PASADENA, Calif.—During the early developmental stages of vertebrates—animals that have a backbone and spinal column, including humans—cells undergo extensive rearrangements, and some cells migrate over large distances to populate particular areas and assume novel roles as differentiated cell types. Understanding how and when such cells switch their purpose in an embryo is an important and complex goal for developmental biologists. A recent study, led by researchers at the California Institute of Technology (Caltech), provides new clues about this process—at least in the case of neural crest cells, which give rise to most of the peripheral nervous system, to pigment cells, and to large portions of the facial skeleton.

"There has been a long-standing mystery regarding why some cells in the developing embryo start out as part of the future central nervous system, but leave to populate peripheral parts of the body," says Marianne Bronner, the Albert Billings Ruddock Professor of Biology at Caltech and corresponding author of the paper, published in the November 1 issue of the journal Genes & Development. "In this paper, we find that an important type of enzyme called DNA-methyltransferase, or DNMT, acts as a switch, determining which cells will remain part of the central nervous system, and which will become neural crest cells."

According to Bronner, DNMT arranges this transition by silencing expression of the genes that promote central nervous system (CNS) identity, thereby giving the cells the green light to become neural crest, migrate, and do new things, like help build a jaw bone. The team came to this conclusion after analyzing the actions of one type of DNMT—DNMT3A—at different stages of development in a chicken embryo.

This is important, says Bronner, because while most scientists who study the function of DNMTs use embryonic stem cells that can be maintained in culture, her team is "studying events that occur in living embryos as opposed to cells grown under artificial conditions," she explains.

"It is somewhat counterintuitive that this kind of shutting off of genes is essential for promoting neural crest cell fate," she says. "Embryonic development often involves switches in the types of inputs that a cell receives. This is an example of a case where a negative factor must be turned off—essentially a double negative—in order to achieve a positive outcome."

Bronner says it was also surprising to see that an enzyme like DNMT has such a specific function at a specific time. DNMTs are sometimes thought to act in every cell, she says, yet the researchers have discovered a function for this enzyme that is exquisitely controlled in space and time.

"It is amazing how an enzyme, at a given time point during development, can play such a specific role of making a key developmental decision within the embryo," says Na Hu, a graduate student in Bronner's lab and lead author of the paper. "Our findings can be applied to stem cell therapy, by giving clues about how to engineer other cell types or stem cells to become neural crest cells."

Bronner points out that their work relates to the discovery, which won a recent Nobel Prize in Medicine or Physiology, that it is possible to "reprogram" cells taken from adult tissue. These induced pluripotent stem (iPS) cells are similar to embryonic stem cells, and many investigators are attempting to define the conditions needed for them to differentiate into particular cell types, including neural crest derivatives.

"Our results showing that DNMT is important for converting CNS cells to neural crest cells will be useful in defining the steps needed to reprogram such iPS cells," she says. "The iPS cells may in turn be useful for repair in human diseases such as familial dysautonomia, a disease in which there is depletion of autonomic and sensory neurons that are neural crest–derived; for repair of jaw bones lost in osteonecrosis; and for many other potential treatments."

In the short term, the team will explore the notion that DNMT enzymes may have different functions in the embryo at different places and times. That's why the next step in their research, says Bronner, is to examine the later role of these enzymes in nervous-system development, like whether or not they effect the length of time during which the CNS is able to produce neural crest cells.

Additional authors on the paper, titled "DNA methyltransferase3A as a molecular switch mediating the neural tube-to-neural crest fate transition," are Pablo Strobl-Mazzulla from the Laboratorio de Biología del Desarrollo in Chascomús, Argentina, and Tatjana Sauka-Spengler from the Weatherall Institute of Molecular Medicine at the University of Oxford. The work was supported by the National Institutes of Health and the United States Public Health Service.

In May 2011, a new therapy created in part by Caltech engineers enabled a paraplegic man to stand and move his legs voluntarily. Now those same researchers are working on a way to automate their system, which provides epidural electrical stimulation to the lower spinal cord. Their goal is for the system to soon be made available to rehab clinics—and thousands of patients—worldwide.

That first patient—former athlete Rob Summers, who had been completely paralyzed below the chest following a 2006 accident—performed remarkably well with the electromechanical system. Although it wasn't initially part of the testing protocol established by the Food and Drug Administration, the FDA allowed Summers to take the entire system with him when he left the Frazier Rehab Institute in Louisville—where his postsurgical physical therapy was done—provided he returns every three months for a checkup.

