Spring Break in the Galápagos

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Spring Break in the Galápagos
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Credit: Kevin Yu

As the culminating event of the new Evolution course at Caltech, a dozen Techers, their TA, and two professors—Rob Phillips and Victoria Orphan—spent a week of spring break living as field researchers on the Galápagos Islands.

Credit: Kevin Yu

Ecuadorian naturalist Ernesto Vaca led the group in their studies of the natural world on the Galápagos. Here, at Playa Las Bachas on Santa Cruz Island, he is describing the molting of the Sally Lightfoot crab. The students kept scientific journals during the trip, writing down questions and observations along the way.

Credit: Laura Santoso

Marine iguanas are endemic to the Galápagos and are the only modern lizards that swim. They offer an excellent example of the way isolation on islands can lead to unique speciation.

Credit: Jeff Marlow

The group's home base for the trip was the research vessel Daphne, shown here anchored in James Bay.

Credit: Jeff Marlow

The group walks over solidified volcanic ash on Santiago Island.

Credit: Victoria Orphan

Flightlessness is one of the key evolutionary adaptations seen on islands. Here, a flightless cormorant is seen diving to gather food.

Credit: Kevin Yu

The landscape of Cerro Dragón (Dragon Hill) on Santa Cruz Island. This was one of many sites where the students were able to see the impact of invasive species such as goats.

Credit: Laura Santoso

The group's mascot—a Darwin bobblehead doll—posing in front of the third largest oceanic caldera in the world at the Sierra Negra volcano.

Credit: Pushpa Neppala

The Sierra Negra volcano on Santa Cruz Island.

Credit: Jeff Marlow

A young sea lion serves as an unexpected roadblock upon the group's arrival at North Seymour Island.

Credit: Ketaki Panse

A blue-footed booby perched atop a volcanic rock on North Seymour Island.

Credit: Laura Santoso

A land iguana with the island Daphne Minor in the background. One of the central questions about the iguanas on the Galápagos is how they arrived on the islands in the first place.

Credit: Aleena Patel

Part of the group explores a mangrove lagoon in Elizabeth Bay on Isla Isabela. According to Orphan, the mangroves are a nursery for many animals, and she encouraged the students to examine the mangrove roots closely. "Really looking closely, you start to see little transparent shrimp running up and down. There's a lot of richness that you can see even by just sitting and observing," she says.

Credit: Ketaki Panse

A beautiful sunset seen from the top of Bartholomew Island.

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As the final element of Evolution, Caltech's new Bi/Ge 105 course, a dozen students spent their spring break snorkeling with penguins and sharks, hiking a volcano, and otherwise taking in the natural laboratory for evolution that is the Galápagos Islands. The second-term course was created and is taught by Rob Phillips, the Fred and Nancy Morris Professor of Biophysics and Biology, and Victoria Orphan, professor of geobiology, and is designed to give students both a broad picture of evolution and a chance to make their own up-close-and-personal observations.

 

Caltech Researchers Discover the Seat of Sex and Violence in the Brain

As reported in a paper published online today in the journal Nature, Caltech biologist David J. Anderson and his colleagues have genetically identified neurons that control aggressive behavior in the mouse hypothalamus, a structure that lies deep in the brain (orange circle in the image at right). Researchers have long known that innate social behaviors like mating and aggression are closely related, but the specific neurons in the brain that control these behaviors had not been identified until now.

The interdisciplinary team of graduate students and postdocs, led by Caltech senior research fellow Hyosang Lee, found that if these neurons are strongly activated by pulses of light, using a method called optogenetics, a male mouse will attack another male or even a female. However, weaker activation of the same neurons will trigger sniffing and mounting: mating behaviors. In fact, the researchers could switch the behavior of a single animal from mounting to attack by gradually increasing the strength of neuronal stimulation during a social encounter (inhibiting the neurons, in contrast, stops these behaviors dead in their tracks).

