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Caltech Professors Awarded 2015 Sloan Fellowships

Five Caltech faculty members have been named among the 2015 class of Sloan Research Fellows. The fellowships, awarded by the Alfred P. Sloan Foundation, honor "early-career scientists whose achievements and potential identify them as rising stars, the next generation of scientific leaders." This year, 126 young scientists were awarded fellowships in eight scientific and technical fields: chemistry, computer science, economics, mathematics, computational and evolutionary biology, neuroscience, ocean sciences, and physics. Candidates must be nominated by a department head or other senior researcher and are reviewed by a selection committee of three distinguished scientists in each field.

Viviana Gradinaru (BS' 05), an assistant professor of biology and the faculty director of the Beckman Institute Pilot Center for Optogenetics and CLARITY, received her fellowship in the area of neuroscience. The CLARITY technique, codeveloped by Gradinaru, is used to render tissues, organs, and even whole organisms transparent. Her research focuses on developing tools and methods for neuroscience as well as investigating the mechanisms underlying deep brain stimulation and its long-term effects on neuronal health, function, and behavior.

Mitchell Guttman, an assistant professor of biology, received the fellowship in the category of computational and evolutionary molecular biology. His work exploring unknown regions of the genome has led to the identification of genes that do not produce proteins, known as long noncoding RNAs (lncRNAs), which act as efficient administrators, gathering and organizing key proteins necessary for packaging genetic information and regulating gene expression. Guttman and his colleagues recently discovered that lncRNAs can shape chromosome structure to remodel the genome and pull in necessary target genes, unlike other proteins that must travel to their targets.

Gregg Hallinan, an assistant professor of astronomy, received his fellowship in the physics category. His group studies the universe at radio wavelengths, particularly examining the radio emissions produced by stars and their planets. His team recently completed construction of a new radio telescope at Caltech's Owens Valley Radio Observatory that can survey the entire sky instantaneously. This project aims to deliver the first detection of radio waves produced by the interaction of the magnetic field of an exoplanet—a planet outside our own solar system—with the stellar wind of its host star.

Heather Knutson, an assistant professor of planetary science, received the fellowship in the physics category. She studies the structure, chemistry, and atmospheric dynamics of extrasolar planets. These planets are often classified into broad categories based on their mass and radius. Knutson's research measuring exoplanet temperatures and characterizing atmospheric compositions adds detail to these classifications. She has helped develop many of the techniques that are now used to study exoplanet atmospheric dynamics.

Xinwen Zhu, an associate professor of mathematics, received the fellowship in the mathematics category. His research interests focus on geometric representation theory, in particular the geometric aspects of the Langlands program, a kind of "unified theory of mathematics" linking together many different mathematical fields of research. This research aims to provide a more intuitive visualization of prime numbers by relating the field to diverse topics such as geometry and quantum physics.

Also included among this year's class of fellows are six other Caltech alumni: Brandi Cossairt (BS '06), Jennifer A. Dionne (MS '05, PhD '09), Aaron Esser-Kahn (BS '04), Michael Kesden (PhD '05), Neal Mankad (PhD '10), and Stephanie Waterman (MS '02).

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Monday, March 2, 2015
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The Secret Life of a Snowflake

Tuesday, February 24, 2015

New Frontiers in Biological Engineering

Genetically Engineered Antibodies Show Enhanced HIV-Fighting Abilities

Capitalizing on a new insight into HIV's strategy for evading antibodies—proteins produced by the immune system to identify and wipe out invading objects such as viruses—Caltech researchers have developed antibody-based molecules that are more than 100 times better than our bodies' own defenses at binding to and neutralizing HIV, when tested in vitro. The work suggests a novel approach that could be used to engineer more effective HIV-fighting drugs.

"Based on the work that we have done, we now think we know how to make a really potent therapeutic that would not only work at relatively low concentrations but would also force the virus to mutate along pathways that would make it less fit and therefore more susceptible to elimination," says Pamela Bjorkman, the Max Delbrück Professor of Biology and an investigator with the Howard Hughes Medical Institute. "If you were able to give this to someone who already had HIV, you might even be able to clear the infection."

