Brain Control with Light

Watson Lecture Preview

Viviana Gradinaru (BS '05) might one day be getting inside your head—but in a good way. An assistant professor of biology at Caltech, Gradinaru is trying to map out the brain's wiring diagrams. Gradinaru will discuss her work at 8:00 p.m. on Wednesday, December 5, in Caltech's Beckman Auditorium. Admission is free.

 

Q: What do you do?

A: I'm a neuroscientist. I'm trying to understand the brain by turning nerve cells in specific circuits on or off and seeing what the effects are. This is very difficult with conventional methods, one of which is to put in an electrode and pass a current that stimulates all the cells in the vicinity in a nondiscriminate fashion.

What we do instead is introduce modulators into well-defined sets of cells. These modulators are light-sensitive proteins called opsins, similar to the rhodopsin that's part of the visual system in your eye. Opsins form channels in the cell wall, and when they absorb light, they change shape and allow ions to flow into or out of the cell. So by using different opsins, we can either inhibit or excite neurons in a reversible fashion. Neurons are not naturally responsive to light, so when we light up the brain through a fiber-optic thread, we know exactly what cells we are affecting. We use genetic engineering to introduce our optical switches into different cell types. It's almost like giving ZIP codes to the opsins to tell them exactly where to go.

 

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

A: When I was an undergraduate here at Caltech, I did a very extensive research project in the lab of professor Paul Patterson. That was where I fell in love with neuroscience. It started as a SURF [Summer Undergraduate Research Fellowship] project, and I ended up staying in his lab until I graduated.

It so happens that I was working on a motor-disorder project—on Huntington's disorder—trying to understand what causes the disease. I was working on protein aggregation in cultured cells, because protein aggregation was a known phenomenon in degenerated nerve-cells in Huntington's disorder. However, I could see how remote it was from the real thing. Working in a dish. And I felt, "we should be doing this in the real thing." But the tools were not available.

When I moved to Stanford for my PhD work, there was this new lab just starting. Professor Deisseroth started the same year I did, and his lab developed this technology and also coined the name optogenetics for it. I wanted to look at the circuits involved in motor behavior, so I joined his lab to work on Parkinson's disorder. However, the technology was rather early, and I ended up spending a lot of time perfecting it before I could probe the circuits. But it was well worth it: I learned the value of making your own tools.

 

Q: What does this tell us that we can apply to people?

A: We can find out more about the circuitry underlying a defined disease, and by understanding the circuitry, we have a better chance to tackle the disease itself. Parkinson's is an interesting example. A very good therapy for Parkinson's after drug therapy stops working is to implant electrodes in the motor centers of the brain. Zapping those brain cells at 100 Hertz—a very high frequency—takes care of the tremor and lets people walk again, which is rather miraculous. It works very well, but we don't understand why it works, because electrical stimulation is nonspecific. We don't know what circuits are being affected. Optogenetics can help here, as a tool to generate information about both the healthy brain and the diseased brain.

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Watson Lecture: "Brain Control with Light"
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An Eye for Science: In the Lab of Markus Meister

Take one look around Markus Meister's new lab and office space on the top floor of the Beckman Behavioral Biology building, and you can tell that he has an eye for detail. Curving, luminescent walls change color every few seconds, wrapping around lab space and giving a warm glow to the open, airy offices that line the east wall. A giant picture of neurons serves as wallpaper, and a column is wrapped in an image from the inside of a retina. And while he may have picked up some tips from his architect wife to help direct the design of his lab, Meister is the true visionary—a biologist studying the details of the eye.

"Since we study the visual system, light is a natural interest for me," says Meister, of the lab he helped plan before joining the Caltech faculty in July. "The architecture team responded to this in so many creative ways. They even installed windows inside the lab space, so that researchers at the bench could see straight through the offices to the nature outside."

Exactly how our eyes process those images of the world around us forms the basis of Meister's research. In particular, he investigates the circuits of nerve cells in the retina—a light-sensitive tissue that lines the inner surface of your eyeball and essentially captures images as they come in through the cornea and lens at the front of your eye. A traditional view of the retina is that it acts like the film in a camera, simply absorbing light and then sending a signal directly to the brain about the image you are viewing.

But Meister, who earned his PhD at Caltech in 1987 and was the Tarr Professor of Molecular and Cellular Biology at Harvard before moving back west, sees things a bit differently.