Joel Burdick, the Richard L. and Dorothy M. Hayman Professor of Mechanical Engineering and Bioengineering at Caltech, and Yu-Chong Tai, a Caltech professor of electrical engineering and mechanical engineering, helped create the therapy, which involves the use of a sheetlike array of electrodes that stimulate Summers' neurons and thus activate the circuits in his lower spinal cord that control standing and stepping. The approach has subsequently been successfully tested on a second paraplegic, and therapists are about to finish testing a third subject, who has shown positive results.

But Tai and Burdick want to keep the technology, as well as the subjects, moving forward. To that end, Tai is developing new versions of the electrode array currently approved for human implantation; these will improve patients' stepping motions, among other advances, and they will be easier to implant. Burdick is also working on a way to let a computer control the pattern of electrical stimulation applied to the spinal cord.

"We need to go further," Burdick says. "And for that, we need new technology."

Because spinal-cord injuries vary from patient to patient, deploying the system has required constant individualized adjustments by clinicians and researchers at the Frazier Institute, a leading center for spinal-cord rehabilitation. "Right now there are 16 electrodes in the array, and for each individual electrode, we send a pulse, which can be varied for amplitude and frequency to cause a response in the patient," Burdick says. Using the current method, he notes, "it takes substantial effort to test all the variables to find the optimum setting for a patient for each of the different functions we want to activate."

The team of investigators, which also includes researchers from UCLA and the University of Louisville, has until now used intelligent guesswork to determine which stimuli might work best. But soon, using a new algorithm developed by Burdick, they will be able to rely on a computer to determine the optimum stimulation levels, based on the patient's response to previous stimuli. This would allow patients to go home after the extensive rehab process with a system that could be continually adjusted by computer—saving Summers and the other patients many of those inconvenient trips back to Louisville. Doctors and technicians could monitor patients' progress remotely.

In addition to providing the subjects with continued benefits from the use of the device, there are other practical reasons for wanting to automate the system. An automated system would be easier to share with other hospitals and clinics around the world, Burdick says, and without a need for intensive training, it could lower the cost.

The FDA has approved testing the system in five spinal-cord injury patients, including the three already enrolled in the trial; Burdick is planning to test the new computerized version in the fourth patient, as well as in Rob Summers during 2013. Once the investigators have completed testing on all five patients, Burdick says, the team will spend time analyzing the data before deciding how to improve the system and expand its use.

The strategy is not a cure for paraplegics, but a tool that can be used to help improve the quality of their health, Burdick says. The technology could also complement stem-cell therapies or other methods that biologists are working on to repair or circumvent the damage to nervous systems that results from spinal-cord injury.

"There's not going to be one silver bullet for treating spinal-cord injuries," Burdick says. "We think that our technique will play a role in the rehabilitation of spinal-cord injury patients, but a more permanent cure will likely come from biological solutions."

Even with the limitations of the current system, Burdick says, the results have exceeded his expectations.

"All three subjects stood up within 48 hours of turning on the array," Burdick says. "This shows that the first patient wasn't a fluke, and that many aspects of the process are repeatable." In some ways, the second and third patients are performing even better than Summers, though it will be some time before the team can fully analyze those results. "We were expecting variations because of the distinct differences in the patients' injuries. Rob gave us a starting point, and now we've learned how to tune the array for each patient and to make adjustments as each patient changes over time.

"I do this work because I love it," Burdick says. "When you work with these people and get to know them and see how they are improving, it's personally inspiring."

Lurking in the crevices of our planet are millions and millions of microscopic worms. They live in soil, plants, water, ice, wildlife, and sometimes even humans. In fact, nematodes—also known as roundworms—are among the most abundant and diverse animals on Earth, where they play a variety of roles.

For the past 25 years, Paul Sternberg, the Thomas Hunt Morgan Professor of Biology at Caltech and a Howard Hughes Medical Institute investigator, has been studying the development and behavior of these creepy-crawly creatures and has recently uncovered important clues about how the worms communicate.

Read about his findings in the Fall 2012 issue of E&S magazine.

PASADENA, Calif.—The California Institute of Technology (Caltech) has been rated the world's number one university in the 2012–2013 Times Higher Education global ranking of the top 200 universities.

Oxford University, Stanford University, Harvard University, and MIT round out the top five.

