New Faculty Member Brings Quantitative Approaches to Biology

Lea Goentoro remembers the precise moment that biology made an impression on her. It was 2002 and she was a PhD candidate in chemical engineering at Princeton. During a presentation at the Institute for Advanced Study, developmental biologist and Nobel laureate Eric Wieschaus—who shared the 1995 Nobel Prize with the late Edward Lewis, Caltech alumnus and former Morgan Professor of Biology—showed a movie of a live fly embryo under a microscope that was undergoing gastrulation, a phase early in development where a single layer of cells is reorganized into a three-layer structure. "The embryonic cells undergo massive rearrangement and things fold in—and it was all on this big screen," says Goentoro. "It was amazing. For me, that was when I thought, 'Wow. I really want to study this.'"

Now, nine years after that fateful day in New Jersey, Goentoro is Caltech's newest faculty member in the Division of Biology. She joined the division in late July as an assistant professor.

"Caltech is a wonderful place to be—the right place," says Goentoro. "When I saw that the division was looking for someone with a quantitative background and a research program that would combine quantitative approaches with biology, I thought it could be a perfect fit."

Although her educational background is in chemical engineering—like her PhD, she also earned her BS in the field from the University of Wisconsin-Madison in 2001—Goentoro has been applying her math and engineering skills to biology problems for the past 10 years. Previous to arriving at Caltech, she was a postdoctoral fellow at the Systems Biology Department at Harvard Medical School.

Her current research focuses on Weber's Law applied at a cellular level. The law, first discovered by an experimental psychologist in the early 1800s, is the idea that we sense our world in a relative way. Imagine that you spend the day outside in the bright sunlight. When you come indoors, it takes a few moments for your eyes to adjust to a different background. The idea of the law is that you will always be able to adjust to these types of changes.

"From my previous work with Marc Kirschner at Harvard, we found that there is a strong suggestion that this concept also applies to individual cells in our body," says Goentoro. "The way our brain processes sensory information seems to apply to the way individual cells process signals."

She hopes to find out whether or not this idea is true. Do individual cells communicate this way, and if so, how is it implemented at the molecular level? Goentoro uses mathematical modeling as one strategy to address these questions. "Not only does it give us new tools, it gives us new ways of thinking about problems in biology," she says. In addition, Goentoro and others in her lab do experiments in human cell cultures and study embryo development in African frogs to try to understand how individual cells are communicating with each other.

"The signaling pathway that we are studying is highly conserved across all animal cells, so that's why we can jump between one system and another," she explains. "Each system allows us to do different experiments. By combining all of them, we can get more information."

When she's not attending to frogs in her lab, or studying cells under a microscope, Goentoro says she'll be exploring her new hometown. An aspiring hiker, she looks forward to tackling local trails. "I've been promised that there is a really good hiking scene here," she says. In addition, she enjoys scouring used bookstores for hidden treasures. Like research, you never know what you might discover.  

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Katie Neith
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Caltech Researchers Increase the Potency of HIV-Battling Proteins

PASADENA, Calif.—If one is good, two can sometimes be better. Researchers at the California Institute of Technology (Caltech) have certainly found this to be the case when it comes to a small HIV-fighting protein.

The protein, called cyanovirin-N (CV-N), is produced by a type of blue-green algae and has gained attention for its ability to ward off several diseases caused by viruses, including HIV and influenza. Now Caltech researchers have found that a relatively simple engineering technique can boost the protein's battling prowess.

"By linking two cyanovirins, we were able to make significantly more potent HIV-fighting molecules," says Jennifer Keeffe, a staff scientist at Caltech and first author of a new paper describing the study in the Proceedings of the National Academy of Sciences (PNAS). "One of our linked molecules was 18 times more effective at preventing infection than the naturally occurring, single protein."

The team's linked pairs, or dimers, were able to neutralize all 33 subtypes of HIV that they were tested against. The researchers also found the most successful dimer to be similar or more potent than seven well-studied anti-HIV antibodies that are known to be broadly neutralizing.

