s disease.
Credit: S. Mazmanian Lab/Caltech

Caltech scientists have discovered for the first time a functional link between bacteria in the intestines and Parkinson's disease (PD). The researchers show that changes in the composition of gut bacterial populations—or possibly gut bacteria themselves—are actively contributing to and may even cause the deterioration of motor skills that is the hallmark of this disease.

The work—which has profound implications for the treatment of PD—was performed in the laboratory of Sarkis Mazmanian, the Luis B. and Nelly Soux Professor of Microbiology and Heritage Medical Research Institute Investigator, and appears in the December 1 issue of Cell.

PD affects 1 million people in the US and up to 10 million worldwide, making it the second most common neurodegenerative disease. Characteristic features of PD include symptoms such as tremors and difficulty walking, aggregation of a protein called alpha-synuclein (αSyn) within cells in the brain and gut, and the presence of inflammatory molecules called cytokines within the brain. In addition, 75 percent of people with PD have gastrointestinal (GI) abnormalities, primarily constipation.

"The gut is a permanent home to a diverse community of beneficial and sometimes harmful bacteria, known as the microbiome, that is important for the development and function of the immune and nervous systems," Mazmanian says. "Remarkably, 70 percent of all neurons in the peripheral nervous system—that is, not the brain or spinal cord—are in the intestines, and the gut's nervous system is directly connected to the central nervous system through the vagus nerve. Because GI problems often precede the motor symptoms by many years, and because most PD cases are caused by environmental factors, we hypothesized that bacteria in the gut may contribute to PD."

To test this, the researchers utilized mice that overproduce αSyn and display symptoms of Parkinson's. One group of mice had a complex consortium of gut bacteria; the others, called germ-free mice, were bred in a completely sterile environment at Caltech and thus lacked gut bacteria. The researchers had both groups of mice perform several tasks to measure their motor skills, such as running on treadmills, crossing a beam, and descending from a pole. The germ-free mice performed significantly better than the mice with a complete microbiome.

"This was the 'eureka' moment," says Timothy Sampson, a postdoctoral scholar in biology and biological engineering and first author on the paper. "The mice were genetically identical; both groups were making too much αSyn. The only difference was the presence or absence of gut microbiota. Once you remove the microbiome, the mice have normal motor skills even with the overproduction of αSyn."

"All three of the hallmark traits of Parkinson's were gone in the germ-free models," Sampson says. "Now we were quite confident that gut bacteria regulate, and are even required for, the symptoms of PD. So, we wanted to know how this happens."

When gut bacteria break down dietary fiber, they produce molecules called short-chain fatty acids (SCFAs), such as acetate and butyrate. Previous research has shown that these molecules also can activate immune responses in the brain. Thus, Mazmanian's group hypothesized that an imbalance in the levels of SCFAs regulates brain inflammation and other symptoms of PD. Indeed, when germ-free mice were fed SCFAs, cells called microglia—which are immune cells residing in the brain—became activated. Such inflammatory processes can cause neurons to malfunction or even die. In fact, germ-free mice fed SCFAs now showed motor disabilities and αSyn aggregation in regions of the brain linked to PD.

In a final set of experiments, Mazmanian and his group collaborated with Ali Keshavarzian, a gastroenterologist at Rush University in Chicago, to obtain fecal samples from patients with PD and from healthy controls. The human microbiome samples were transplanted into germ-free mice, which then remarkably began to exhibit symptoms of PD. These mice also showed higher levels of SCFAs in their feces. Transplanted fecal samples from healthy individuals, in contrast, did not trigger PD symptoms, unlike mice harboring gut bacteria from PD patients.

"This really closed the loop for us," Mazmanian says. "The data suggest that changes to the gut microbiome are likely more than just a consequence of PD. It's a provocative finding that needs to be further studied, but the fact that you can transplant the microbiome from humans to mice and transfer symptoms suggests that bacteria are a major contributor to disease."

The findings have important implications for the treatment of Parkinson's, the researchers say.

"For many neurological conditions, the conventional treatment approach is to get a drug into the brain. However, if PD is indeed not solely caused by changes in the brain but instead by changes in the microbiome, then you may just have to get drugs into the gut to help patients, which is much easier to do," Mazmanian says. Such drugs could be designed to modulate SCFA levels, deliver beneficial probiotics, or remove harmful organisms. "This new concept may lead to safer therapies with fewer side effects compared to current treatments."

The paper is titled "Gut Microbiota Regulate Motor Deficits and Neuroinflammation in a Model of Parkinson's Disease." Other Caltech coauthors include Taren Thron, Gnotobiotic Facility manager and research technician for the Mazmanian laboratory; undergraduate Gauri G. Shastri; postdoctoral scholar Collin Challis; graduate student Catherine E. Schretter; and Viviana Gradinaru, assistant professor of biology and biological engineering and Heritage Medical Research Institute Investigator. The work was funded by the Larry L. Hillblom Foundation, the Knut and Alice Wallenberg Foundation, the Swedish Research Council, Mr. and Mrs. Larry Field, the Heritage Medical Research Institute, and the National Institutes of Health. 

Caltech and the Tianqiao and Chrissy Chen Institute Launch Major Neuroscience Initiative

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Initiative kicked off with $115 million gift from philanthropists Tianqiao Chen and Chrissy Luo to establish a new institute and provide continuous funds for neuroscience research. Caltech to construct $200 million biosciences complex.
News Writer: 
Kathy Svitil

Caltech and the Tianqiao and Chrissy Chen Institute Launch Major Neuroscience Initiative

Caltech and the Tianqiao and Chrissy Chen Institute Launch Major Neuroscience Initiative
Caltech leadership and faculty join philanthropist Chrissy Luo to discuss how a neuroscience initiative and associated institute will create a unique environment and opportunities for interdisciplinary research that deepens our understanding of the brain.
Credit: Caltech

Spearheaded by a $115 million gift from visionary philanthropists Tianqiao Chen and Chrissy Luo, Caltech and the Tianqiao and Chrissy Chen Institute are announcing the launch of a campus-wide neuroscience initiative to create a unique environment for interdisciplinary brain research. The goal of the new endeavor is to deepen our understanding of the brain—the most powerful biological and chemical computing machine—and how it works at the most basic level as well as how it fails because of disease or through the aging process.

Central to the initiative is the creation of the Tianqiao and Chrissy Chen Institute for Neuroscience at Caltech, where research investigations will span a continuum, from deciphering the basic biology of the brain to understanding sensation, perception, cognition, and human behavior, with the goal of making transformational advances that will inform new scientific tools and medical treatments.

The Tianqiao and Chrissy Chen Institute at Caltech will be supported through the Chens' investment, which includes endowed funds to be used at the discretion of Caltech's leadership to support activities such as seeding new lines of research and supporting promising early-career faculty and scholars. In addition, as part of the neuroscience initiative, Caltech will construct a $200 million biosciences complex named in honor of the Chens that will include state-of-the-art facilities for the Chen Institute at Caltech.

Involving faculty from across the university's six academic divisions, the Chen Institute at Caltech will catalyze a campus-wide interdisciplinary community of neuroscientists, biologists, chemists, physicists, engineers, computer scientists, and social scientists, all with the shared goal of understanding the fundamental principles that underlie brain function. The new building will be a nexus for neuroscience research on campus. It will comprise shared lab spaces and centralized areas that foster interaction and collaboration, amplifying and extending Caltech's long traditions in molecular, cellular, and systems neuroscience. As part of the commitment to the partnership, Caltech will also co-invest significant resources to be deployed for the Chen Institute at Caltech's operations.

Chen and Luo, who are husband and wife, are deeply committed to supporting brain research to promote and improve the well-being of humanity. Caltech, with its intimate research environment and quantitative approach to probing the biological and computational complexity of the brain, as well as its robust history in the fields of neuroscience and fundamental biology, is uniquely poised to advance discoveries and to develop new insights that will lead to innovation and improvement in the human condition.

"It is a privilege to launch this vital collaborative effort with Tianqiao Chen and Chrissy Luo," says Caltech president Thomas Rosenbaum, the Sonja and William Davidow Presidential Chair and professor of physics. "We share a vision with our cornerstone partners, the Chens, of translating insights into the fundamental biology, chemistry, and physics of the brain into a deeper understanding of how human beings perceive and interact with the world, and how technological interventions can improve the human experience."

Chen and Luo founded Shanda Interactive Entertainment Limited in 1999, which became the largest online entertainment developer and publisher in China. The company has since transformed into a global private investment company. The couple are longtime philanthropists who have provided funding toward medical programs for children in China and Mongolia, supported education for underprivileged families, and contributed to disaster relief and rebuild efforts in China. Through collaborations with top global universities, the Tianqiao and Chrissy Chen Institute's brain research initiative will be focused on three areas: brain discovery, treatment, and development. This gift to Caltech represents the Tianqiao and Chrissy Chen Institute's first investment in this initiative and at an institution in the United States.

"Our involvement in the Internet and entertainment industries allowed us to witness the ability for technology advancements to influence human perception, as well as to observe the resultant meaningful effects on human behavior," says Tianqiao Chen, co-founder of the Tianqiao and Chrissy Chen Institute. "However, there is little understanding about how the brain processes and connects what lies in between—sensation, perception, cognition, and action. We believe uncovering how the brain perceives, interprets, and interacts with the world is pivotal in so many aspects. It can shape groundbreaking industries such as artificial intelligence, robotics, and virtual reality. It also plays a critical role in addressing social issues such as aging and behavioral deficiencies. It can even help answer many ultimate questions about life, such as its origin, purpose, and ending. This is the mission of our philanthropy, and we are dedicating an initial one billion dollars to this cause."