"We are pleased to be among the best, and we celebrate the achievements of all our peer institutions," says Caltech president Jean-Lou Chameau. "Excellence is achieved over many years and is the result of our focus on extraordinary people. I am proud of our talented faculty, who educate outstanding young people while exploring transformative ideas in an environment that encourages collaboration rather than competition."

Times Higher Education compiled the listing using the same methodology as in last year's survey. Thirteen performance indicators representing research (worth 30 percent of a school's overall ranking score), teaching (30 percent), citations (30 percent), international outlook (which includes the total numbers of international students and faculty and the ratio of scholarly papers with international collaborators, 7.5 percent), and industry income (a measure of innovation, 2.5 percent) make up the data. Included among the measures are a reputation survey of 17,500 academics; institutional, industry, and faculty research income; and an analysis of 50 million scholarly papers to determine the average number of citations per scholarly paper, a measure of research impact.

In addition to placing first overall in this year's survey, Caltech came out on top in the teaching indicator as well as in subject-specific rankings for engineering and technology and for the physical sciences.

"Caltech held on to the world's number one spot with a strong performance across all of our key performance indicators," says Phil Baty, editor of the Times Higher Education World University Rankings. "In a very competitive year, when Caltech's key rivals for the top position reported increased research income, Caltech actually managed to widen the gap with the two universities in second place this year—Stanford University and the University of Oxford. This is an extraordinary performance."

Data for the Times Higher Education's World University Rankings were provided by Thomson Reuters from its Global Institutional Profiles Project, an ongoing, multistage process to collect and validate factual data about academic institutional performance across a variety of aspects and multiple disciplines.

The Times Higher Education site has the full list of the world's top 400 schools and all of the performance indicators.

PASADENA, Calif.—Sarkis Mazmanian, a microbiology expert at the California Institute of Technology (Caltech) whose studies of human gut bacteria have revealed new insights into how these microbes can be beneficial, was named a MacArthur Fellow and awarded a five-year, $500,000 "no strings attached" grant. Each year, the John D. and Catherine T. MacArthur Foundation awards the unrestricted fellowships—also known as "genius" grants—to individuals who have shown "extraordinary originality and dedication in their creative pursuits and a marked capacity for self-direction," according to the foundation's website.

"I was in a state of shock when I heard the news," says Mazmanian, a professor of biology at Caltech, who was tricked into taking the award announcement call; he thought he was simply being added to a prescheduled conference call. "It's not the kind of thing you ever expect—I do what I do because I love science and it makes me happy, so this is terrific and a nice reward. At the same time, I never think of awards as goals of mine because they seem so unattainable. My goals are to make discoveries, so I was just in absolute disbelief."

Long before he was named a 2012 MacArthur Fellow, Mazmanian was showing the attributes that the foundation seeks to reward, particularly a capacity for self-direction. As a graduate student in the in the early 2000s, he decided to stray from the normal path of study and try something new. 

"I had been studying microbial pathogenesis—or bacteria that make us sick—which is what 99.9 percent of the field of microbiology does to this day," says Mazmanian. "Toward the end of my PhD, I decided that I wanted to study organisms that didn't necessarily cause disease, but were associated with our bodies. Ten years ago, this was completely on the fringe of science—we knew that the organisms existed in our intestines and all over our bodies, but had no idea what they were doing."  

Today, Mazmanian's work examines some of the trillions of bacteria living in our bodies that make up complex communities of microbes and regulate processes like digestion and immunity. His main focus is to understand how "good" bacteria promote human health—work that has transformed a quickly evolving field of research that is investigating the connection between gut bacteria and their relationship to both disease and health.

Medical Microbiologist Sarkis Mazmanian: 2012 MacArthur Fellow | MacArthur Foundation

His research helped lay the groundwork for the Human Microbiome Project (HMP), an initiative of the National Institutes of Health that aims to characterize, for the first time, "the microbial communities found at several different sites on the human body, including nasal passages, oral cavities, skin, gastrointestinal tract, and urogenital tract, and to analyze the role of these microbes in human health and disease," according to the HMP website.

His laboratory was the first to demonstrate that specific gut bacteria direct the development of the mammalian immune system and provide protection from intestinal diseases. This means, he says, that fundamental aspects of health are absolutely dependent on microbial interaction within our bodies. In addition, he says that many disorders whose incidences are increasing in Western countries—such as inflammatory bowel disease, multiple sclerosis, and asthma—involve a common immunologic defect believed to be caused by the absence of intestinal bacteria. An understanding of the beneficial immune responses promoted by gut bacteria may lead to the development of natural therapeutics for immunologic and perhaps neurologic diseases, says Mazmanian.