"There is a lot of preprocessing that occurs in the retina, so the signal that gets sent to the brain ultimately is quite different from the raw image that is projected onto the retina by the lens in your eye," he says. "And it's not just one kind of processing. There are on the order of 20 different ways in which the retina manipulates a raw image and then sends those results onto the brain through the optic nerve. An ongoing puzzle is trying to figure out how that is possible with the limited circuitry that exists in the retina."

Meister and his lab are dedicated to finding new clues to help decode that puzzle. In a recent study, published in Nature Neuroscience, he and Hiroki Asari, a postdoctoral scholar in biology at Caltech, studied the connections between particular cells within the retina. Their specific discovery, he explains, has to do with the associations between bipolar cells, which are the neurons in the middle of the retina, and ganglion cells, which are the very last neurons in the retina that send signals to the brain. What they found is that the connections between these bipolar cells and ganglion cells are much more diverse than had been expected.

"Each upstream bipolar cell can make different neural circuits to do particular kinds of computations before it sends signals to ganglion cells," says Asari, who began his postdoctoral work at Harvard and moved to Caltech with the Meister lab.

The team was also able to show that in many cases, the processing of information in the retina involves amacrine cells, a type of cell in the eye that seems to be involved in fine-tuning the properties of individual bipolar cell actions.

"It's a little bit like electronics, where you have a transistor—one wire controlling the connection between two other wires—that is absolutely central to everything," says Meister. "In a way, this connection between the amacrine cells and the bipolar cell and the ganglion cell looks a little bit like a transistor, in that the amacrine cell can control how the signal flows from the bipolar to the ganglion cell. That's an analogy that I think will help us understand the intricacy of the signal flow in the retina. A goal that we have is to ultimately understand these neural circuits in the same way that we understand electronic circuits."

The next step in this particular line of research is to figure out exactly where the amacrine cells are making their impact on bipolar cells. They believe most of the action happens at the synapses, the connection points between the cells. Studying this area requires new technology to get a good look at the tiny connectors. Luckily, Meister's new lab includes an in-house shop room—complete with a milling machine, a band saw, and other power tools needed to build things like microscopes.

"In this lab, we're doing things on many levels—from the giant milling machine all the way down to measurements on the micron scale," says Meister.

He also plans to expand his research focus. The team has started to study the visual behavior of mice, evaluating, for example, the kinds of innate reactions—those that don't require any other knowledge about the environment—they have to certain visual stimuli. Ultimately, the researchers would like to know which of the pathways that come out of the retina control which behaviors, and if they can find a link between the processing of vision that occurs early in the eye and how the animal functions in its environment using its visual system.

"In my new lab at Caltech, I'm trying to branch out further into the visual system to leverage the understanding we have about the front end—namely processing in the retina—to better understand the different actions that occur in the brain, all the way to certain behaviors of the animal that are based on visual stimuli," he says.

Meister says that he's also excited to get back into an environment that's more focused on math, physics, and engineering—something he hopes to take advantage of at both the faculty/colleague level and the student level.

"Our research subject is one that I feel connects me with so many different areas of science—from molecular genetics to theoretical physics," he explains. "You can rely on a wide range of collaborators and people who are interested in different aspects of the subject. To me, that's been the most satisfying part of my career. I have collaborative projects with neurosurgeons, a theoretical physicist who develops models of visual processing, a particle physicist who builds miniature detector electronics, a molecular genetics expert. These interactions really keep you broadly connected."

And he's hoping to connect to even more people now that he's settled in his Beckman Behavioral Biology lab—even if it's just for a friendly visit.

"I know we're in a remote corner of the building at the north end of the top floor, but we try to keep our door open at all times," says Meister. "There are only five people in the lab right now, and it gets kind of lonely. We're going to build the group up, but in the meantime it would be nice if people came to visit us."

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A Fresh Look at Psychiatric Drugs

Caltech researchers propose a new approach to understanding common treatments

Drugs for psychiatric disorders such as depression and schizophrenia often require weeks to take full effect. "What takes so long?" has formed one of psychiatry's most stubborn mysteries. Now a fresh look at previous research on quite a different drug—nicotine—is providing answers. The new ideas may point the way toward new generations of psychiatric drugs that work faster and better.

For several years, Henry Lester, Bren Professor of Biology at Caltech, and his colleagues have worked to understand nicotine addiction by repeatedly exposing nerve cells to the drug and studying the effects. At first glance, it's a simple story: nicotine binds to, and activates, specific nicotine receptors on the surface of nerve cells within a few seconds of being inhaled. But nicotine addiction develops over weeks or months; and so the Caltech team wanted to know what changes in the nerve cell during that time, hidden from view.