Chrissy Luo, co-founder of Shanda and the Tianqiao and Chrissy Chen Institute, adds, "We spent two years learning the subject from highly regarded global universities with whom we continue to have conversations. We chose Caltech as our first partner not just for their strong reputation as a leading research institution, but also for the admiration in their natural alignment with Shanda's culture, which is focused on creating excellence and discovery. We have enjoyed the strong working relationship with Caltech and are firmly confident of this partnership."

Caltech's pioneering work in neuroscience includes Seymour Benzer's discovery that the fruit fly Drosophila melanogaster could be used as a simple organism to study how genes influence behavior. It is also illustrated by Roger Sperry's Nobel Prize–winning discovery that the right and left sides of the human brain must communicate with each other for proper cognitive function. Caltech also has been the home of achievements in computational neuroscience such as the development of very-large-scale integrated circuits, their application to machine learning and machine vision, and the establishment in 1986 of the world's first graduate program in Computation and Neural Systems (CNS), which continues to this day.

"Everything that we are as human beings—our ability to see the world and ask questions about our universe—is rooted in the structure and function of our brains," says Steve Mayo (PhD '87), the Bren Professor of Biology and Chemistry and the William K. Bowes Jr. Leadership Chair of the Division of Biology and Biological Engineering. "One of the greatest challenges and opportunities of our time is to be able to unlock that structure and how it relates to function, which will have an enormous impact on the lives of real people."

David J. Anderson, the Seymour Benzer Professor of Biology and a Howard Hughes Medical Institute Investigator, will serve as the director of the new neuroscience institute, which will comprise five interdisciplinary research centers—including four new centers, founded through the gift from the Chens, and one existing center. Anderson will be named the inaugural holder of the Tianqiao and Chrissy Chen Institute for Neuroscience Leadership Chair.

The five centers are:

  • The T&C Chen Brain-Machine Interface Center

    Led by Richard Andersen, Caltech's James G. Boswell Professor of Neuroscience, the T&C Chen Brain-Machine Interface Center will advance Caltech's work on a new generation of brain-machine interfaces. Caltech investigators have been developing devices that can communicate with and stimulate the brain. Recordings allow intentions to be read out to assist paralyzed people to perform fluid motions using robotic limbs simply by thinking about moving. Stimulation will allow the evocation of new perceptions, helping those who have lost sensation from paralysis or brain diseases. The T&C Chen Brain-Machine Interface Center will support every aspect of this effort, from the investigation of the basic science of intention and perception to technology development and clinical studies.
     
  • The T&C Chen Center for Social and Decision Neuroscience

    Under the direction of Colin Camerer, Caltech's Robert Kirby Professor of Behavioral Economics, the T&C Chen Center for Social and Decision Neuroscience will investigate two important higher-order core functions of the human brain: making decisions and processing and guiding social interactions. Using the center's resources for computational modeling and brain imaging, researchers from different areas of science will collaborate to understand these two core functions. Their findings will help improve how we make personal decisions, allow researchers to design devices and interventions to benefit society, and inform new treatments for neurologically based disorders such as anxiety and autism.
     
  • The T&C Chen Center for Systems Neuroscience

    The T&C Chen Center for Systems Neuroscience—directed by Doris Tsao, Caltech professor of biology and a Howard Hughes Medical Institute Investigator—will address the challenge of understanding how a large group of neurons firing in concert gives rise to cognition. The Caltech researchers working in this center will explore the neural circuits and computations that underlie perception, thought, emotion, memory, decision making, and behavior. Scientists within the center will collaborate to tackle each of these brain systems, as well as the larger question of how these systems interact so seamlessly. The center will back their new and best ideas with seed funding, computing resources, and labs in which they can develop powerful new scientific tools.
     
  • The Center for Molecular and Cellular Neuroscience

    The new Center for Molecular and Cellular Neuroscience, led by Viviana Gradinaru, Caltech assistant professor of biology and biological engineering and a Heritage Medical Research Institute Investigator, will unite a contingent of Caltech researchers who are making discoveries about the brain's anatomy and development, how neurons communicate, and how processes in the brain can go wrong. In bringing these researchers together, the center will catalyze fundamental new approaches that will help us to understand how the brain works as a whole and to develop new instruments and methods for analyzing the roles that cells and molecules can play in perception, behavior, and disease.
     
  • The Caltech Brain Imaging Center

    The Caltech Brain Imaging Center (CBIC), originally founded in 2003 through a gift from the Gordon and Betty Moore Foundation and directed by John O'Doherty, Caltech professor of psychology, will make available state-of-the-art instruments and expert staff to provide detailed measurements of the working brain. The CBIC has already made possible more than a decade of discoveries, helping faculty and students gain insight into how people learn and make economic decisions, how they perceive the world and experience conscious thought, and what makes up the neural basis of disorders such as autism, addiction, and congenital brain abnormalities.

"Integrating the biology and the social science of how humans make decisions is one of the most promising frontiers for improving the human condition," says Jean-Laurent Rosenthal (PhD '88), the Rea A. and Lela G. Axline Professor of Business Economics and the Ronald and Maxine Linde Leadership Chair of the Division of the Humanities and Social Sciences. "The collaborations that began with the Caltech Brain Imaging Center helped create the new field of neuroeconomics. The Chen Institute at Caltech and its centers will allow us to make new advances to understand why some individuals are so much more successful than others in learning from their social environment."

"Modern neuroscience is one of the most interdisciplinary fields of human intellectual endeavor in the 21st century, and no single researcher or laboratory can master all of the diverse approaches necessary to solve the challenging problems of brain structure, function, and dysfunction," Anderson says. "The Chen Institute at Caltech provides an unprecedented opportunity for Caltech faculty and students in different fields to join forces to take on these challenges, by creating new collaborations at the interface between traditional scientific disciplines. Computational approaches—grounded in Caltech's traditional strength in the physical sciences—will provide a common glue that binds these collaborations together."

Adds Anderson, "Caltech's traditional strengths in basic biology and the physical sciences provide an ideal crucible in which to forge new tools that will crack the most fundamental problems of brain function, such as perception, emotion, cognition, and communication, as well as to develop radical new therapies for currently intractable brain disorders."

Protein Disrupts Infectious Biofilms

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News Writer: 
Lori Dajose
image of a the PodA crystal structure
Crystal structure of the PodA protein complex with three molecules of 1-hydroxyphenazine, the reaction product, bound in the active sites.
Credit: Kyle Costa/Caltech

Many infectious pathogens are difficult to treat because they develop into biofilms, layers of metabolically active but slowly growing bacteria embedded in a protective layer of slime, which are inherently more resistant to antibiotics. Now, a group of researchers at Caltech and the University of Oxford have made progress in the fight against biofilms. Led by Dianne Newman, the Gordon M. Binder/Amgen Professor of Biology and Geobiology, the group identified a protein that degrades and inhibits biofilms of Pseudomonas aeruginosa, the primary pathogen in cystic fibrosis (CF) infections.

The work is described in a paper in the journal Science that will appear online December 8.

"Pseudomonas aeruginosa causes chronic infections that are difficult to treat, such as those that inhabit burn wounds, diabetic ulcers, and the lungs of individuals living with cystic fibrosis," Newman says. "In part, the reason these infections are hard to treat is because P. aeruginosa enters a biofilm mode of growth in these contexts; biofilms tolerate conventional antibiotics much better than other modes of bacterial growth. Our research suggests a new approach to inhibiting P. aeruginosa biofilms."

The group targeted pyocyanin, a small molecule produced by P. aeruginosa that produces a blue pigment. Pyocyanin has been used in the clinical identification of this strain for over a century, but several years ago the Newman group demonstrated that the molecule also supports biofilm growth, raising the possibility that its degradation might offer a new route to inhibit biofilm development.

To identify a factor that would selectively degrade pyocyanin, Kyle Costa, a postdoctoral scholar in biology and biological engineering, turned to a milligram of soil collected in the courtyard of the Beckman Institute on the Caltech campus. From the soil, he isolated another bacterium, Mycobacterium fortuitum, that produces a previously uncharacterized small protein called pyocyanin demethylase (PodA).

Adding PodA to growing cultures of P. aeruginosa, the team discovered, inhibits biofilm development.

"While there is precedent for the use of enzymes to treat bacterial infections, the novelty of this study lies in our observation that selectively degrading a small pigment that supports the biofilm lifestyle can inhibit biofilm expansion," says Costa, the first author on the study. The work, Costa says, is relevant to anyone interested in manipulating microbial biofilms, which are common in natural, clinical, and industrial settings. "There are many more pigment-producing bacteria out there in a wide variety of contexts, and our results pave the way for future studies to explore whether the targeted manipulation of analogous molecules made by different bacteria will have similar effects on other microbial populations."

While it will take several years of experimentation to determine whether the laboratory findings can be translated to a clinical context, the work has promise for the utilization of proteins like PodA to treat antibiotic-resistant biofilm infections, the researchers say.

"What is interesting about this result from an ecological perspective is that a potential new therapeutic approach comes from leveraging reactions catalyzed by soil bacteria," says Newman. "These organisms likely co-evolved with the pathogen, and we may simply be harnessing strategies other microbes use to keep it in check in nature. The chemical dynamics between microorganisms are fascinating, and we have so much more to learn before we can best exploit them."