"This award is extremely well-deserved—Sarkis has revolutionized the way we think about the interactions between microorganisms and people," says Stephen L. Mayo, William K. Bowes Jr. Foundation Chair of Caltech's Division of Biology, and Bren Professor of Biology and Chemistry. "His research has had an important impact in making the connection between personal hygiene and the immune system, and even neurological diseases like autism."

When the award announcement went public, Mazmanian was in Armenia, his native homeland, teaching a one-week course on host-microbial interaction to PhD students at a molecular biology institute. He travels to the country once a year to volunteer his services. The timing, he says, couldn't be better, as he hopes to use some of the prize money to develop an international educational outreach program.

"I think that when you have a windfall like this, the least you can do is help people who are in need," says Mazmanian, who credits the members of his lab for his research success. "In many countries, they are in need of education and resources, like lab equipment, text books, you name it. It would be a terrific if I could use the money to help advance science in countries where there is hardship."

Mazmanian received his bachelor's degree in 1995 and his PhD in microbiology in 2002, both from UCLA. Following a postdoctoral fellowship at Harvard, he joined the Caltech faculty as an assistant professor in 2006. In 2012, he was promoted to professor of biology. In 2011, Mazmanian was the recipient of a Burroughs Welcome Fund award for research in the pathogenesis of infectious disease, and in 2008 he was awarded a Searle Scholarship and was named one of Discover magazine's "20 Best Brains Under 40," which highlighted young innovators in science.

This year's crop of 23 Fellows includes stringed-instrument bow maker Benoît Rolland and mathematician Maria Chudnovsky; Mazmanian joins the ranks of Caltech's previous MacArthur Fellows, including 2010 awardee John Dabiri.

For more information on the 2012 MacArthur Fellows, visit the foundation website at www.macfound.org.

PASADENA, Calif.—As the saying goes, "A picture is worth a thousand words." For people in certain professions—acting, modeling, and even politics—this phrase rings particularly true. Previous studies have examined how our social judgments of pictures of people are influenced by factors such as whether the person is smiling or frowning, but until now one factor has never been investigated: the distance between the photographer and the subject. According to a new study by researchers at the California Institute of Technology (Caltech), this turns out to make a difference—close-up photo subjects, the study found, are judged to look less trustworthy, less competent, and less attractive.

The new finding is described in this week's issue of the open-access journal PLoS One.

Pietro Perona, the Allen E. Puckett Professor of Electrical Engineering at Caltech, came up with the initial idea for the study. Perona, an art history enthusiast, suspected that Renaissance portrait paintings often featured subtle geometric warping of faces to make the viewer feel closer or more distant to a subject. Perona wondered if the same sort of warping might affect photographic portraits—with a similar effect on their viewers—so he collaborated with Ralph Adolphs, Bren Professor of Psychology and Neuroscience and professor of biology, and CNS graduate student Ronnie Bryan (PhD '12) to gather opinions on 36 photographs representing two different images of 18 individuals. One of each pair of images was taken at close range and the second at a distance of about seven feet.

"It turns out that faces photographed quite close-up are geometrically warped, compared to photos taken at a larger distance," explains Bryan. "Of course, the close picture would also normally be larger, higher resolution and have different lighting—but we controlled for all of that in our study. What you're left with is a warping effect that is so subtle that nobody in our study actually noticed it. Nonetheless, it's a perceptual clue that influenced their judgments."

That subtle distance warping, however, had a big effect: close-up photos made people look less trustworthy, according to study participants. The close-up photo subjects were also judged to look less attractive and competent.

"This was a surprising, and surprisingly reliable, effect," says Adolphs. "We went through a bunch of experiments, some testing people in the lab, and some even over the Internet; we asked participants to rate trustworthiness of faces, and in some experiments we asked them to invest real money in unfamiliar people whose faces they saw as a direct measure of how much they trusted them."

Across all of the studies, the researchers saw the same effect, Adolphs says: in photos taken from a distance of around two feet, a person looked untrustworthy, compared to photos taken seven feet away. These two distances were chosen by the researchers because one is within, and the other outside of, personal space—which on average is about three to four feet from the body.