CV-N binds well to certain carbohydrates, such as the kind found in high quantities connected to the proteins on the envelope that surrounds the HIV virus. Once attached, CV-N prevents a virus from infecting cells, although the mechanism by which it accomplishes this is not well understood.

What is known is that each CV-N protein has two binding sites where it can bind to a carbohydrate and that both sites are needed to neutralize HIV.

Once the Caltech researchers had linked two CV-Ns together, they wanted to know if the enhanced ability of their engineered dimers to ward off HIV was related to the availability of additional binding sites. So they engineered another version of the dimers—this time with one or more of the binding sites knocked out—and tested their ability to neutralize HIV.

It turns out that the dimers' infection-fighting potency increased with each additional binding site—three sites are better than two, and four are better than three. The advantages seemed to stop at four sites, however; the researchers did not see additional improvements when they linked three or four CV-N molecules together to create molecules with six to eight binding sites.

Although CV-N has a naturally occurring dimeric form, it isn't stable at physiological temperatures, and thus mainly exists in single-copy form. To create dimers that would be stable under such conditions, the researchers covalently bound together two CV-N molecules in a head-to-tail fashion, using flexible polypeptide linkers of varying lengths.

Interestingly, by stabilizing the dimers and locking them into a particular configuration, it seems that the group created proteins with distances between binding sites that are very similar to those between the carbohydrate binding sites in a broadly neutralizing anti-HIV antibody.

"It is possible that we have created a dimer that has its carbohydrate binding sites optimally positioned to block infection," says Stephen Mayo, Bren Professor of Biology and Chemistry, chair of the Division of Biology, and corresponding author of the new paper.

Because it is active against multiple disease-causing viruses, including multiple strains of HIV, CV-N holds unique promise for development as a drug therapy. Other research groups have already started investigating its potential application in prophylactic gels and suppositories.

"Our hope is that those who are working to make prophylactic treatments using cyanovirin will see our results and will use CVN2L0 instead of naturally occurring cyanovirin," Keeffe says. "It has higher potency and may be more protective." 

The paper, entitled "Designed oligomers of cyanovirin-N show enhanced HIV neutralization," was published in the online edition of PNAS. In addition to Keeffe and Mayo, other authors on the paper include research technician Priyanthi N.P. Gnanapragasam, former biology graduate student Sarah K. Gillespie, biology graduate student John Yong, and Pamela J. Bjorkman, the Max Delbruck Professor of Biology at Caltech and a Howard Hughes Medical Institute investigator. 

The work was funded by the National Security Science and Engineering Faculty Fellowship program, the Defense Advanced Research Projects Agency Protein Design Processes program, and the Bill and Melinda Gates Foundation through the Grand Challenges in Global Health Initiative.

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Kimm Fesenmaier
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Sharper, Deeper, Faster: Interdisciplinary Team Develops Advanced Live-Imaging Approach

PASADENA, Calif.— For modern biologists, the ability to capture high-quality, three-dimensional (3D) images of living tissues or organisms over time is necessary to answer problems in areas ranging from genomics to neurobiology and developmental biology. The better the image, the more detailed the information that can be drawn from it. Looking to improve upon current methods of imaging, researchers from the California Institute of Technology (Caltech) have developed a novel approach that could redefine optical imaging of live biological samples by simultaneously achieving high resolution, high penetration depth (for seeing deep inside 3D samples), and high imaging speed.

The imaging technique is explained in a paper in the advance online publication of the journal Nature Methods, released on July 14. It will also appear in an upcoming print version of the journal.  

"Before our work, the state-of-the-art imaging techniques typically excelled in only one of three key parameters: resolution, depth, or speed. With our technique, it's possible to do well in all three and, critically, without killing, damaging, or adversely affecting the live biological samples," says biologist Scott Fraser, director of the Biological Imaging Center at Caltech's Beckman Institute and senior author of the study. 