The paper is titled "Pyocyanin degradation by a tautomerizing demethylase inhibits Pseudomonas aeruginosa biofilms." In addition to Costa and Newman, other co-authors include Caltech graduate student Nathaniel Glasser and Professor Stuart Conway of the University of Oxford. The work was funded by the National Institutes of Health's National Institute of Allergy and Infectious Diseases, the National Science Foundation, the Howard Hughes Medical Institute, the Molecular Observatory at the Beckman Institute at Caltech, the Gordon and Betty Moore Foundation, and the Sanofi-Aventis Bioengineering Research Program at Caltech.

Caltech Computes: Disrupting and Uniting Science and Engineering

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News Writer: 
Robert Perkins

Adam Wierman - Caltech Computes - Alumni College 2016

Adam Wierman - Caltech Computes - Alumni College 2016
Adam Wierman gives the introduction to the 2016 Alumni College event.
Credit: Caltech Academic Media Technologies

Driven by the disruptive force of computer science—which increasingly impacts how researchers work and collaborate by providing them with the ability to extract meaningful information from enormous data sets—whole new fields are developing at the intersection of science and engineering that will shape our future.

About 200 Caltech alumni, students, faculty, and friends filled the Beckman Institute Auditorium on November 12 for the Caltech Alumni Association's sold-out event, Caltech Computes: Disrupting Science and Engineering with Computational Thinking, which showcased the impact of a computational approach on a variety of fields, including biology, astronomy, and economics.

"…probability, optimization, machine learning, statistics: No matter what discipline you're in, you need these fields," the event's faculty coordinator, Adam Wierman, said at the event while introducing a series of faculty speakers. Wierman is a professor of computing and mathematical sciences (CMS) in the Division of Engineering and Applied Science (EAS). "It's from this intellectual core that new fields are emerging. [For example,] when you take biology and connect it to this core, you get bioinformatics or computational genomics," he said.

Wierman, executive officer for CMS and the director of Information Science and Technology at Caltech, is leading an initiative to reenvision information science as a hub for the rest of campus.

The future of computer science at Caltech and the world in general, he noted, can be summarized by the shorthand "CS+X," as in, "What happens when you take computational thinking and combine it with some other discipline? Something new and disruptive."

In 2004, Caltech announced grants of $25 million from the Annenberg Foundation and $22.2 million from the Gordon and Betty Moore Foundation in support of this interdisciplinary initiative.

Since that time, there has been an explosion in interest in computer science—by both faculty and students. Currently more than 40 percent of the undergraduate population is majoring or minoring in computer science. Students today see the interdisciplinary nature of their advisers' research, and actively pursue the computer science skillset they will need to thrive in any career they choose, Wierman said—an ethos showcased at the Alumni Association event.

 "This weekend illustrated the innovative work occurring across Caltech's campus, as well as the dedicated outreach efforts of the Caltech Alumni Association," Wierman says.

Speakers at the event included representatives from a half-dozen fields and nearly every division across campus:

CS+Data

Pietro Perona, Allen E. Puckett Professor of Electrical Engineering, whose Visipedia project is capable of distinguishing individual bird and tree species, using a combination of machine learning and expert human input. [Watch the talk]

Yisong Yue, assistant professor of computing and mathematical sciences, who is collaborating with Joel Burdick, the Richard L. and Dorothy M. Hayman Professor of Mechanical Engineering and Bioengineering and JPL research scientist, to develop a prosthesis that can utilize machine learning to help patients with spinal injuries to stand again. "Every patient is unique and every injury is unique. You need it to learn on the fly," Yue said in his talk. [Watch the talk]

CS+Astronomy

George Djorgovski, professor of astronomy, director of the Center for Data Driven Discovery, and executive officer for astronomy in the Division of Physics, Mathematics and Astronomy. Djorgovski searches for "things that go bang in the night"—such as supernovas—by scanning enormous data sets gathered by sky surveys. "At some point, it's all ones and zeroes and it doesn't matter whether the data came from a seismograph or telescopes," he said at the event. [Watch the talk]

CS+Biology

Richard Murray (BS '85), the Thomas E. and Doris Everhart Professor of Control and Dynamical Systems and Bioengineering, who is creating synthetic biological machines with programming written directly into their DNA. [Watch the talk]

Lulu Qian, assistant professor of bioengineering, who wants to use DNA origami to create a real-life version of "Hermione's bag" (referencing the bottomless storage of the fictional Harry Potter character's purse). [Watch the talk]

CS+Physics

Thomas Vidick, assistant professor of computing and mathematical sciences, who is exploring how the mysterious nature of quantum mechanics can be utilized to create unbreakable cryptography. [Watch the talk]

Xie Chen, assistant professor of theoretical physics, who is developing a new model for quantum computing that overcomes the fragility of traditional approaches. [Watch the talk]

CS+Economics

Federico Echenique, the Allen and Lenabelle Davis Professor of Economics and executive officer for the social sciences in the Division of Humanities and Social Sciences, who showed how to improve algorithms that govern how student applications are reviewed assuaged frustrated parents in the Boston public school system. [Watch the talk]

CS+Chemistry

Tom Miller, professor of chemistry, whose advanced algorithms allow more precise computational models, paving the way toward more efficient and less volatile lithium-ion batteries. [Watch the talk]

CS+Energy

Steven Low, professor of computer science and electrical engineering, who envisions a future in which algorithms govern electric vehicle charging, reducing the need for a massive charging infrastructure. [Watch the talk]

CS+Visualization

 Peter Schröder, the Shaler Arthur Hanisch Professor of Computer Science and Applied and Computational Mathematics, whose discussion of the application of algorithms from quantum mechanics to the generation of computer-simulated fluids gave the audience a look "under the hood of what makes Hollywood fly," he said. [Watch the talk]

Caltech Biologist Disputes Conclusions of Recent Papers on Biological Magnetism

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News Writer: 
Robert Perkins
graphic
Credit: Caltech

Caltech biologist Markus Meister is disputing recent research claiming to have solved what he describes as "the last true mystery of sensory biology"—the ability of animals to detect magnetic fields. This "magnetic sense" provides a navigational aid to a variety of organisms, including flies, homing pigeons, moles, and bats. 

In three separate papers appearing in journals published by the Nature Publishing Group, teams of researchers from Peking University in Beijing, the University of Virginia, and Rockefeller University in New York build a scientific case, based on the existence of particular iron-laden protein molecules, for how living cells might be affected by magnetic fields. If correct, these findings would help explain how animals sense magnetism and how cellular functions might one day be controlled using magnetic fields.

An important property of iron is that it can be magnetized like the needle on a compass. Because the described proteins contain so much iron, the argument goes, they would be affected by Earth's magnetic field, providing a mechanism through which organisms could sense that field.

The problem, says Meister, Anne P. and Benjamin F. Biaggini Professor of Biological Sciences, is that each of the proteins described in the trio of Nature papers do not contain enough iron to be affected by magnetic fields.

"We're talking a disparity of between five and 10 orders of magnitude. The amount of iron in the molecules isn't even close to being enough," says Meister, who discusses his analysis of the three studies in a paper published by the journal eLife. That difference is enormous. Meister likens it to claiming to have built an electric car that could run for a year—on a single AA battery.

After noting the issue, Meister checked in with colleagues in the field, including Joseph Kirschvink (BS, MS '75), Nico and Marilyn Van Wingen Professor of Geobiology at Caltech, who is known for work on magnetoreception based on magnetite (Fe3O4), a ferromagnetic iron ore. In 2001, Kirschvink published evidence that crystals of magnetite in animals may play a role in animal magnetic sensitivity. Kirschvink agreed with Meister's analysis. "Markus is spot-on," says Kirschvink.

In one of the papers, published in Nature Materials in November 2015, a group led by Siying Qin of Peking University report the discovery of an iron-rich rod-like protein complex in the eyes of the fruit fly Drosophila that, the authors say, could be the source of the fly's magnetoreception. They named the complex MagR, for magnetoreceptor protein.

MagR includes 40 iron atoms. These iron atoms, the Peking University researchers say, provide enough of a magnetic moment (movement in response to a magnetic field) that roughly 45 percent of isolated proteins orient with their long axis along the geomagnetic field. In other words, the paper suggests that the proteins align in response to Earth's magnetic field so that they point to magnetic north like the needle on a compass.

However, Meister says that the proteins actually do not have enough iron content to be sensitive to magnetic fields.

The smallest iron particles that are known to have a permanent magnetic moment at room temperature are crystals of Fe3O4, which are about 30 nanometers in size. Each crystal contains about 1 million tightly packed iron atoms. That means that even if all 40 iron atoms in a MagR protein manage to link up somehow and operate as a single unit, the protein's resulting magnetic moment would still be too small to align with Earth's geomagnetic field at room temperature. Magnetism is locked in a battle against the chaos-inducing energy of heat, which works to randomize the orientation of the protein complex. This thermal effect is about five orders of magnitude stronger than any magnetic pull on the 40 iron atoms.

"This is back-of-the-envelope physics," Meister says.

The other two papers—one in Nature Neuroscience by Michael Wheeler of the University of Virginia and one in Nature Medicine by Sarah Stanley of Rockefeller University—explore the possibility of engineering mechanisms that would use iron atoms in cells to control ion channels.