These results suggest that the level of activity within the population of neurons may control the decision between mating and fighting.  

The neurons initially were identified because they express a protein receptor for the hormone estrogen, reinforcing the view that estrogen plays an important role in the control of male aggression, contrary to popular opinion. Because the human brain contains a hypothalamus that is structurally similar to that in the mouse, these results may be relevant to human behavior as well.

The results of the study were published in journal Nature on April 16. David J. Anderson is the Seymour Benzer Professor of Biology and an investigator with the Howard Hughes Medical Institute.

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For Cells, Internal Stress Leads to Unique Shapes

From far away, the top of a leaf looks like one seamless surface; however, up close, that smooth exterior is actually made up of a patchwork of cells in a variety of shapes and sizes. Interested in how these cells individually take on their own unique forms, Caltech biologist Elliot Meyerowitz, postdoctoral scholar Arun Sampathkumar, and colleagues sought to pinpoint the shape-controlling factors in pavement cells, which are puzzle-piece-shaped epithelial cells found on the leaves of flowering plants. They found that these unusual shapes were the cell's response to mechanical stress on the microtubule cytoskeleton—protein tubes that act as a scaffolding inside the cells. These microtubules guide oriented deposition of cell-wall components, thus providing structural support.

The researchers studied this supportive microtubule arrangement in the tissue of pavement cells from the first leaves—or cotyledons—of a young Arabidopsis thaliana plant (right). By fluorescently marking the cells' microtubules (yellow, top surface of cell; purple, bottom surface of cell), the researchers could image the cell's structural arrangement—and watch how this arrangement changed over time. They could also watch the microtubule modifications that occurred due to changes in the mechanical forces experienced by the cells.

Microtubules strengthen a cell's structure by lining up in the direction of stress or pressure experienced by the cell and guiding the deposition of new cell-wall material, providing a supportive scaffold for the cell's shape. However, Meyerowitz and colleagues found that this internal stress is also influenced by the cell's shape. The result is a feedback loop: the cell's shape influences the microtubule arrangement; this arrangement, in turn, affects the cell's shape, which modulates the microtubules, and so on. Therefore, the unusual shape of the pavement cell represents a state of balance—an individual cell's tug-of-war to maintain structural integrity while also dynamically responding to the pushes and pulls of mechanical stress.

The results of the study were published in the journal eLife on April 16. Elliot Meyerowitz is George W. Beadle Professor of Biology and an investigator with the Howard Hughes Medical Institute.

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Antennae Help Flies "Cruise" In Gusty Winds

Caltech researchers uncover a mechanism for how fruit flies regulate their flight speed, using both vision and wind-sensing information from their antennae.

Due to its well-studied genome and small size, the humble fruit fly has been used as a model to study hundreds of human health issues ranging from Alzheimer's to obesity. However, Michael Dickinson, Esther M. and Abe M. Zarem Professor of Bioengineering at Caltech, is more interested in the flies themselves—and how such tiny insects are capable of something we humans can only dream of: autonomous flight. In a report on a recent study that combined bursts of air, digital video cameras, and a variety of software and sensors, Dickinson and his team explain a mechanism for the insect's "cruise control" in flight—revealing a relationship between a fly's vision and its wind-sensing antennae.

The results were recently published in an early online edition of the Proceedings of the National Academy of Sciences.

Inspired by a previous experiment from the 1980s, Dickinson's former graduate student Sawyer Fuller (PhD '11) wanted to learn more about how fruit flies maintain their speed in flight. "In the old study, the researchers simulated natural wind for flies in a wind tunnel and found that flies maintain the same groundspeed—even in a steady wind," Fuller says.

Because the previous experiment had only examined the flies' cruise control in gentle steady winds, Fuller decided to test the limits of the insect's abilities by delivering powerful blasts of air from an air piston in a wind tunnel. The brief gusts—which reached about half a meter per second and moved through the tunnel at the speed of sound—were meant to probe how the fly copes if the wind is rapidly changing.