The story that developed is that nicotine infiltrates deep into the cell, entering a protein-making structure called the endoplasmic reticulum and increasing its output of the same nicotine receptors. These receptors then travel to the cell's surface. In other words, nicotine acts "inside out," directing actions that ultimately fuel and support the body's addiction to nicotine.

"That nicotine works 'inside out' was a surprise a few years ago," says Lester. "We originally thought that nicotine acted only from the outside in, and that a cascade of effects trickled down to the endoplasmic reticulum and the cell's nucleus, slowly changing their function."

In a new research review paper, published in Biological Psychiatry, Lester—along with senior research fellow Julie M. Miwa and postdoctoral scholar Rahul Srinivasan—proposes that psychiatric medications may work in the same "inside-out" fashion—and that this process explains how it takes weeks rather than hours or days for patients to feel the full effect of such drugs.

"We've known what happens within minutes and hours after a person takes Prozac, for example," explains Lester. "The drug binds to serotonin uptake proteins on the cell surface, and prevents the neurotransmitter serotonin from being reabsorbed by the cell. That's why we call Prozac a selective serotonin reuptake inhibitor, or SSRI." While the new hypothesis preserves that idea, it also presents several arguments for the idea that the drugs also enter into the bodies of the nerve cells themselves.

There, the drugs would enter the endoplasmic reticulum similarly to nicotine and then bind to the serotonin uptake proteins as they are being synthesized. The result, Lester hypothesizes, is a collection of events within neurons that his team calls "pharmacological chaperoning, matchmaking, escorting, and abduction." These actions—such as providing more stability for various proteins—could improve the function of those cells, leading to therapeutic effects in the patient. But those beneficial effects would occur only after the nerve cells have had time to make their intracellular changes and to transport those changes to the ends of axons and dendrites.

"These 'inside-out' hypotheses explain two previously mysterious actions," says Lester. "On the one hand, the ideas explain the long time required for the beneficial actions of SSRIs and antischizophrenic drugs. But on the other hand, newer, and very experimental, antidepressants act within hours. Binding within the endoplasmic reticulum of dendrites, rather than near the nucleus, might underlie those actions."

Lester and his colleagues first became interested in nicotine's effects on neural disorders because of a striking statistic: a long-term tobacco user has a roughly twofold lower chance of developing Parkinson's disease. Because there is no medical justification for using tobacco, Lester's group wanted more information about this inadvertent beneficial action of nicotine. They knew that stresses on the endoplasmic reticulum, if continued for years, could harm a cell. Earlier this year, they reported that nicotine's "inside-out" action appears to reduce endoplasmic reticulum stress, which could prevent or forestall the onset of Parkinson's disease.

Lester hopes to test the details of "inside-out" hypotheses for psychiatric medication. First steps would include investigating the extent to which psychiatric drugs enter cells and bind to their nascent receptors in the endoplasmic reticulum. The major challenge is to discover which other proteins and genes, in addition to the targets, participate in "matchmaking, escorting, and abduction."

"Present-day psychiatric drugs have a lot of room for improvement," says Lester. "Systematic research to produce better psychiatric drugs has been hampered by our ignorance of how they work. If the hypotheses are proven and the intermediate steps clarified, it may become possible to generate better medications."

 

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Tuesday, April 9, 2013
Avery Library

Spring Teaching Assistant Orientation

Developmental Bait and Switch

Caltech-led team discovers enzyme responsible for neural crest cell development

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.

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Progress for Paraplegics

Caltech investigators expand project to restore functions to people with spinal-cord injuries

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."

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Two Faculty Members Named Packard Fellows

Two Caltech faculty members have been awarded Packard Fellowships for Science and Engineering. Biologist Alexei Aravin and astronomer John Johnson each were awarded $875,000, to be distributed over five years.

"I'm very excited about this fellowship," says Aravin, an assistant professor of biology. "It will allow my lab to pursue new, ambitious goals that are difficult to fund using traditional sources."

Aravin studies RNA molecules, which encode the information contained in genes to help create proteins. His lab is probing the mechanisms that determine the stability and fate of RNA. He's also trying to figure out how noncoding RNA—which doesn't encode information but nevertheless plays crucial roles in the cell—functions and is produced.

Johnson's research focuses on discovering and characterizing planets around other stars. "My broad goals," he says, "are to gain a better understanding of planet formation, place our solar system in a broader galactic context, and eventually find places in the galaxy where other life forms might reside." He plans to use the money to help support postdocs in his research group and to start a visitor program in which scientists from other institutions are invited to brainstorm and collaborate.