Ion channels are gateways in cellular membranes that allow for the passage of ions across the membrane, thus transmitting signals into and out of the cell. These signals control cellular functions. For example, ion channels in nerve cells can transmit pain signals. Being able to selectively open and close ion channels with magnetic fields, rather than with medications, would offer clinicians a minimally invasive technique to control cells—for example, managing pain without the use of pharmaceuticals.

Both Wheeler's and Stanley's findings hinge on the use of ferritin, a hollow protein shell that, previous research has shown, can be packed with iron. (Most organisms naturally produce ferritin to store iron, which is toxic when floating freely throughout cells.) Both groups attached a ferritin ball to an ion channel that resides in the cell membrane, with the goal of creating a mechanism for opening or closing the channel by manipulating the ball with magnetic fields. Wheeler proposed physically tugging on the ferritin ball with a magnetic field, while Stanley used a magnetic field to heat the ferritin and trigger the attached ion channel's opening and closing.

Neither scheme can possibly work, Meister says.

Indeed, Meister's calculations show that ferritin is too small by many orders of magnitude to be affected by magnetic fields. "In both cases, one can blame the choice of ferritin," Meister says. Since ferritin has no permanent magnetic moment, magnetic fields interact with it only weakly. "If the reported effects really occurred as described, they probably have nothing to do with ferritin."

However, he suggests, there may be a viable route to controlling ion channel function in cells using much larger magnetic particles, like those found in certain magnetic bacteria.

While missteps in science are common and indeed part of the scientific process—hence the need for peer-review for articles—Meister worries that these announcements could discourage other scientists from trying to understand the causes of magnetism in biological contexts.

"It's like the brass ring has already been snatched," Meister says. "It's all too easy for someone to look at that and think, 'All right, I guess that's been answered. I'll try to tackle some other problem, then.'"

Meister's paper is titled "Physical Limits to Magnetogenetics" and can be found online. 

Visualizing Gene Expression with MRI

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News Writer: 
Lori Dajose
An illustration of aquaporin's effect on cells.
An illustration of aquaporin's effect on cells.
Credit: M. Shapiro Laboratory/Caltech

Genes tell cells what to do—for example, when to repair DNA mistakes or when to die—and can be turned on or off like a light switch. Knowing which genes are switched on, or expressed, is important for the treatment and monitoring of disease. Now, for the first time, Caltech scientists have developed a simple way to visualize gene expression in cells deep inside the body using a common imaging technology.

Researchers in the laboratory of Mikhail Shapiro, assistant professor of chemical engineering and Heritage Medical Research Institute Investigator, have invented a new method to link magnetic resonance imaging (MRI) signals to gene expression in cells—including tumor cellsin living tissues. The technique, which eventually could be used in humans, would allow gene expression to be monitored non-invasively, requiring no surgical procedures such as biopsies.

The work appears in the December 23 online edition of the journal Nature Communications.

In MRI, hydrogen atoms in the body—atoms that are mostly contained in water molecules and fat—are excited using a magnetic field. The excited atoms, in turn, emit signals that can be used to create images of the brain, muscle, and other tissues, which can be distinguished based on the local physical and chemical environment of the water molecules. While this technique is widely used, it usually provides only anatomical snapshots of tissues or physiological functions such as blood flow rather than observations of the activity of specific cells.

"We thought that if we could link signals from water molecules to the expression of genes of interest, we could change the way the cell looks under MRI," says Arnab Mukherjee, a postdoctoral scholar in chemical engineering at Caltech and co-lead author on the paper.

The group turned to a protein that naturally occurs in humans, called aquaporin. Aquaporin sits within the membrane that envelops cells and acts as a gatekeeper for water molecules, allowing them to move in and out of the cell. Shapiro's team realized that increasing the number of aquaporins on a given cell made it stand out in MRI images acquired using a common clinical technique called diffusion-weighted imaging, which is sensitive to the movement of water molecules. They then linked aquaporin to genes of interest, making it what scientists call a reporter gene. This means that when a gene of interest is turned on, the cell will overexpress aquaporin, making the cell look darker under diffusion-weighted MRI.

The researchers showed that this technique was successful in monitoring gene expression in a brain tumor in mice. After implanting the tumor, they gave the mice a drug to trigger the tumor cells to express the aquaporin reporter gene, which made the tumor look darker in MRI images.

"Overexpression of aquaporin has no negative impact on cells because it is exclusive to water and simply allows the molecules to go back and forth across the cell membrane," Shapiro says. Under normal physiological conditions the number of water molecules entering and exiting an aquaporin-expressing cell is the same, so that the total amount of water in each cell does not change. "Aquaporin is a very convenient way to genetically change the way that cells look under MRI."

Though the work was done in mice, it has the potential for clinical translation, according to Shapiro. Aquaporin is a naturally occurring gene and will not cause an immune reaction. Previously developed reporter genes for MRI have been much more limited in their capabilities, requiring the use of specific metals that are not always available in some tissues.

"An effective reporter gene for MRI is a 'holy grail' in biomedical imaging because it would allow cellular function to be observed non-invasively," says Shapiro. "Aquaporins are a new way to think about this problem. It is remarkable that simply allowing water molecules to more easily get into and out of cells in a tissue gives us the ability to remotely see those cells in the middle of the body."

The paper is titled "Non-invasive imaging using reporter genes altering cellular water permeability." In addition to Shapiro and Mukherjee, other coauthors include Caltech graduate students Di Wu (MS '16 and co-lead author) and Hunter Davis. The work was funded by the Dana Foundation, a Burroughs Wellcome Career Award at the Scientific Interface, the Heritage Medical Research Institute, and the National Institutes of Health.


A Gift of History, a Gift for the Future

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photo of Donald Glaser
Donald Glaser (PhD '50)
Credit: Caltech Archives

The path that the late Nobel laureate Donald Glaser (PhD '50) cut in the scientific world was distinctively Caltech. He focused on fundamental questions about the universe and created tools that led to new revelations.

His curiosity, and his desire to make the biggest difference he could, drove him to switch his focus from high energy physics to molecular biology, and later to neurobiology. As an unexpected side effect, his work also has inspired artists and composers.

Donald Glaser and his family have made a pair of significant commitments to the Caltech community.

Learn more and view the slideshow on the Caltech campaign website

Fixating on Faces

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News Writer: 
Lori Dajose
An image of a region of the brain overlaid with different colors.
Dots represent locations of electrodes in the amygdala region of the brain. Each electrode measured activity of a single brain cell.
Credit: J. Minxha/Adolphs lab

When we are walking down a crowded street, our brains are constantly active, processing a myriad of visual stimuli. Faces are particularly important social stimuli, and, indeed, the human brain has networks of neurons dedicated to processing faces. These cells process social information such as whether individual faces in the crowd are happy, threatening, familiar, or novel.

New research from Caltech now shows that the activation of face cells depends highly on where you are paying attention—it is not enough for a face to simply be within your field of vision. The findings may lead to a better understanding of the mechanisms behind social cognitive defects that characterize conditions such as autism.

The research was conducted in the laboratories of Ralph Adolphs (PhD '93), Bren Professor of Psychology and Neuroscience and professor of biology, and collaborator Ueli Rutishauser (PhD '08) of Cedars-Sinai Medical Center in Los Angeles and a visiting associate in biology and biological engineering at Caltech.

A paper about the work appears in the January 24 issue of Cell Reports.

"The ability to recognize other human faces is the basis of social awareness and interaction," Adolphs says. "Previous work on this subject has typically been conducted under rather artificial conditions—a single, large image is displayed on a monitor in front of a subject to focus on. We wanted to understand how brain activity changes with eye movements and capture the natural dynamics of how people constantly shift their attention in crowded scenes."

The researchers focused on face cells in a particular region of the brain called the amygdala.

"We know that a damaged amygdala can result in profound deficits in face processing, especially in recognizing emotions, but how amygdala neurons normally contribute to face perception is still a big open question," says Juri Minxha, a graduate student in Caltech's computation and neural systems program and lead author on the paper. "Now, we have discovered that face cells in the amygdala respond differently depending on where the subject is fixating."

When a face cell responds to a stimulus, it fires electrical impulses or "spikes." By working with patients who already had electrodes implanted within their amygdalae for clinical reasons, the group measured the activity of individual face cells while simultaneously monitoring where a subject looked. Subjects were shown images of human faces, monkey faces, and a variety of other objects such as flowers and shapes. This study is the first in which subjects were free to look around at various parts of a screen and focus their attention on different things.

The study found two types of face cells: those that fire more spikes when the patient is looking at a human face and those that fire a few spikes when the patient is looking at a face of another species (in this case, that of a monkey). Neither type of face cell fired when the subjects were paying attention to objects that were not faces, even if those objects were near a face in the image.

"We saw that if a person was paying attention to a flower picture, for example, the face cells would not fire even if the flower was close to a face," says senior author Rutishauser. "This suggests that the responses of face cells are controlled by where we are focusing our attention."

Experiments in monkeys, performed in collaboration with Katalin Gothard of the University of Arizona, showed similar results. In both groups of subjects, face cells were most responsive to conspecifics—faces of the same species. "This is remarkable because many aspects of social perception and social behavior are different between the two species," Gothard says. "This discovery now indicates that the primate amygdala is an integral part of the network of brain areas dedicated to processing the faces we pay attention to, and is the first such direct comparison between humans and monkeys."