The flies' response to this dynamic stimulus was then tracked automatically by a set of five digital video cameras that recorded the fly's position from five different perspectives. A host of computers then combined information from the cameras and instantly determined the fly's trajectory and acceleration.

To their surprise, the Caltech team found that the flies in their experiments, unlike those in the previous studies, accelerated when the wind was pushing them from behind and decelerated when flying into a headwind. In both cases the flies eventually recovered to maintain their original groundspeed, but the initial response was puzzling, Fuller says. "This response was basically the opposite of what the fly would need to do to maintain a consistent groundspeed in the wind," he says.

In the past, researchers assumed that flies—like humans and most other animals—used their vision to measure their speed in wind, accelerating and decelerating their flight based on the groundspeed their vision detected. But Fuller and his colleagues were also curious about the in-flight role of the fly's wind-sensing organs: the antennae.

Using the fly's initial response to strong wind gusts as a marker, the researchers tested the response of each sensory mode individually. To investigate the role of wind sensation on the fly's cruise control, they delivered strong gusts of wind to normal flies, as well as flies whose antennae had been removed. The flies without antenna still increased their speed in the same direction as the wind gust, but they only accelerated about half as much as the flies whose antennae were still intact. In addition, the flies without antennae were unable to maintain a constant speed, dramatically alternating between acceleration and deceleration. Together, these results suggested that the antennae were indeed providing wind information that was important for speed regulation.

In order to test the response of the eyes separately from that of the antennae, Fuller and his colleagues projected an animation on the walls of the fly-tracking arena that would trick the eyes into thinking there was no speed increase, even though the antenna could feel the increased windspeed. When the researchers delivered strong headwinds to flies in this environment, the flies decelerated and were unable to recover to their original speed.

"We know that vision is important for flying insects, and we know that flies have one of the fastest visual systems on the planet," Dickinson says, "But this response showed us that as fast as their vision is, if they're flying too fast or the wind is blowing them around too quickly, their visual system reaches its limit and the world starts getting blurry." That is when the antennae kick in, he says.

The results suggest that the antennae are responsible for quickly sensing changes in windspeed—and therefore are responsible for the fly's initial deceleration in a headwind. The information received from the fly's eyes—which is processed much more slowly than information from the wind sensors on the antenna—is responsible for helping the fly regain its cruising speed.

"Sawyer's study showed that the fly can take another sensor—this little tiny antenna, which doesn't require nearly the amount of processing area within the brain as the eyes—and the fly is able to use that information to compensate for the fact that the information coming out of the eyes is a bit delayed," Dickinson says. "It's kind of a neat trick, using a cheap little sensor to compensate for the limitations of a big, heavy, expensive sensor."

Beyond learning more about the fly's wind-sensing capabilities, Fuller says that this information will also help engineers design small flying robots—creating a sort of man-made fly. "Tiny flying robots will take a lot of inspiration from flies. Like flies, they will probably have to rely heavily on vision to regulate groundspeed," he says.

"A challenge here is that vision typically takes a lot of computation to get right, just like in flies, but it's impossible to carry a powerful processor to do that quickly on a tiny robot. So they'll instead carry tiny cameras and do the visual processing on a tiny processor, but it will just take longer. Our results suggest that little flying vehicles would also do well to have fast wind sensors to compensate for this delay."

The work was published in a study titled "Flying Drosophila stabilize their vision-based velocity controller by sensing wind with their antennae." Other coauthors include former Caltech senior postdoc Andrew D. Straw, Martin Y. Peek (BS '06), and Richard Murray, Thomas E. and Doris Everhart Professor of Control and Dynamical Systems and Bioengineering at Caltech, who coadvised Fuller's graduate work. The study was supported by the Institute for Collaborative Biotechnologies through funding from the U.S. Army Research Office and by a National Science Foundation Graduate Fellowship.