The research team achieved this imaging hat trick by first employing an unconventional imaging method called light-sheet microscopy, where a thin, flat sheet of light is used to illuminate a biological sample from the side, creating a single illuminated optical section through the sample. The light given off by the sample is then captured with a camera oriented perpendicularly to the light sheet, harvesting data from the entire illuminated plane at once. This allows millions of image pixels to be captured simultaneously, reducing the light intensity that needs to be used for each pixel. This not only enables fast imaging speed but also decreases the light-induced damage to the living samples, which the teams demonstrated using the embryos of fruit fly and zebrafish.

To achieve sharper image resolution with light-sheet microscopy deep inside the biological samples, the team used a process called two-photon excitation for the illumination. This process has been used previously to allow deeper imaging of biological samples; however, it usually is used to collect the image one pixel at a time by focusing the exciting light to a single small spot.

"The conceptual leap for us was to realize that two-photon excitation could also be carried out in sheet-illumination mode," says Thai Truong, a postdoctoral fellow in Fraser's laboratory and first author of the paper. This novel side-illumination with a two-photon illumination is the topic of a pending patent.

"With this approach, we believe that we can make a contribution to advancing biological imaging in a meaningful way," continues Truong, who did his PhD training in physics. "We did not want to develop a fanciful optical imaging technique that excels only in one niche area, or that places constraints on the sample so severe that the applications will be limited. With a balanced high performance in resolution, depth, and speed, all achieved without photo-damage, two-photon light-sheet microscopy should be applicable to a wide variety of in vivo imaging applications." He credits this emphasis on wide applicability to the interdisciplinary nature of the team—which includes two biologists, two physicists, and one electrical engineer.

"We believe the performance of this imaging technique will open up many applications in life sciences and biomedical research—wherever it is useful to observe, non-invasively, dynamic biological process in 3D and with cellular or subcellular resolution," says Willy Supatto, co–author of the paper and a former postdoctoral fellow in Fraser's laboratory (now at the Centre National de la Recherche Scientifique, in France).

One example of such an application would be to construct 3D movies of the entire embryonic development of an organism, covering the entire embryo in space and time. These movies could capture what individual cells are doing, as well as important genes' spatiotemporal expression patterns—elucidating the activation of those genes within specific tissues at specific times during development.

"The goal is to create 'digital embryos,' providing insights into how embryos are built, which is critical not only for basic understanding of how biology works but also for future medical applications such as robotic surgery, tissue engineering, or stem-cell therapy," says Fraser. The team's first attempt at this can be seen in the accompanying movie, in which the cell divisions and movements that built the entire fruit fly embryo were captured without perturbing its development. 

The Nature Methods paper is titled "Deep and fast live imaging with two-photon scanned light-sheet microscopy." David Koos, senior research scientist at Caltech's Beckman Institute, and John Choi, a former postdoctoral fellow in Fraser's laboratory, also contributed to the study.

The research was supported by the Beckman Institute and the U.S. National Institutes of Health.

 

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Katie Neith
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Neutralizing HIV

Each time a virus invades a healthy individual, antibodies created by the body fight to fend off the intruders. For some viruses, like HIV, the antibodies are very specific and are generated too slowly to combat the rapidly changing virus. However, in the past few years, scientists have found that some HIV-positive people develop highly potent antibodies that can neutralize different subtypes of the HIV virus.

Now, a study involving researchers at Caltech points to the possibility of using these neutralizing antibodies in the development of a vaccine. The paper, published in the July 14 issue of Science Express, describes a group of novel antibodies that were isolated from HIV-infected individuals using a new cloning approach.

These antibodies are the most potent anti-HIV antibodies targeting the CD4 binding site— a functional site on the surface of HIV needed for cell entry and infection—that have ever been identified, says Ron Diskin, a post-doctoral scholar at Caltech who worked on the paper. David Ho (BS '74), scientific director of the Aaron Diamond AIDS Research Center in New York, also contributed to the study, which was led by researchers at Rockefeller University.