The studies showed that when the monkey and human subjects were viewing images of the same species, the monkeys' face cells reacted about one-tenth of a second more quickly than the face cells of humans, validating a long-standing hypothesis that face cells in monkeys would respond more quickly than corresponding cells in humans. The tenth-of-a-second difference is larger than what can be explained by variation in human and monkey brain size, leaving open the question of why human face cells have a delayed response. "The power of this comparative approach is that it identifies critical differences in brain function that might be unique to humans," Rutishauser says.

"The experimental design brings researchers a step closer to studying how the brain works during natural behaviors," Minxha says. "Ideally, we would want to observe neural activity while a person actually moves through a crowded scene. The next step is to study how face-cell activation changes with the subject's emotional state, or when they are interacting with someone. We would also like to understand how face-cell responses are different in subjects with specific clinical disorders, such as in people with autism, which is work we have been conducting as well."

The paper is titled "Fixations gate species-specific responses to free viewing of faces in the human and macaque amygdala." Other co-authors include Clayton Mosher and Jeremiah Morrow of the University of Arizona and Adam Mamelak of Cedars-Sinai Medical Center. The work was funded by the National Science Foundation, the National Institute of Mental Health, the McKnight Endowment Fund for Neuroscience, and a NARSAD Young Investigator Award from the Brain and Behavior Research Foundation.

Neuroscience Prize Awarded to David Anderson

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News Writer: 
Lori Dajose
David Anderson in front of a whiteboard with equations.
D. Anderson
Credit: Caltech

David Anderson, the Seymour Benzer Professor of Biology and a Howard Hughes Medical Institute Investigator, has been awarded the 17th Perl-UNC Neuroscience Prize from the University of North Carolina Chapel Hill School of Medicine. The award, a $20,000 prize, is given to honor seminal discoveries in the field of neuroscience. Anderson is being recognized for "his discovery of neural circuit mechanisms controlling emotional behaviors," according to the award citation.

Anderson, who was recently appointed as the director of the Tianqiao and Chrissy Chen Institute for Neuroscience at Caltech, seeks to understand the neurobiology of emotion. His work has identified specific populations of neurons in key regions of the mouse brain that control emotional behaviors such as aggression and defense. Additionally, he and his team discovered similar mechanisms operating in the brains of fruit flies, suggesting that analogous processes function in different organisms.

"The same regions also exist in the human brain and probably do the same thing, but that has not been studied," Anderson says. "All together, our studies have opened up the study of emotional behaviors to modern, genetically based methods for probing neural circuit structure and function."

Anderson received his undergraduate degree from Harvard and doctorate from The Rockefeller University. He arrived at Caltech in 1986. In 2007, he was elected to the National Academy of Sciences.

"I am both surprised and thrilled to have been chosen for this prestigious award by the prominent neuroscientists on the Perl Prize committee," he says. "The recognition that this prize bestows belongs equally to the talented students and postdoctoral researchers who have trained in my laboratory. Without their effort and brilliance, the work that is honored here would not have come to fruition."

Small but Mighty: Fruit Fly Muscles

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News Writer: 
Lori Dajose
Fruit fly flight simulator.
The fruit fly flight simulator.
Credit: Caltech

Fruit flies are capable of impressive aerial maneuvers, as is grudgingly acknowledged by anyone who has unsuccessfully tried to swat away one of the familiar kitchen pests. Interestingly, the flies perform these nimble evasive movements using only 12 flight muscles, each controlled by one brain cell, or neuron. In comparison, hummingbirds can produce almost identical aerial patterns but use 100 times more neurons per muscle.

Now, new research from Caltech provides the first understanding into how so few muscles produce such complex flight.

The findings, an advance at the intersection of biomechanics and neurobiology, are described in a paper appearing in the January 26 issue of Current Biology.

Key to understanding how flies control their flight is their complex wing hinge—the elaborate joint that transforms the action of muscles inside the body into the sweeping motion of the wing.

"Because the wings of birds, bats, and pterosaurs evolved from limbs, they are equipped with shoulder, elbow, wrist, and finger joints—each with their own set of muscles," says Michael Dickinson, Caltech's Esther M. and Abe M. Zarem Professor of Bioengineering. Flying insects, on the other hand, do not have any muscles in their wings. Rather, there is a single, mechanically elaborate joint called the wing hinge connecting the wing to the body; it is controlled by power muscles and steering muscles. "The evolution of the insect wing is one of the most important moments in evolutionary history. Insects developed the ability to fly and subsequently changed our planet, pollinating flowers and driving ecosystems," he says. "We have no idea how fly wings evolved. Until now, we also did not know how flies controlled them."

"Insect power muscles are the most powerful muscles in any animal on the planet," says Thad Lindsay, first author on the paper and postdoctoral scholar in biology and biological engineering. "However, this means that they are ill-suited to actually control wing movement precisely. That's where the tiny steering muscles come in."

The group discovered that the muscles flies use to steer are divided into two types. One type, the tonic muscles—there are five—are always in use, making fine-tuned adjustments to steer the fly. The other type, the seven phasic muscles, are largely inactive unless a rapid, powerful movement is required. These steering muscles are affixed to four skeletal structures at the base of the wing; each structure is equipped with at least one tonic and one phasic muscle to control the wing's motion.

The team studied these minuscule muscles—their length is about the width of a human hair—by using genetically modified fruit flies. Muscles contract when their calcium levels rise, and these fruit flies were engineered to produce a protein that glows with different intensity depending on the amount of calcium present. Each fly was tethered to a pin and placed within a fruit-fly flight simulator, where it was presented with visual stimuli to simulate various directions of rotation, such as pitching forward or rolling sideways. The fly's wing muscles responded accordingly and a specialized microscopic camera recorded the muscles as they lit up brightly.

The researchers found that a division of labor within the steering muscles provides flies with an elegant and efficient means of flight control. The tonic muscles act continuously to keep the fly in perfect trim, while the fly activates the phasic muscles only when it needs to perform a rapid maneuver.

"Much of neuroscience is about sensory information and sensory systems like vision, olfaction, and hearing," Dickinson says. "We know so much less about how the motor systems of animals are organized. But now that we understand the organization of the flight system of flies, it gives us a clear set of blueprints for how to study the entire brain because we have a much better idea of how sensory information flows through the brain. It is a little bit like solving a mystery by skipping ahead to the end of a novel. We had no idea that we would see such a clean kind of overarching organization in the animal's motor system."

The paper is titled "The function and organization of the motor system controlling flight maneuvers in flies." Anne Sustar of the University of Washington is a coauthor. The work was funded by the National Science Foundation.

Protein Chaperone Takes Its Job Seriously

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Caltech biochemists reveal how a ribosomal protein is protected by its chaperone
News Writer: 
Whitney Clavin
structural rendering of ribosomal protein
Structural rendering of a ribosomal protein (yellow and red) bound to its chaperone (blue). By capturing an atomic-resolution snapshot of the pair of proteins interacting with each other, Ferdinand Huber, a graduate student in the lab of André Hoelz revealed that chaperones can protect their ribosomal proteins by tightly packaging them up. The red region illustrates where the dramatic shape alterations occur when the ribosomal protein is released from the chaperone during ribosome assembly.
Credit: Huber and Hoelz/Caltech

For proteins, this would be the equivalent of the red-carpet treatment: each protein belonging to the complex machinery of ribosomes—components of the cell that produce proteins—has its own chaperone to guide it to the right place at the right time and protect it from harm.

In a new Caltech study, researchers are learning more about how ribosome chaperones work, showing that one particular chaperone binds to its protein client in a very specific, tight manner, almost like a glove fitting a hand. The researchers used X-ray crystallography to solve the atomic structure of the ribosomal protein bound to its chaperone.

"Making ribosomes is a bit like baking a cake. The individual ingredients come in protective packaging that specifically fits their size and shape until they are unwrapped and blended into a batter," says André Hoelz, professor of chemistry at Caltech, a Heritage Medical Research Institute (HMRI) Investigator, and Howard Hughes Medical Institute (HHMI) Faculty Scholar." What we have done is figure out how the protective packaging fits one ribosomal protein, and how it comes unwrapped." Hoelz is the principal investigator behind the study published February 2, 2017, in the journal Nature Communications. The finding has potential applications in the development of new cancer drugs designed specifically to disable ribosome assembly.

In all cells, genetic information is stored as DNA and transcribed into mRNAs that code for proteins. Ribosomes translate the mRNAs into amino acids, linking them together into polypeptide chains that fold into proteins. More than a million ribosomes are produced per day in an animal cell.

Building ribosomes is a formidable undertaking for the cell, involving about 80 proteins that make up the ribosome itself, strings of ribosomal RNA, and more than 200 additional proteins that guide and regulate the process. "Ribosome assembly is a dynamic process, where everything happens in a certain order. We are only now beginning to elucidate the many steps involved," says Hoelz.

To make matters more complex, the proteins making up a ribosome are first synthesized outside the nucleus of a cell, in the cytoplasm, before being transported into the nucleus where the initial stages of ribosome assembly take place.

Chaperone proteins help transport ribosomal proteins to the nucleus while also protecting them from being chopped up by a cell's protein shredding machinery. The components that specifically aim this machinery at unprotected ribosomal proteins, recently identified by Raymond Deshaies, professor of biology at Caltech and an HHMI Investigator, ensures that equal numbers of the various ribosomal proteins are available for building the massive structure of a ribosome.