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Friday, April 11, 2014
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Spring Ombudsperson Training

Cell Biologist Alexander Varshavsky Wins Albany Medical Center Prize

Alexander Varshavsky, Howard and Gwen Laurie Smits Professor of Cell Biology at Caltech, has been named the recipient of the 2014 Albany Medical Center Prize in Medicine and Biomedical Research.

The award, of which Varshavsky is the sole recipient this year, recognizes him for his groundbreaking work in biology, specifically for the "discovery of critical molecular determinants and biological functions of intracellular protein degradation," a set of fundamentally important processes that is central to the physiology of both individual cells and multicellular organisms.

"Studies by my laboratory, initially at MIT and later at Caltech, focused on the understanding of how and why cells destroy their own proteins to withstand stress, to grow and divide, to differentiate into new kinds of cells, and to do countless other things that make living organisms so astonishing and fascinating," Varshavsky says.

He and colleagues in his lab have spent the past several decades studying the ubiquitin system, a set of biological pathways that have in common a small protein called ubiquitin. This highly complex system was found to mediate the regulated degradation of intracellular proteins, and other processes as well. It was gradually understood that functions of this system are relevant to just about everything that living cells do.

"The field of ubiquitin research has been expanding at an amazing pace, and is now one of the largest arenas in biomedical science," Varshavsky says. "Both earlier and recent discoveries illuminate the ubiquitin system and protein degradation from many different angles and continue to foster our ability to tackle human diseases, from cancer, infections, and cardiovascular illnesses to neurodegenerative syndromes and the aging process itself."

Varshavsky is the second Caltech faculty member to receive the $500,000 Albany Prize for research in life sciences. The late Caltech geneticist and molecular biologist Seymour Benzer was a recipient of the Albany Prize in 2006.

"I feel privileged having been able to contribute to the birth of my field, and to partake in its later development," Varshavsky says. "I am most grateful to distinguished members of the Albany Prize Committee for their decision to recognize our contributions with this major award."

Varshavsky received his BS from Russia's Moscow State University in 1970 and his PhD from Moscow's Institute of Molecular Biology in 1973. He has been Smits Professor at Caltech since 1992.

A member of the National Academy of Sciences, the American Academy of Arts and Sciences, the American Philosophical Society, and the Academia Europaea, Varshavsky has received many international prizes in biology and medicine, including the 2014 Breakthrough Prize in Life Sciences, the 2012 King Faisal Prize for Science (Saudi Arabia), the 2011 Otto Warburg Prize (Germany), the 2008 Gotham Prize in Cancer Research, the 2006 Gagna and Van Heck Prize (Belgium), the 2006 Griffuel Prize (France), the 2005 Stein and Moore Award, the 2001 Horwitz Prize, the 2001 Merck Award, the 2001 Wolf Prize in Medicine (Israel), the 2000 Lasker Award in Basic Medical Research, and the 1999 Gairdner Award (Canada).

One of the largest awards for medicine and science in the United States, the Albany Prize was founded by businessman and philanthropist Morris "Marty" Silverman in 2000 to recognize scientists and physicians whose work has resulted in "significant outcomes that offer medical value of national or international importance." Varshavsky will be honored at a ceremony in Albany on May 21.

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Wednesday, April 16, 2014
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Teaching & Learning in the American System: Student-Teacher Interactions

Say Hello to Your Little Friends: How Gut Bacteria Can Be Harnessed as Novel Therapies for Disease

Watson Lecture Preview

On Wednesday, April 2, Professor of Biology Sarkis Mazmanian will introduce you to the array of bacteria—your microbiome—residing on your skin, in your mouth, and even deep in your guts. Millions of years of coevolution have inextricably linked you and your microbiome, whose chemical "factories" help keep you healthy by doing such things as synthesizing vitamins and digesting your food. Recently, Mazmanian's laboratory has uncovered the surprising roles they play in fending off certain diseases.

The talk begins at 8:00 p.m. in Caltech's Beckman Auditorium. Admission is free.