At Caltech, the researchers conducted structural studies and were able to show, based on similarity to a previously known antibody (VRC01), that the new antibodies indeed target the CD4 receptor binding site. CD4 positive cells are the point of HIV infection and where the virus multiplies.  

This study is important for several different reasons, according to Diskin. "First, it provides extremely useful reagents that can be used for passive immunization to treat infected individuals," he says. "Second, it demonstrates that a comparable and highly effective anti-HIV immune response was elicited in different individuals, which strongly supports the idea that an effective vaccine will be feasible to develop."

Next, researchers at Caltech will address the structural mechanisms that make those antibodies so potent. In fact, they are currently investigating those structural aspects of the neutralization mechanisms.

"We're very excited to have the opportunity to use structural biology to learn what makes these new antibodies so potent against HIV," says Pamela Bjorkman, Caltech's Delbruck Professor of Biology and a co-author of the study. "We hope that visualizing how these antibodies interact with HIV proteins will allow the design of even more potent anti-HIV reagents and provide critical information for vaccine design."

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Katie Neith
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Tracking Bacteriophages

Viruses are parasites; they need to live inside another organism to survive. Figuring out just who a virus's host is can be difficult, however. Especially when you're talking about bacteriophages—a particularly pervasive group of bacteria-infecting viruses.

The problem lies in identifying which bacteriophages are infecting which bacteria, without having to culture either the viruses or their hosts in the lab, which can often be a difficult if not impossible task.

To address that issue, a team led by Caltech biophysicist Rob Phillips has created a genetic-analysis technique—called microfluidic digital polymerase chain reaction (PCR)—that can "physically link single bacterial cells harvested from a natural environment with a viral marker genes," the scientists report in the July 1 issue of the journal Science.

The team looked at the bacterial community found in the hindgut of a termite—specifically, a termite collected in 2005 in Costa Rica. The typical termite hindgut contains over 250 different species of bacteria, "making it ideally suited to explore many potential, diverse phage-host interactions," the scientists say.

What they found was that microfluidic digital PCR allowed them to see interactions between the viruses and their bacterial hosts in uncultivated cells harvested directly from the hindgut. They noted, for instance, that variants of a viral packaging gene had made their way into hosts across an entire genus of bacteria; in another gene-tracking experiment, however, they found little evidence of lateral gene transfer or switching of the gene from one host to another, despite plenty of opportunity.

"Our approach does not require culturing hosts or viruses," the researchers write, "and provides a method for examining virus-bacteria interactions in many environments."

For more on the new technology and its potential applications, check out the paper's abstract or this press release from the National Science Foundation, one of the funders of the research.

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Lori Oliwenstein
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$6 Million Gift To Spur Innovative Research Collaborations Between Caltech, City of Hope

PASADENA, Calif.—As part of a program to foster innovative biomedical research projects, an anonymous donor has pledged $3 million each to the California Institute of Technology (Caltech) and City of Hope to strengthen scientific collaborations between the two leading research institutions.

The gifts to Caltech and City of Hope will build upon support for research projects featuring partnerships between Caltech and City of Hope investigators. They will carry forward a program of collaborations between the two institutions that began in 2008 and has since helped start several promising projects in cancer, AIDS, and diabetes research.

"By combining the intellect, creativity, and passion of researchers from both of our institutions, we hope to accelerate the speed at which potentially game-changing discoveries in medical science are moved from the laboratory to patient care," says Caltech president Jean-Lou Chameau. "Private support is absolutely critical to achieving this goal, so we greatly appreciate this generous gift."

The biomedical initiative is meant to support those original, interdisciplinary, early-stage translational medical research projects that do not yet qualify for traditional sources of funding. Translational medicine is also known as bench-to-bedside research, in which basic science discoveries are developed into new therapies or treatments. Through the Caltech–City of Hope program, investigators will be able to leverage their unique strengths by working together. Eventually, these projects could lead to a clinical-trial phase with patients, which could then lead to new pharmaceuticals, medical devices, or other treatments.