Structural rendering of a chaperone called Acl4 bound to ribosomal protein L4

Previously, Hoelz and his team, in collaboration with the laboratory of Ed Hurt at the University of Heidelberg, discovered that a ribosomal protein called L4 is bound by a chaperone called "Assembly chaperone of RpL4," or Acl4. The chaperone ushers L4 through the nucleus, protecting it from harm, and delivers it to a developing ribosome at a precise time and location. In the new study, the team used X-ray crystallography, a process that involves exposing protein crystals to high-energy X-rays, to solve the structure of the bound pair. The technique was performed at Caltech's Molecular Observatory beamline at the Stanford Synchrotron Radiation Lightsource.

"This was not an easy structure to solve," says Ferdinand Huber, a graduate student at Caltech in the Hoelz lab and first author of the new study. "Solving the structure was incredibly exciting because you could see with your eyes, for the very first time, how the chaperone embraces the ribosomal protein to protect it."

Hoelz says that the structure was a surprise because it was not known previously that chaperones hold on to their ribosomal proteins so tightly. He says they want to study other chaperones in the future to see if they function in a similar fashion to tightly guard ribosomal proteins. The results may lead to the development of new drugs for cancer therapy by preventing cancer cells from supplying the large numbers of ribosomes required for tumor growth.

The study, called "Molecular Basis for Protection of Ribosomal Protein L4 from Cellular Degradation," was funded by a PhD fellowship of the Boehringer Ingelheim Fonds, a Faculty Scholar Award of the Howard Hughes Medical Research Institute, a Heritage Medical Research Institute Principal Investigatorship, a Kimmel Scholar Award of the Sidney Kimmel Foundation for Cancer Research, a Teacher-Scholar Award of the Camille & Henry Dreyfus Foundation, and Caltech startup funds.

 

Sleeping With the (Zebra)fishes

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News Writer: 
Lori Dajose
David Prober
David Prober
Credit: Caltech

People can reject food and control their thirst, but we cannot keep from falling asleep. Even though we spend a third of our lives asleep and treat the prevalence of sleep disorders, we know remarkably little about why we sleep or how sleep is regulated.

On February 22, at 8 p.m. in Beckman Auditorium, Caltech assistant professor of biology David Prober will discuss his lab's efforts to find new approaches to answer these questions and the discoveries they've made using the zebrafish as a simple animal model—discoveries that may have implications for our understanding of sleep in humans as well. Admission is free.

What do you do?

My lab studies how genes and neurons regulate sleep. Most sleep research is performed using laboratory mice. We are taking a different approach by using zebrafish, a small tropical fish that can be found in pet stores and has recently emerged as a powerful animal model for exploring many questions in biology. Zebrafish have several advantages for studying sleep, including a brain that is anatomically similar to ours but much simpler, optical transparency that allows us to monitor the activity of neurons throughout the brain while the animals are awake or asleep, and a small size that enables large-scale experiments. Zebrafish also have a diurnal sleep/wake pattern similar to that of humans and unlike the nocturnal mice that are commonly used for sleep research. As a result, zebrafish are, in some ways, a better animal model than mice to explore how sleep is regulated in humans.

Why is this important?

We spend a third of our lives asleep, and sleeplike behaviors have been observed across the animal kingdom, including in animals as simple as jellyfish. These observations suggest that sleep serves an ancient and essential function, but we don't know what this function is or how sleep is regulated. These questions are medically relevant because sleep disorders are common, but few effective therapies are available. Beyond a basic desire to understand this biological mystery, we hope that determining how sleep is regulated will lead to novel therapies for sleep disorders and may also provide clues as to the function of sleep.

Howdidyougetintothislineofwork?

Our work is inspired by [late professor emeritus] Seymour Benzer, whose seminal research showing that genes can regulate complex behaviors in fruit flies was performed in the space that my lab now occupies at Caltech. After studying genetic mechanisms that underlie cancer for my PhD, I wanted to change fields and focus on a significant and long-standing question that I knew would keep me busy for many years. After considering several avenues of research, I kept coming back to sleep as one of the last great mysteries of biology and one that has proved to be relatively intractable to solving. It's amazing that, despite decades of intense research, we still have a poor understanding of why we sleep or how sleep is regulated. When we began this work, the zebrafish had just started to be used to ask how genes and neurons regulate a variety of behaviors, so using zebrafish to address mechanisms that underlie sleep was an exciting, albeit risky, undertaking. Fortunately, this approach has proved to be fruitful and has allowed us to address long-standing questions in the sleep field.

 

Named for the late Caltech professor Earnest C. Watson, who founded the series in 1922, the Watson Lectures present Caltech and JPL researchers describing their work to the public. Many past Watson Lectures are available online at Caltech's YouTube site.

A Conversation with Lior Pachter (BS '94)

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Lior Pachter
Lior Pachter
Credit: Courtesy of L. Pachter/Caltech

Lior Pachter (BS '94) is Caltech's new Bren Professor of Computational Biology. Recently, he was elected a fellow of the International Society for Computational Biology, one of the highest honors in the field. We sat down with him to discuss the emerging field of applying computational methods to biology problems, the transition from mathematics to biology, and his return to Pasadena.

What is computational biology?

Computational biology is the art of developing and applying computational methods to answer questions in biology, such as studying how proteins fold, identifying genes that are associated with diseases, or inferring human population histories from genetic data. I have interests in both the development of computational methods and in answering specific biology questions, primarily related to the function of RNA, a molecule central to the function of cells. RNA molecules transmit information through their roles as products of DNA transcription and as the precursors to translation to protein; they also act as enzymes catalyzing biochemical reactions. I am interested in understanding these functions of RNA through tools that involve the combination of computational methods with sequencing methods that together allow for high-resolution probing of RNA activity and structure in cells.

How did you get interested in this field?

During my PhD studies at MIT, I took a course in computational biology. In the course of working on a final project for the class, I got connected to the Human Genome Project—a large-scale endeavor to identify the full DNA sequence of a human genome—and I found the biology and associated math questions very interesting. This led me to change my intended direction of research from algebraic combinatorics to computational biology, and my interests expanded from math to statistics, computer science, and genomics.

Is it common for mathematicians to become biologists?

It's not very common. However, many prominent genomics biologists have backgrounds in mathematics, computer science, or statistics. For example, one of my mentors in graduate school was Eric Lander, the director of the Broad Institute of MIT and Harvard, who received a PhD in mathematics and then transitioned to working in biology. His transition, like mine years later, was sparked by the possibilities and challenges of utilizing genome sequencing to understand biology.

While genome sequencing has obviously been useful in revealing the sequences that are involved in coding various aspects of the molecular biology of the cell, it has had a secondary impact that is less obvious at first glance. The low cost and high throughput (the ability to process large volumes of material) of genome sequencing allowed for a more "big-data" approach to biology, so that experiments that previously could only be applied to individual genes could suddenly be applied in parallel to all of the genes in the genome. The design and analysis of such experiments demand much more sophisticated mathematics and statistics than had previously been needed in biology.

A result of the scale of these new experiments is the emergence of very large data sets in biology whose interpretation demands the application of state-of-the-art computer science methods. The problems require interdisciplinary dexterity and involve not only management of large data sets but also the development of novel abstract frameworks for understanding their structure. For example, there's a new technique called RNA-seq, developed by biologists including Barbara Wold [Caltech's Bren Professor of Molecular Biology], which involves measuring transcription—the process of copying segments of DNA into RNA—in cells. The RNA-seq technique consists of transforming RNA molecules into DNA sequences that allow the researchers to identify and count the original RNA molecules. The development of this technique required not only novel biochemistry and molecular biology, but also new definitions and ideas for how to think about transcriptomes, which are the sets of all the RNA molecules in a cell. I work on improvements to the assay, as well as the development of the associated statistics, computer science, and mathematics.

What did you do before becoming a professor at Caltech?

I was born in Israel and moved to South Africa when I was two. I lived there until moving to Palo Alto, California, at 15. After high school, I studied mathematics at Caltech and pursued my PhD in applied mathematics at MIT. I spent time at Berkeley as a postdoc before becoming professor of mathematics, molecular and cell biology, and computer science, and I held the Raymond and Beverly Sackler Chair in Computational Biology. I joined the Caltech faculty in early 2017.

What is it like to be back here?

It's a great pleasure. As an undergrad, I made very strong connections with very special people who just had a pure love of science. I've always missed the unique culture and atmosphere at Caltech and, returning now as a professor, I can feel the spirit of the Institute—an intense love of science emanating from individuals that is unlike anywhere else. It's a homecoming of sorts.


Computing with Biochemical Circuits Made Easy

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News Writer: 
Lori Dajose
A man at a computer. Artistic biological objects flow from it.
Detail from painting "What Dreams Are Made Of."
Credit: Ann Erpino

Electronic circuits are found in almost everything from smartphones to spacecraft and are useful in a variety of computational problems from simple addition to determining the trajectories of interplanetary satellites. At Caltech, a group of researchers led by Assistant Professor of Bioengineering Lulu Qian is working to create circuits using not the usual silicon transistors but strands of DNA.

The Qian group has made the technology of DNA circuits accessible to even novice researchers—including undergraduate students—using a software tool they developed called the Seesaw Compiler. Now, they have experimentally demonstrated that the tool can be used to quickly design DNA circuits that can then be built out of cheap "unpurified" DNA strands, following a systematic wet-lab procedure devised by Qian and colleagues.

A paper describing the work appears in the February 23 issue of Nature Communications.