 

Q: What do you do?

A: Our laboratory studies how beneficial microbes in the gastrointestinal tract interact with the immune and nervous systems. We each carry two to three pounds of bacteria—known as the human microbiome—in our bodies, and we have 10 times more microbial cells than we do human ones. We're outnumbered by an order of magnitude, but our cells are about 1,000 times bigger. Although most of these bacteria reside in our guts, in the colon, their metabolic products are found throughout the body. We think that these molecules can flip switches in biological circuits—even those in our brains. Pasteur knew about the bacteria in our intestines 150 years ago, but the evidence that some are beneficial is less than a decade old.

 

Q: As President Lyndon Johnson used to say, "How does this help Grandma?"

A: [laughs] As Sarkis says, "How does this change the world?" It's an entirely new perception. The game-changer is that we have found specific microbes that, at least in animal models, interact with the immune and nervous systems to ameliorate inflammatory bowel disease, multiple sclerosis, and even autism.

Western civilization has successfully controlled infectious, disease-causing microbes through antibiotics, vaccination, personal hygiene, and sanitation. These approaches are usually indiscriminate, and have also changed our association with microbes as a whole. And if some microbes are actively conferring health on us, say by secreting some substance that helps our immune system function properly, then removing them may result in disease.

We're all born sterile, and in the first three years of life we develop a complex consortium of microorganisms. Our first exposure is during the birthing process. Children born through natural childbirth are more resistant to allergies and autoimmune diseases than children who are born through C-sections, and the same is true with children who are breast-fed versus formula-fed. We don't yet know where the rest of our microbes come from, but my best guess is human contact. I mean, just think about human contact now, versus a thousand years ago. There's hand sanitizers, soap and water, indoor plumbing . . . We're not recolonizing ourselves, reexposing ourselves to our own microbes, let alone exposing our children to our adult microbes. Throughout human evolution there has been a cycle by which we have inoculated our kids, and I think we've disturbed—or even broken—that cycle.

We can now begin to think about supplementing or replacing those beneficial organisms, so I don't think it's far-fetched that, within a decade or so, doctors might examine your microbiome as well as looking at your lipid levels and your sugar levels and doing other routine diagnostics. And if they identify an organism that you are missing, you might be prescribed an FDA-approved pill that contains microbes—or microbial products—to restore the benefits you've lost.

Eating yogurt is not going to do it, nor will playing in the dirt, nor will the probiotics at health-food stores. None of those organisms coevolved with humans, so in essence they just pass through your system. This is a very important point: there's a distinction between the microbes in the environment and the microbes in your gut.

 

Q: How did you get into this line of work?

A: As a graduate student, I was studying Staphylococcus aureus, which causes staph infection. Staph infections are a huge problem in the community, and in hospitals, and we discovered some fruitful mechanisms to inhibit staph from causing disease. But as I was thinking about the next phase of my career, I read an article about all these bacteria that live in our gut that nobody was studying. And that interested me, so very, very quickly I decided that I was going to go into the unknown. I was just convinced, in this almost intuitive way, that all these bacteria must either be neutral, and were not doing anything—which is very unlikely, if you understand microbial metabolic processes—or that some subset of them must be doing something beneficial. Otherwise, why would they still be there? So I wanted to study the good guys, and I wanted to do what nobody else was doing. And this is the beauty of Caltech. We do the things here that nobody else is bold enough, or daring enough, to do.

 

 

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 iTunes U site.

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Watson Lecture Preview: Sarkis Mazmanian on the Microbiome
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Caltech Appoints Diana Jergovic to Newly Created Position of Vice President for Strategy Implementation

Caltech has named Diana Jergovic as its vice president for strategy implementation. In the newly created position, Jergovic will collaborate closely with the president and provost, and with the division chairs, faculty, and senior leadership on campus and at the Jet Propulsion Laboratory, to execute and integrate Caltech's strategic initiatives and projects and ensure that they complement and support the overall education and research missions of the campus and JPL. This appointment returns the number of vice presidents at the Institute to six.