"When we effectively apply the strengths of both City of Hope and Caltech to scientific research, we can more easily leverage groundbreaking discovery into the development of improved therapies for people facing serious illness such as cancer, HIV or diabetes," says Michael A. Friedman, president and chief executive officer of City of Hope. "We are very grateful for the generosity of donors who support our combined efforts to help patients everywhere."

Some of the Caltech–City of Hope projects that have already received seed funding include the investigation of a chemical compound that has been unexpectedly effective in reducing breast cancer tumors, the study of a gene that plays a role in tumor suppression, and a novel method of selectively killing HIV-infected cells using synthetic RNA molecules.

The gifts to the two institutions also provide support for an annual public event. The most recent event was held May 17 at Caltech. It featured presentations by Nobel Laureate David Baltimore, president emeritus and Robert Andrews Millikan Professor of Biology at Caltech; and John A. Zaia, the Aaron D. and Edith Miller Chair in Gene Therapy; Chair and Professor of Virology; and Deputy Director for Clinical Research at the Comprehensive Cancer Center at City of Hope.

As part of the pledge, Caltech and City of Hope have been challenged to raise an additional $3 million each toward their collaboration. The Caltech challenge is eligible for the Gordon and Betty Moore Matching Program, which, for a limited time, will contribute $1 for every $2 raised by Caltech.

Caltech has an extensive history of discovery in the biological sciences, and its faculty and alumni have won nine Nobel Prizes in medically related fields. City of Hope is a leading research, treatment, and education center for cancer, diabetes, and other life-threatening diseases.

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Mike Rogers
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Caltech Scientist Awarded $5 Million Grant for Plant Research

PASADENA, Calif.—Elliot Meyerowitz, a plant genetics and developmental biology expert at the California Institute of Technology (Caltech), has been awarded one of 15 five-year, $5 million grants for fundamental plant science research.

The awards were made by the Howard Hughes Medical Institute (HHMI) and the Gordon and Betty Moore Foundation (GBMF).

Meyerowitz, the George W. Beadle Professor of Biology at Caltech, is an expert in the study of Arabidopsis thaliana, a small flowering plant in the mustard family and a model organism for plant genetics and molecular biology studies. During three decades of study, his work revealed the mechanism by which plants create their characteristic patterns of leaves and flowers; uncovered the first plant hormone receptor; and led to the sequencing of the Arabidopsis genome.

Traditionally, fundamental plant research often has been overlooked and underfunded. Indeed, despite the importance of plant science to food production, human health, environmental protection, and renewable-energy science, basic plant research represents only 2 percent of the funding for life sciences from the federal government.

The $75 million in awards represents an unprecedented influx of cash.

"I think this sort of funding is overdue, but not surprising," Meyerowitz says. "Medical researchers and policy makers are becoming increasingly aware that health and agriculture are critically related. The World Health Organization estimates that 10 percent of the entire world disease burden is due to undernutrition. The United Nations Food and Agriculture Organization estimates 925 million people are undernourished, and most estimates indicate that more people die of starvation every year, worldwide, than of cancer. Plants are also at the heart of many solutions to our energy problems and the relation of energy use to climate change," he adds, "because plants absorb carbon dioxide and emit oxygen."

"We think the creation of our joint program underscores the importance of investing in fundamental plant science, and we hope it will encourage others in the United States to make analogous commitments," said HHMI President Robert Tjian, in an announcement about the awards.

Meyerowitz is currently on leave from Caltech and serving as the inaugural director of the Sainsbury Laboratory at the University of Cambridge, which concentrates on understanding plant development and plant diversity through experimental and computational approaches. Meyerowitz will use the funding from the HHMI and the GBMF to develop a new interface between plant developmental biology and computational modeling, based on a method known as computational morphodynamics—the study of the three-way interaction of physical, informational, and geometrical processes that influences the changing form, shape, and structure of living cells, tissues, and organisms.