Although DNA is best known as the molecule that encodes the genetic information of living things, they are also useful chemical building blocks. This is because the smaller molecules that make up a strand of DNA, called nucleotides, bind together only with very specific rules—an A nucleotide binds to a T, and a C nucleotide binds to a G. A strand of DNA is a sequence of nucleotides and can become a double strand if it binds with a sequence of complementary nucleotides.

DNA circuits are good at collecting information within a biochemical environment, processing the information locally and controlling the behavior of individual molecules. Circuits built out of DNA strands instead of silicon transistors can be used in completely different ways than electronic circuits. "A DNA circuit could add 'smarts' to chemicals, medicines, or materials by making their functions responsive to the changes in their environments," Qian says. "Importantly, these adaptive functions can be programmed by humans."

To build a DNA circuit that can, for example, compute the square root of a number between 0 and 16, researchers first have to carefully design a mixture of single and partially double-stranded DNA that can chemically recognize a set of DNA strands whose concentrations represent the value of the original number. Mixing these together triggers a cascade of zipping and unzipping reactions, each reaction releasing a specific DNA strand upon binding. Once the reactions are complete, the identities of the resulting DNA strands reveal the answer to the problem.

With the Seesaw Compiler, a researcher could tell a computer the desired function to be calculated and the computer would design the DNA sequences and mixtures needed. However, it was not clear how well these automatically designed DNA sequences and mixtures would work for building DNA circuits with new functions; for example, computing the rules that govern how a cell evolves by sensing neighboring cells, defined in a classic computational model called "cellular automata."

"Constructing a circuit made of DNA has thus far been difficult for those who are not in this research area, because every circuit with a new function requires DNA strands with new sequences and there are no off-the-shelf DNA circuit components that can be purchased," says Chris Thachuk, senior postdoctoral scholar in computing and mathematical sciences and second author on the paper. "Our circuit-design software is a step toward enabling researchers to just type in what they want to do or compute and having the software figure out all the DNA strands needed to perform the computation, together with simulations to predict the DNA circuit's behavior in a test tube. Even though these DNA strands are still not off-the-shelf products, we have now shown that they do work well for new circuits with user-designed functions."

"In the 1950s, only a few research labs that understood the physics of transistors could build early versions of electronic circuits and control their functions," says Qian. "But today many software tools are available that use simple and human-friendly languages to design complex electronic circuits embedded in smart machines. Our software is kind of like that: it translates simple and human-friendly descriptions of computation to the design of complex DNA circuits."

The Seesaw Compiler was put to the test in 2015 in a unique course at Caltech, taught by Qian and called "Design and Construction of Programmable Molecular Systems" (BE/CS 196 ab). "How do you evaluate the accessibility of a new technology? You give the technology to someone who is intellectually capable but has minimal prior background," Qian says. 

"The students in this class were undergrads and first-year graduate students majoring in computer science and bioengineering," says Anupama Thubagere, a graduate student in biology and bioengineering and first author on the paper. "I started working with them as a head teaching assistant and together we soon discovered that using the Seesaw Compiler to design a DNA circuit was easy for everyone."

However, building the designed circuit in the wet lab was not so simple. Thus, with continued efforts after the class, the group set out to develop a systematic wet-lab procedure that could guide researchers—even novices like undergraduate students—through the process of building DNA circuits. "Fortunately, we found a general solution to every challenge that we encountered, now making it easy for everyone to build their own DNA circuits," Thubagere says.

The group showed that it was possible to use cheap, "unpurified" DNA strands in these circuits using the new process. This was only possible because steps in the systematic wet-lab procedure were designed to compensate for the lower synthesis quality of the DNA strands.

"We hope that this work will convince more computer scientists and researchers from other fields to join our community in developing increasingly powerful molecular machines and to explore a much wider range of applications that will eventually lead to the transformation of technology that has been promised by the invention of molecular computers," Qian says.

The paper is titled, "Compiler-aided systematic construction of large-scale DNA strand displacement circuits using unpurified components." Other Caltech co-authors include graduate students Robert Johnson and Kevin Cherry, alumnus Joseph Berleant (BS '16), and undergraduate Diana Ardelean. The work was funded by the National Science Foundation, the Banting Postdoctoral Fellowships program, the Burroughs Wellcome Fund, and Innovation in Education funds from Caltech.

Electrons Use DNA Like a Wire for Signaling DNA Replication

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News Writer: 
Whitney Clavin
Illustration of DNA replication
A protein called DNA primase (tan) begins to replicate DNA when an iron-sulfur cluster within it is oxidized, or loses an electron (blue and purple). Once this primase has made an RNA primer, a protein signaling partner, presumably DNA polymerase alpha (blue), sends an electron from its reduced cluster, which has an extra electron (yellow and red). The electron travels through the DNA/RNA helix to primase, which comes off the DNA. This electron transfer signals the next steps in replication.
Credit: Caltech

In the early 1990s, Jacqueline Barton, the John G. Kirkwood and Arthur A. Noyes Professor of Chemistry at Caltech, discovered an unexpected property of DNA—that it can act like an electrical wire to transfer electrons quickly across long distances. Later, she and her colleagues showed that cells take advantage of this trait to help locate and repair potentially harmful mutations to DNA.

Now, Barton's lab has shown that this wire-like property of DNA is also involved in a different critical cellular function: replicating DNA. When cells divide and replicate themselves in our bodies—for example in the brain, heart, bone marrow, and fingernails—the double-stranded helix of DNA is copied. DNA also copies itself in reproductive cells that are passed on to progeny.

The new Caltech-led study, based on work by graduate student Elizabeth O'Brien in collaboration with Walter Chazin's group at Vanderbilt University, shows that a key protein required for replicating DNA depends on electrons traveling through DNA.

"Nature is the best chemist and knows exactly how to take advantage of DNA electron-transport chemistry," says Barton, who is also the Norman Davidson Leadership Chair of Caltech's Division of Chemistry and Chemical Engineering.

"The electron transfer process in DNA occurs very quickly," says O'Brien, lead author of the study, appearing in the February 24 issue of Science. "It makes sense that the cell would utilize this quick-acting pathway to regulate DNA replication, which necessarily is a very rapid process."

The researchers found their first clue that DNA replication might involve the transport of electrons through the double helix by taking a closer look at the proteins involved. Two of the main players in DNA replication, critical at the start of the process, are the proteins DNA primase and DNA polymerase alpha. DNA primase typically binds to single-stranded, uncoiled DNA to begin the replication process. It creates a "primer" made of RNA to help DNA polymerase alpha start its job of copying the single strand of DNA to create a new segment of double-helical DNA.

DNA primase and DNA polymerase alpha molecules both contain iron-sulfur clusters. Barton and her colleagues previously discovered that these metal clusters are crucial for DNA electron transport in DNA repair. In DNA repair, specific proteins send electrons down the double helix to other DNA-bound repair proteins as a way to "test the line," so to speak, and make sure there are no mutations in the DNA. If there are mutations, the line is essentially broken, alerting the cell that mutations are in need of repair. The iron-sulfur clusters in the DNA repair proteins are responsible for donating and accepting traveling electrons.

Barton and her group wanted to know if the iron-sulfur clusters were doing something similar in the DNA-replication proteins.

"We knew the iron-sulfur clusters must be doing something in the DNA-replication proteins, otherwise why would they be there? Iron can damage the DNA, so nature would not have wanted the iron there were it not for a good reason," says Barton.

Through a series of tests in which mutations were introduced into the DNA primase protein, the researchers showed that this protein needs to be in an oxidized state—which means it has lost electrons—to bind tightly to DNA and participate in DNA electron transport. When the protein is reduced—meaning it has gained electrons—it does not bind tightly to DNA.

"The electronic state of the iron-sulfur cluster in DNA primase acts like an on/off switch to initiate DNA replication," says O'Brien.

What's more, the researchers demonstrated that electron transport through DNA plays a role in signaling DNA primase to leave the DNA strand. (Though DNA primase must bind to single-stranded DNA to kick off replication, the process cannot begin in earnest until the protein pops back off the strand).

The scientists propose that the DNA polymerase alpha protein, which sits on the double helix strand, sends electrons down the strand to DNA primase. DNA primase accepts the electrons, becomes reduced, and lets go of the DNA. This donation and acceptance of electrons is done with the help of the iron-sulfur clusters.

"You have to get the DNA primase off the DNA quickly—that really starts the whole replication process," says Barton. "It's a hand off of electrons from one cluster to the other through the DNA double helix."

Many proteins involved in DNA reactions also contain iron-sulfur clusters and may also play roles in DNA electron transport chemistry, Barton says. What began as a fundamental question 25 years ago about whether DNA could support migration of electrons continues to lead to new questions about the chemical workings of cells. "That's the wonder of basic research," she says. "You start with one question and the answer leads you to new questions and new areas."

The study, titled, "The [4Fe4S] Cluster of Human DNA Primase functions as a Redox Switch using DNA Charge Transport," was funded by the National Institutes of Health. The collaborative work also included Vanderbilt coauthors Marilyn Holt, Matthew Thompson, Lauren Salay, and Aaron Ehlinger.

New Cancer Drug Targets Cellular Garbage Disposal

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By inhibiting the proteasome—the cell's garbage disposal—in a novel way, a new treatment causes cancer cells to fill up with "trash" and self-destruct
News Writer: 
Lori Dajose
Green and blue fluorescent dots.
Aggregates of dysfunctional proteins, in fluorescent green, result from a new cancer treatment. These aggregates build up in cancer cells, causing them to die.
Credit: Courtesy of the Deshaies lab

The genomes of cancer cells—cells that do not obey signals to stop reproducing—are riddled with genetic mutations, causing them inadvertently to make many dysfunctional proteins. Like all other cells, cancer cells need to be vigilant about cleaning themselves up in order to survive. Now, biologists in the laboratory of Ray Deshaies, Caltech professor of biology and Howard Hughes Medical Institute Investigator, have developed a new way to inhibit the cancer cell cleanup mechanism, causing the cells to fill up with defective proteins and thus self-destruct.