In some of the studies, the researchers digitally warped images of faces taken at a distance to artificially manipulate how trustworthy they would appear. "Once you know the relation between the distance warp and the trustworthiness judgment, you could manipulate photos of faces and change the perceived trustworthiness,'' notes Perona.

He says that the group is now planning to build on these findings, using machine-vision techniques—technologies that can automatically analyze data in images. For example, one application would be for a computer program to have the ability to evaluate any face image in a magazine or on the Internet and to estimate the distance at which the photo was taken.

"The work might also allow us to estimate the perceived trustworthiness of a particular face image," says Perona. "You could imagine that many people would be interested in such applications—particularly in the political arena."

The study, "Perspective Distortion from Interpersonal Distance Is an Implicit Visual Cue for Social Judgments of Faces," was funded by grants from the National Institute of Mental Health and from the Gordon and Betty Moore Foundation.

PASADENA, Calif.—At any given moment, millions of cells are on the move in the human body, typically on their way to aid in immune response, make repairs, or provide some other benefit to the structures around them. When the migration process goes wrong, however, the results can include tumor formation and metastatic cancer. Little has been known about how cell migration actually works, but now, with the help of some tiny worms, researchers at the California Institute of Technology (Caltech) have gained new insight into this highly complex task.

The team's findings are outlined this week online in the early edition of the Proceedings of the National Academy of Sciences (PNAS).

"In terms of cancer, we know how to find primary tumors and we know when they're metastatic, but we're missing information on the period in between when cells are crawling around, hanging out, and doing who knows what that leads to both of these types of diseases," says Paul Sternberg, Thomas Hunt Morgan Professor of Biology at Caltech, and corresponding author of the paper.

To learn more about those crawling, or migrating, cells, Sternberg looked at the animal he knows best—the tiny Caenorhabditis elegans, a common species of roundworm that he has been studying for many years. Despite their small size, the worms actually share quite a few genes with humans. 

"Migration is such a conserved process," says Mihoko Kato, a senior research fellow in biology at Caltech and a coauthor of the paper. "So whether it happens in C. elegans or in mammals, like humans, we think that many of the same genes are going to be involved."

Contained in each cell—be it human or worm—are thousands of genes, all of which have a special job, or jobs, to do. Of these genes, roughly one-third are active in a given cell. To see what genes are expressed during migration, Sternberg and Kato, along with Erich Schwarz, a research fellow in Sternberg's lab, studied a single cell, called the linker cell (LC), in the worms; during reproductive development, LCs travel almost the entire length of the worm's body.

Using high-powered microscopy, the team identified LCs at two intervals, 12 hours apart, during the worm's larval stage, and removed them from the animals. Then, using sequencing and computational analysis, they determined the genes that were actively expressed at these two migration time points. This method of study is called transcriptional profiling.

"By understanding the normal migration of a single cell, we can understand something about how the cells are programmed to navigate their environment," says Sternberg, who is also an investigator with the Howard Hughes Medical Institute. "Our view of cancer metastasis is that the tumor cells confront some obstacle and then they have to evolve to get through or around that obstacle. The way they probably do that is by using some aspect of the normal program that exists somewhere in the genome."

He says that learning more about different ways that cells migrate may lead to the development of new types of drugs that block this process by targeting specific genes. The team plans additional transcriptional profiling studies to obtain more detailed information about the functions of particular C. elegans genes involved in migration—and, eventually, of similar genes in higher organisms, including humans.

"We selected genes present in both worms and humans, but which have not been studied much before us," says Schwarz.  "Since we found that some of these genes help worm LCs migrate, we think each one may have a related human gene helping cells migrate, too."

"The nice thing about this technology is that you can use it with any cell type," adds Kato, who points out that their studies have already helped identify new functions for known genes possessed by both the worms and humans. "It's a similar process to do transcriptome profiling using human cells."

In addition to identifying drug targets, the team is also hoping to find a good signature, or molecular marker, for migrating cells. "This kind of information could be very useful diagnostically, to help identify cells that are doing things that they shouldn't be doing, or weird combinations of genes that shouldn't be expressed together, which is what a tumor cell might have," says Sternberg. "This work lays the foundation for really understanding what information is critically needed from mammalian cells for tumor cells to be able to migrate."

The study, "Functional transcriptomics of a migrating cell in Caenorhabditis elegans," was funded by the National Institutes of Health and the Howard Hughes Medical Institute.