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Kathy Svitil
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From Pre-Gut Cells to Glory

Caltech researchers discover a genomic control system that regulates gut formation in sea-urchin embryos

PASADENA, Calif.—For all animals, development begins with the embryo. It is here that uniform cells divide and diversify, and blueprints are laid for future structures, like skeletal and digestive systems. Although biologists have known for some time that signaling processes—messages that tell a cell to express certain genes so as to become certain parts of these structures—exist at this stage, there has not been a clear framework explanation of how it all comes together.

Now, a research team at the California Institute of Technology (Caltech) has outlined exactly how specific sets of cells in sea-urchin embryos differentiate to become the endoderm, the early domain of the embryo that eventually forms the gut. Their findings were reported in a paper entitled "A gene regulatory network controlling the embryonic specification of endoderm," published by the journal Nature online on May 29, in advance of the print version.

"If you only look at the genetic information of cells in an embryo, they all have the same genome and they all start from the single-cell zygote," says Isabelle S. Peter, a senior postdoctoral scholar at Caltech and coauthor of the study. "But then cells start to divide and, at some point, these cells are no longer identical in the genes that they express. We wanted to know how this process is achieved—how differences are established in cells in the right place and at the right time."

In order for undifferentiated cells to change their state and become a specific part of the body, the right genes need to be expressed, and the wrong ones repressed. The most important genes are regulatory genes, which control the expression of other genes, and form a gene regulatory network (GRN) that doles out differentiation instructions by turning genes on or off at specific times during embryonic development.

In the work described in the Nature paper, Peter and Eric H. Davidson, the Norman Chandler Professor of Cell Biology at Caltech and the other coauthor on the study, were able to analyze systematically the specification process controlled by the GRN and map out a master plan that, for the first time, shows the relationships between all the regulatory genes in specific parts of the embryo.

They studied sea-urchin embryos over a 24-hour period, beginning at hour eight of the embryo's existence. During this period, different physical domains exist in the embryo, each of which represents a future structure in the body, like the gut. All the regulatory genes known to exist in the sea-urchin genome and to be expressed in the embryo have been studied, and it was found that certain regulatory genes are expressed in the cells of each domain. Some of the domains will express certain regulatory genes in common, but the combination of genes found in each domain is unique. In addition, they found that this process is dynamic—where the genes are expressed changes over time. For example, two genes that are coexpressed in one domain at an early stage of the process may then be expressed in different domains at a later stage.

"It's like you are building a complicated edifice," explains Davidson. "And before anything is actually there, the building instructions have already been handed to all the workers. They all know what they are going to have to do once the bulldozer comes in and starts moving earth around."

The team focused on pinning down the precise regulatory genes in the progression of pre-gut cells (which eventually form the gut), following them from their initial stage as undifferentiated cells, to the point of gastrulation. During gastrulation the endoderm cells reorganize from a single layer into an internal tube with three regions that serve as the foundation for the future foregut, midgut, and hindgut structures. The researchers were able to pinpoint which regulatory genes were expressed at which specific times in the 24-hour period, and how those genes interacted over time to turn each other on and off.

"The instructions for development have to be in the genome somewhere, but you would be surprised how fragmentary the information about how that works was until we did this system-level analysis," says Davidson. "You can never understand it by looking at one gene. You can never understand it by looking at a third of the genes. You really have to get the whole system mapped out—and that's what we did."

In 2008, Davidson—who has been studying the biological processes of sea urchins for many years—led a research team that sketched a rough outline, for the first time, of how the GRN works to produce the sea urchin's skeletal system. "We are light-years beyond that with this new study," he says. "That was about solving network subcircuits, but now we have a framework that causally explains the far more complex process of development required for gut formation in terms of the genome's regulatory instruction code." This advance opens a much larger range of developmental scenarios to causal network analysis.