Johnson, an assistant professor of astronomy, was meeting with a student when he got the phone call notifying him of the award. "I don't remember my exact reaction, but it certainly startled the poor student," he says. "I spent the rest of the day grinning like an idiot."

According to the Packard Foundation, the fellowships were established in 1988 to allow promising professors to pursue research early in their careers with few funding and reporting constraints. Each year, presidents from 50 universities each nominate two early-career professors for the fellowship. A panel of scientists and engineers then select 16 fellows. To date, there have been more than 400 professors who have received Packard Fellowships. Aravin and Johnson join 26 members of current and past Caltech faculty who have been named Packard Fellows.

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Wordy Worms

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.

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Traveling with Purpose

Biologist spends summer vacation volunteering in India

Pamela Bjorkman has been studying HIV at Caltech since 2005. In the lab, she has made significant gains in the fight against the virus, developing antibodies that neutralize most strains. But years spent at the bench were beginning to make her feel disconnected from the possible impact of her work. So this summer she visited India, spending time with HIV-positive women and others who are at risk.

"What I wanted to do was see the real side of HIV, where it affects people," says Bjorkman, the Max Delbrück Professor of Biology and an investigator with the Howard Hughes Medical Institute. "We work in the lab where we have no contact with HIV-infected people—the human impact of the disease is very removed from what we think about in our work."

This was not her first trip to the nation of over 1.2 billion people, where nearly 30 percent of the population lives in poverty. She first visited in 1985 and returned with her teenage daughter in 2008 to work at an orphanage in the Jaipur area called Udayan. The home for children is part of an umbrella organization called Vatsalya that also runs an HIV-education program for female sex workers, among other projects aimed at empowering women and teaching street children vocational skills.

"The orphanage is really incredible," says Bjorkman, whose daughter accompanied her on her most recent trip as well. "There are an estimated 18 million children living on the street in India—a lot who are not actually orphans, but on the street anyway. The organization takes in as many children as it can—around 60—and those kids are never adopted. When they come to the orphanage, the group there becomes their family."

The mission of the organization—founded in 1995 by Jaimala and Hitesh Gupta, both of whom have backgrounds in public health—is to "provide a caring environment where our disadvantaged and vulnerable people can develop their capabilities with dignity." The orphanage is a nearly self-sufficient compound that includes a school, a farm, a garden, and dormitories. They even have a psychologist who visits with the children, many of whom suffered abuse at very young ages.

"It's really an amazing place," says Bjorkman. "Here these kids are, all living with the most horrible back stories, and they are full of joy and respectful and helpful. It makes you realize how incredibly privileged we are here in Pasadena and that we take a lot for granted."

Bjorkman and her daughter stayed at Udayan for two weeks each time they visited, helping to teach the children English and math, participating in art and dance projects, and helping with gardening and cooking. This summer, Bjorkman also traveled to Ajmer, where the group's HIV-education program is located. There, she met with women struggling with the stigma of HIV, particularly because they rely on sex work to support their children and send them to private school; public schools in many impoverished areas of India are notoriously bad.

"The organization identifies women in the community who are sex workers and are interested in learning some other trade, or who need help because of HIV infection," she explains. "The terrible thing is that when they find out they are HIV infected, many of the women start working more because their futures are more uncertain.  Plus, they hesitate to take medication because if anyone finds out that they are positive, they will lose customers." 

The organization provides counseling, runs a female condom education program, offers training classes for those wanting to become proficient at another job, and works to get HIV-positive women on antiretroviral medications. While visiting with the women, Bjorkman talked with them about how the virus works and why it's so tough to treat once it's in the body.

"This is the reason that I'm doing the HIV research," she says. "It's not to get our own papers out first, it's to actually do something that might make a difference. Meeting the women put a lot of the competition and the unpleasantness associated with the rat race of science into perspective."

Bjorkman plans to return to India, but in the meantime she's doing all she can to raise awareness for Vatsalya and their various projects. Like any nonprofit, the organization could use monetary donations, but she hopes that her story inspires others at Caltech to donate their time. Anyone, she says, can volunteer through Vatsalya and receive room, board, and meals at the orphanage for a nominal daily donation.

"Caltech undergrad and grad students don't necessarily have that much money, but they may have time and this would be an amazing way to get to know another culture," she says. "These people are really doing a great job—both with the orphanage and with the HIV program that I had direct experience with. Once you see the way it works, it's really inspiring."

For more information on Vatsalya and the work they do, visit their website. Or contact Pamela Bjorkman to find out how you can become directly involved with this organization.  

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Caltech Again Named World's Top University in <i>Times Higher Education</i> Global Ranking

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.

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