The findings appear online in a paper in the February 27 issue of Nature Chemical Biology.

The proteasome is a hollow cylindrical structure that serves as a kind of cellular garbage disposal. It lets in proteins through small openings on each end, chops them up, and spits out the remains. When a bad protein is made by a cell, the protein gets tagged with chains composed of at least four copies of a small protein called ubiquitin. The tags signal to the proteasome that the bad protein needs to be destroyed. One part of the proteasome, called Rpn11, cuts off the ubiquitin chain as the defective protein is being stuffed into the garbage disposal. This step is necessary because the ubiquitin chain is too big to fit inside the proteasome.

A new compound developed by the Deshaies group, in collaboration with researchers from UC San Diego, inhibits Rpn11 activity, making it impossible for the proteasome to fully destroy bad proteins. Massive accumulation of these bad proteins causes catastrophic stress to the cell that results in cell death.

While the compound affects the proteasomes in all cells, normal cells are thought to produce fewer dysfunctional proteins than cancer cells. Some types of cancer cells are therefore more sensitive than normal cells to proteasome inhibition and thus even a small dose of the drug can be fatal to them.

"All current cancer drugs that target the proteasome work by inhibiting the protein-chopping enzymes on the inside of the proteasome; therefore they all have similar drawbacks and tend to lose efficacy over time," says Jing Li, a postdoctoral scholar in biology and biological engineering and first author on the paper. "Our research offers an alternative path to disabling proteasome function, including in cells that no longer respond to the existing drugs."

The compound was tested in human cancer cells in the laboratory, but more work needs to be done to further improve its potency and to evaluate its potential as a therapeutic drug through testing in animals.

The paper is titled "Capzimin is a potent and specific inhibitor of proteasome isopeptidase Rpn11." In addition to Li and Deshaies, other Caltech coauthors are postdoctoral fellow Tanya Yakushi and Sonja Hess, director of the Proteome Exploration Laboratory. The work was funded by grants from the Caltech Gates Grubstake Fund, Amgen, the National Institutes of Health, the Gordon and Betty Moore Foundation, the Beckman Institute, and the Howard Hughes Medical Institute.

Parasitic Fish Offer Evolutionary Insights

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Lamprey show that vertebrates once might have relied on a different mechanism for developing neurons in the gut.
News Writer: 
Lori Dajose
A side view of the lamprey gut, showing many large serotonergic neurons (green) sitting on the side of the gut.
A side view of the lamprey gut, showing many large serotonergic neurons (green) sitting on the side of the gut. These gut neurons are matured and developed.
Credit: Courtesy of the Bronner laboratory

Lamprey are slimy, parasitic eel-like fish, one of only two existing species of vertebrates that have no jaw. While many would be repulsed by these creatures, lamprey are exciting to biologists because they are so primitive, retaining many characteristics similar to their ancient ancestors and thus offering answers to some of life's biggest evolutionary questions. Now, by studying the lamprey, Caltech researchers have discovered an unexpected mechanism for the evolution of the neurons of the peripheral nervous system—nerves outside of the brain and spinal cord.

The work was done in the laboratory of Marianne Bronner, the Albert Billings Ruddock Professor of Biology at Caltech, and appears in a paper in the March 20 online issue of Nature.

For over a decade, the Bronner group has studied lamprey because of the unique insights they offer into the evolution of vertebrates, and particularly the evolution of new structures like jaws. Her laboratory at Caltech maintains one of the very few laboratory populations of lamprey in the world.

Bronner was especially interested in how the lamprey compares with other vertebrates in the evolution of its gut neurons. These neurons control the movement of muscles for digestion and manage other aspects of gut physiology, such as secretion and water balance.

"We were interested in the origins of lamprey gut neurons because in other vertebrates they arise from a particular embryonic cell type, called neural crest cells," says Stephen Green, postdoctoral scholar in biology and biological engineering and co-first author on the paper. "We knew that lamprey have many kinds of neural crest cells, but we knew little about which cells give rise to gut neurons."

Neural crest cells are a type of stem cell; during vertebrate embryonic development, they eventually differentiate into specialized cells such as those that make facial skeleton cells or those that create pigment cells. In particular, a population called vagal neural crest cells are known to become the gut neurons. But Bronner and her team noticed that while mature lamprey have gut neurons like other vertebrates, lamprey embryos lack these vagal cells.

"Adult lamprey have gut neurons, but we were unable to find the vagal precursor cells," says Bronner. "So, where do the gut neurons come from?"

To find out, the team drew inspiration from studies of mice that, due to a mutation, lack vagal neural crest cells. The mice do, however, have a small number of gut neurons from an unexpected source—cells called Schwann cell precursors (SCPs). SCPs exist along nerves that run from the spine to various parts of the body. These cells are known to develop into Schwann cells, which form a protective barrier around the nerves.

Bronner and her team fluorescently tagged these cells in lamprey embryos and found that, during development, the cells migrated from the spine toward the gut. Sure enough, some of these SCPs developed into gut neurons.

"Our findings suggest that gut neurons in ancient vertebrates may have come predominantly from SCPs, and that these original gut neurons were later outnumbered by neurons that arose from vagal neural crest cells," says Green. "Lamprey have relatively simple guts, with no looping and few total neurons. We speculate that vagal neural crest cells might be essential for the more complicated guts of higher vertebrates like mice and humans."

The paper is titled "Ancient evolutionary origin of vertebrate enteric neurons from trunk-derived neural crest." Former graduate student Benjamin Uy (PhD '16) is a co-first author. The work was funded by the National Institutes of Health.

Altered Perceptions

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How the electrical activity of the brain gives rise to the rich world of perception
News Writer: 
Lori Dajose
Images of mens faces, and images of clocks, teapots, and oranges.
Images shown to test face patch activity. Face patches are regions in the brain that respond strongly to faces. Additionally, they have a smaller response to objects like clocks and apples. These responses are used to shape our perceptions.
Credit: Courtesy of D. Tsao

The human brain is constantly abuzz with electrical activity as brain cells, called neurons, respond to sensory input and give rise to the world we perceive. Six particular regions of the brain, called face patches, contain neurons that respond more to faces than to any other type of object. New research from Caltech shows how perturbations in these face cells alter perception, answering a longstanding question in cognitive science.

The research was led by Doris Tsao (BS '96), professor of biology, Tianqiao and Chrissy Chen Center for Systems Neuroscience Leadership Chair, and Howard Hughes Medical Institute Investigator. A paper describing the work appeared online in the March 13 issue of Nature Neuroscience.

"Face cells will produce the maximum response when a subject is observing faces, but they will also produce a small amount of activity when a subject is looking at round objects like an apple or a clock," says Tsao. "There has been a long debate in cognitive science: Is the brain actually using these small responses to generate perception? Do face cells help us perceive clocks and apples?"

Tsao and her team aimed to test this by altering the perception of a trained monkey. First, the monkey was trained to look left if the two images were identical, and to look right if they were different. Then, the researchers showed the monkey two identical images of faces, but while it was viewing the second one, the researchers stimulated specific face patches. The monkey's response changed dramatically: the animal almost always indicated that the two identical faces were different—implying that the activity of face patch neurons plays a large role in generating our perception of faces. Surprisingly, the group found that stimulating face cells also had a significant effect on the perception of certain other objects.

"There was a study a few years ago in humans, where a neurosurgeon stimulated the face area of a person, and the person exclaimed, 'Whoa! Your face just metamorphosed,'" says Tsao. "Our study systematically perturbed each patch in the face patch network with a much larger set of stimuli, and we found that we could also perturb the perception of cartoon faces, two-toned abstract images called Mooney faces, and even apples. So we've shown that the class of objects that can be affected by face patch stimulation is quite large, much larger than only realistic photographs of faces. Even more surprisingly, we found that some of the objects whose percept we could alter with stimulation did not even activate the face patch we were stimulating—the face patch neurons were completely silent to these objects."

What could explain this? The group discovered that the face patch located most posterior in the temporal lobe, thought to harbor the earliest stage of face processing, was more permissive and activated by the objects whose percept could be altered by face patch stimulation. Patches that were in a more anterior part of the temporal lobe were more specialized for faces. These findings show that while face patches play a large causal role in generating the perception of faces, these regions are also part of a complex network involved in processing a much larger class of objects. The results set the stage for future experiments to study how activity across the entire network is integrated to produce perception of an object.

The work may have applications for engineers who design algorithms to teach machines to recognize objects.

"Machine vision engineers often ask: how many specialized networks do we need for robust object vision?" Tsao says. "Do we need a special network to recognize purses, shoes, cars, food? Or can we have one general purpose network? Our results suggest that the answer is a hybrid, and this may have important engineering implications."

The paper is titled "The effect of face patch microstimulation on perception of faces and objects." Coauthors include former postdoctoral scholars Sebastian Moeller and Trinity Crapse, and current Caltech postdoctoral scholar Le Chang. Funding was provided by the Howard Hughes Medical Institute, the National Institutes of Health, and the Humboldt Foundation.

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