"Supporting the faculty is Caltech's highest priority," says Edward Stolper, provost and interim president, "and as we pursue complex interdisciplinary and institutional initiatives, we do so with the expectation that they will evolve over a long time horizon. The VP for strategy implementation will help the Institute ensure long-term success for our most important new activities."

In her present role as associate provost for academic and budgetary initiatives at the University of Chicago, Jergovic serves as a liaison between the Office of the Provost and the other academic and administrative offices on campus, and advances campus-wide strategic initiatives. She engages in efforts spanning every university function, including development, major construction, and budgeting, as well as with faculty governance and stewardship matters. Jergovic also serves as chief of staff to University of Chicago provost Thomas F. Rosenbaum, Caltech's president-elect.

"In order to continue Caltech's leadership role and to define new areas of eminence, we will inevitably have to forge new partnerships and collaborations—some internal, some external, some both," Rosenbaum says. "The VP for strategy implementation is intended to provide support for the faculty and faculty leaders in realizing their goals for the most ambitious projects and collaborations, implementing ideas and helping create the structures that make them possible. I was looking for a person who had experience in delivering large-scale projects, understood deeply the culture of a top-tier research university, and could think creatively about a national treasure like JPL."

"My career has evolved in an environment where faculty governance is paramount," Jergovic says. "Over the years, I have cultivated a collaborative approach working alongside a very dedicated faculty leadership. My hope is to bring this experience to Caltech and to integrate it into the existing leadership team in a manner that simultaneously leverages my strengths and allows us together to ensure that the Institute continues to flourish, to retain its position as the world's leading research university, and to retain its recognition as such."

Prior to her position as associate provost, Jergovic was the University of Chicago's assistant vice president for research and education, responsible for the financial management and oversight of all administrative aspects of the Office of the Vice President for Research and Argonne National Laboratory. She engaged in research-related programmatic planning with a special emphasis on the interface between the university and Argonne National Laboratory. This ranged from the development of the university's Science and Technology Outreach and Mentoring Program (STOMP), a weekly outreach program administered by university faculty, staff, and students in low-income neighborhood schools on the South Side of Chicago, to extensive responsibilities with the university's successful bid to retain management of Argonne National Laboratory.

From 1994 to 2001, Jergovic was a research scientist with the university-affiliated National Opinion Research Center (NORC) and, in 2001, served as project director for NORC's Florida Ballot Project, an initiative that examined, classified, and created an archive of the markings on Florida's 175,000 uncertified ballots from its contested 2000 presidential election.

Jergovic earned a BS in psychology and an MA and PhD in developmental psychology, all from Loyola University Chicago, and an MBA from the Booth School of Business at the University of Chicago.

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An Equation to Describe the Competition Between Genes

Caltech researchers develop and verify predictive mathematical model

In biology, scientists typically conduct experiments first, and then develop mathematical or computer models afterward to show how the collected data fit with theory. In his work, Rob Phillips flips that practice on its head. The Caltech biophysicist tackles questions in cellular biology as a physicist would—by first formulating a model that can make predictions and then testing those predictions. Using this strategy, Phillips and his group have recently developed a mathematical model that accounts for the way genes compete with each other for the proteins that regulate their expression.

A paper describing the work appears in the current issue of the journal Cell. The lead authors on the paper are Robert Brewster and Franz Weinert, postdoctoral scholars in Phillips's lab.

"The thing that makes this study really interesting is that we did our calculations before we ever did any experiments," says Phillips, the Fred and Nancy Morris Professor of Biophysics and Biology at Caltech and principal investigator on the study. "Just as it is amazing that we have equations for the orbits of planets around stars, I think it's amazing that we are beginning to be able to write equations that predict the complex behaviors of a living cell."