Sea urchins' gene regulatory systems, Davidson points out, are the closest—among the thoroughly studied invertebrate systems—to those of mammals, in terms of evolutionary relationships. This means the mechanisms the team uncovered in their work are likely to illuminate our own developmental regulatory systems. This could have implications for human health.

"If you believe that medicine consists of putting Band-Aids on things, then we have no relevance to that," says Davidson. "But if you believe that we should understand how life works before trying to find a cure when something goes wrong, then understanding biological processes from their initial stages comes first."

The team would next like to take their framework analysis and apply it to later stages in development—to when the gut is actually present. "We would like to understand how the different compartments in the gut are established, which would also make the work more directly informative to the development of the human gut," says Peter.

They would also like to extend the analysis to as much of the sea-urchin embryo as they can, says Davidson, as well as to formalize their findings to make an abstract computer model of how the gene regulatory system works. This will allow them to validate this particular network and to eventually do experiments that involve manipulating the cells to produce different results.

"Basically everything that happens in us, or in any animal during development, is encoded in genomic regulatory instructions," says Davidson. "Now we have an explanation as to how that works, which is very exciting. We can only move forward from here."

The work was funded by the Swiss National Science Foundation and the National Institutes of Health.

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Katie Neith
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Learning to Tolerate Our Microbial Self

PASADENA, Calif.—The human gut is filled with 100 trillion symbiotic bacteria—ten times more microbial cells than our own cells—representing close to one thousand different species. "And yet, if you were to eat a piece of chicken with just a few Salmonella, your immune system would mount a potent inflammatory response," says Sarkis K. Mazmanian, assistant professor of biology at the California Institute of Technology (Caltech).

Salmonella and its pathogenic bacterial kin don't look that much different from the legion of bacteria in our gut that we blissfully ignore, which raises the question: What decides whether we react or don't? Researchers have pondered this paradox for decades.

In the case of a common "friendly" gut bacterium, Bacteroides fragilis, Mazmanian and his colleagues have figured out the surprising answer: "The decision is not made by us," he says. "It's made by the bacteria. Since we are their home, they hold the key to our immune system."

What's more, the bacteria enforce their "decision" by hijacking cells of the immune system, say Mazmanian and his colleagues, who have figured out the mechanism by which the bacteria accomplish this feat—and revealed an explanation for how the immune system distinguishes between beneficial and pathogenic organisms.

In addition, the work, described in the April 21 issue of Science Express, "suggests that it's time to reconsider how we define self versus non-self," Mazmanian says.

Like other commensal gut bacteria—those that provide nutrients and other benefits to their hosts, without causing harm—B. fragilis was thought to live within the interior of the gut (the lumen), and thus far away from the immune system. "The dogma is that the immune system doesn't respond to symbiotic bacteria because of immunological ignorance," Mazmanian explains. "If we can't see them, we won't react to them."

But using a technique called whole-mount confocal microscopy to study the intestines of mice, he and his colleagues found that the bacteria actually live in a unique ecological niche, deep within the crypts of the colon, "and thus in intimate contact with the gut mucosal immune system," he says.

"The closeness of this association highlights that an active communication is occurring between the bacteria and their host," says Caltech postdoctoral scholar June L. Round.

From that vantage point, the bacteria are able to orchestrate control over the immune system—and, specifically, over the behavior of immune cells known as regulatory T cells, or Treg cells. The normal function of Treg cells is to prevent the immune system from reacting against our own tissues, by shutting down certain immune responses; they therefore prevent autoimmune reactions (which, when uncontrolled, can lead to diseases such as multiple sclerosis, type 1 diabetes, lupus, psoriasis, and Crohn's disease).

Bacteroides fragilis has evolved to produce a molecule that tricks the immune system into activating Treg cells in the gut, but in this case, Mazmanian says, "the purpose is to keep the cells from attacking the bugs. Beautiful, right?"