A number of research teams are interested in modeling gene expression—accurately describing all the processes involved in going from a gene to the protein or other product encoded by that DNA. For simplicity's sake, though, most such models do not take competition into consideration. Instead, they assume that each gene has plenty of whatever it needs in order to be expressed—including the regulatory proteins called transcription factors. However, Phillips points out, there often is not enough transcription factor around to regulate all of the genes in a cell.  For one thing, multiple copies of a gene can exist within the same cell. For example, in the case of genes expressed on circular pieces of DNA known as plasmids, it is common to find hundreds of copies in a single cell. In addition, many transcription factors are capable of binding to a variety of different genes. So, as in a game of musical chairs, the genes must compete for a scarce resource—the transcription factors.

Phillips and his colleagues wanted to create a more realistic model by adding in this competition. To do so, they looked at how the level of gene expression varies depending on the amount of transcription factor present in the cell. To limit complexity, they worked with a relatively simple case—a gene in the bacterium E. coli that has just one binding site where a transcription factor can attach. In this case, when the transcription factor binds to the gene, it actually prevents the gene from making its product—it represses expression.

To build their mathematical model, the researchers first considered all the various ways in which the available transcription factor can interact with the copies of this particular gene that are present in the cell, and then developed a statistical theory to represent the situation.

"Imagine that you go into an auditorium, and you know there are a certain number of seats and a certain number of people. There are many different seating arrangements that could accommodate all of those people," Phillips says. "If you wanted to, you could systematically enumerate all of those arrangements and figure out things about the statistics—how often two people will be sitting next to each other if it's purely random, and so on. That's basically what we did with these genes and transcription factors."

Using the resulting model, the researchers were able to make predictions about what would happen if the level of transcription factor and the number of gene copies were independently varied so that the proteins were either in high demand or there were plenty to go around, for example.

With predictions in hand, the researchers next conducted experiments while looking at E. coli cells under a microscope. To begin, they introduced the genes on plasmids into the cells. They needed to track exactly how much transcription factor was present and the rate of gene expression in the presence of that level of transcription factor. Using fluorescent proteins, they were able to follow these changes in the cell over time: the transcription factor lit up red, while the protein expressed by the gene without the transcription factor attached glowed green. Using video fluorescence microscopy and a method, developed in the lab of Caltech biologist Michael Elowitz, for determining the brightness of a single molecule, the researchers were able to count the level of transcription factor present and the rate at which the green protein was produced as the cells grew and divided.

The team found that the experimental data matched the predictions they had made extremely well. "As expected, we find that there are two interesting regimes," says Brewster. "One is that there's just not enough protein to fill the demand. Therefore, all copies of the gene cannot be repressed simultaneously, and some portion will glow green all the time. In that case, there are correlations between the various copies of the genes. They know, in some sense, that the others exist. The second case is that there is a ton of this transcription factor around; in that case, the genes act almost exactly as if the other genes aren't there—there is enough protein to shut off all of the genes simultaneously."

The data fit so well with their model, in fact, that Phillips and his colleagues were able to use plots of the data to predict how many copies of the plasmid would be found in a cell as it grew and multiplied at various points throughout the cell cycle.

"Many times in science you start out trying to understand something, and then you get so good at understanding it that you are able to use it as a tool to measure something else," says Phillips. "Our model has become a tool for measuring the dynamics of how plasmids multiply. And the dynamics of how they multiply isn't what we would have naively expected. That's a little hint that we're pursuing right now."

Overall, he says, "this shows that the assertion that biology is too complicated to be predictive might be overly pessimistic, at least in the context of bacteria."

The work described in the paper, "The Transcription Factor Titration Effect Dictates Level of Gene Expression," was supported by the National Institutes of Health and by the Fondation Pierre-Gilles de Gennes. Additional coauthors are Mattias Rydenfelt, a graduate student in physics at Caltech; Hernan Garcia, a former member of Phillips's lab who is now at Princeton University; and Dan Song, a graduate student at Harvard Medical School.

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