In their Science paper, Mazmanian and colleagues describe the entire molecular pathway that produces this effect. It starts with the bacteria producing a complex sugar molecule called polysaccharide A (PSA). PSA is sensed by particular receptors, known as Toll-like receptors, on the surfaces of Treg cells, thus activating those cells specifically. In response, Treg cells suppress yet another type of cell, the T helper 17 (Th17) cells. Normally, Th17 cells induce pro-inflammatory responses—those that would result, for example, in the elimination of foreign bacteria or other pathogens from the body. By shutting those cells down, B. fragilis gets a free pass to colonize the gut. "Up until now, we have thought that triggering of Toll-like receptors resulted solely in the induction of pathways that eliminate bacteria," says Round. "However, our studies suggest that multiple yet undiscovered host pathways allow us to coexist with our microbial partners."

When Mazmanian and his colleagues blocked this mechanism—by removing the PSA molecule, by removing the Toll-like receptor for PSA, or by eliminating the Treg cells themselves—the bacteria were attacked by the immune system and expelled. "They can no longer co-opt the immune system into inducing an anti-inflammatory response, so the formerly benign bacterium now looks like a pathogen," he says, "although the bug itself is exactly the same."

"Our immune system arose in the face of commensal colonization and thus likely evolved specialized molecules to recognize good bacteria," says Round. Mazmanian suspects that genetic mutations in these pathways could be responsible for certain types of immune disorders, including inflammatory bowel disease: "The question is, do patients get sick because they are rejecting bacteria they shouldn't reject?"

On a more philosophical level, Mazmanian says, the findings suggest that our concept of "self" should be broadened to include our many trillions of microbial residents. "These bacteria live inside us for our entire lives, and they've evolved to look and act like us, as part of us," he says. "As far as our immune system is concerned, the molecules made by gut bacteria should be tolerated similarly to our own molecules. Except in this case, the bacteria 'teaches' us to tolerate them, for both our benefit and theirs."

The other coauthors on the paper, "The Toll-like receptor 2 pathway establishes colonization by a commensal of the human microbiota," are S. Melanie Lee, Jennifer Li, and Gloria Tran of Caltech; Bana Jabri of the University of Chicago; and Talal A. Chatila of the David Geffen School of Medicine at UCLA. June L. Round was supported by a Jane Coffin Childs Memorial Fund postdoctoral fellowship. The work was supported by the National Institutes of Health, the Damon Runyon Cancer Research Foundation, and the Crohn's and Colitis Foundation of America.

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Kathy Svitil
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Caltech Biologist Recognized for Cellular Noise Research

Nearly ten years ago, Michael Elowitz, Caltech Bren Scholar and professor of biology, bioengineering, and applied physics, first amplified the idea that stochasticity—or noise—plays an important role in the process of gene expression. Prior to his work, such cellular noise was treated as a mysterious property.

For his pioneering work on gene expression noise, Elowitz has been named the winner of the 2011 Human Frontier Science Program (HFSP) Nakasone Award. The HFSP is a program that funds frontier research in the life sciences and the award is for breakthrough contributions at the frontier of the life sciences, either conceptual or methodological, that have had a major impact on basic biological research.

Elowitz's work introduced conceptual and experimental tools to detect gene expression noise, to quantify its level, and to evaluate its effect on cellular function. Genetic noise is now considered a core aspect of biology–one that functions actively in diverse cellular functions, including differentiation, regulation, and evolution.

Because of Elowitz's findings, noise has gone from being considered a curiosity of cellular life to being recognized as a key process whose effects must be considered in almost any analysis of biological systems. Stochastic processes are thought to enable stem cell differentiation and reprogramming, and developmental cell fates are controlled by noise. Thanks to Elowitz's work, noise is now recognized as an essential and functional element that distinguishes and enables the core cellular behaviors of life. 

Elowitz will give the HFSP Nakasone Lecture at the annual meeting of HFSP awardees to be held in Montreal, Canada in June

Writer: 
Katie Neith
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