The researchers describe the work in the January 29 issue of Cell. Rachel Galimidi, a graduate student in Bjorkman's lab at Caltech, is lead author on the paper.

The researchers hypothesized that one of the reasons the immune system is less effective against HIV than other viruses involves the small number and low density of spikes on HIV's surface. These spikes, each one a cluster of three protein subunits, stick up from the surface of the virus and are the targets of antibodies that neutralize HIV. While most viruses are covered with hundreds of these spikes, HIV has only 10 to 20, making the average distance between the spikes quite long.

That distance is important with respect to the mechanism that naturally occurring antibodies use to capture their viral targets. Antibodies are Y-shaped proteins that evolved to grab onto their targets with both "arms." However, if the spikes are few and far between—as is the case with HIV—it is likely that an antibody will bind with only one arm, making its connection to the virus weaker (and easier for a mutation of the spike to render the antibody ineffective).

To test their hypothesis, Bjorkman's group genetically engineered antibody-based molecules that can bind with both arms to a single spike. They started with the virus-binding parts, or Fabs, of broadly neutralizing antibodies—proteins produced naturally by a small percentage of HIV-positive individuals that are able to fight multiple strains of HIV until the virus mutates. When given in combination, these antibodies are quite effective. Rather than making Y-shaped antibodies, the Caltech group simply connected two Fabs—often from different antibodies, to mimic combination therapies—with different lengths of spacers composed of DNA.

Why DNA? In order to engineer antibodies that could latch onto a spike twice, they needed to know which Fabs to use and how long to make the connection between them so that both could readily bind to a single spike. Previously, various members of Bjorkman's group had tried to make educated guesses based on what is known of the viral spike structure, but the large number of possible variations in terms of which Fabs to use and how far apart they should be, made the problem intractable.

In the new work, Bjorkman and Galimidi struck upon the idea of using DNA as a "molecular ruler." It is well known that each base pair in double-stranded DNA is separated by 3.4 angstroms. Therefore, by incorporating varying lengths of DNA between two Fabs, they could systematically test for the best neutralizer and then derive the distance between the Fabs from the length of the DNA. They also tested different combinations of Fabs from various antibodies—sometimes incorporating two different Fabs, sometimes using two of the same.

"Most of these didn't work at all," says Bjorkman, which was reassuring because it suggested that any improvements the researchers saw were not just created by an artifact, such as the addition of DNA.

But some of the fabricated molecules worked very well. The researchers found that the molecules that combined Fabs from two different antibodies performed the best, showing an improvement of 10 to 1,000 times in their ability to neutralize HIV, as compared to naturally occurring antibodies. Depending on the Fabs used, the optimal length for the DNA linker was between 40 and 62 base pairs (corresponding to 13 and 21 nanometers, respectively).

Taking this finding to the next level in the most successful of these new molecules, the researchers replaced the piece of DNA with a protein linker of roughly the same length composed of 12 copies of a protein called tetratricopeptide repeat. The end product was an all-protein antibody-based reagent designed to bind with both Fabs to a single HIV spike.

"That one also worked, showing more than 30-fold average increased potency compared with the parental antibodies," says Bjorkman. "That is proof of principle that this can be done using protein-based reagents."

The greater potency suggests that a reagent made of these antibody-based molecules could work at lower concentrations, making a potential therapeutic less expensive and decreasing the risk of adverse reactions in patients.

"I think that our work sheds light on the potential therapeutic strategies that biotech companies should be using—and that we will be using—in order to make a better antibody reagent to combat HIV," says Galimidi. "A lot of companies discount antibody reagents because of the virus's ability to evade antibody pressure, focusing instead on small molecules as drug therapies. Our new reagents illustrate a way to get around that."

The Caltech team is currently working to produce larger quantities of the new reagents so that they can test them in humanized mice—specialized mice carrying human immune cells that, unlike most mice, are sensitive to HIV.

Along with Galimidi and Bjorkman, additional Caltech authors on the paper, "Intra-Spike Crosslinking Overcomes Antibody Evasion by HIV-1," include Maria Politzer, a lab assistant; and Anthony West, a senior research specialist. Joshua Klein, a former Caltech graduate student (PhD '09), and Shiyu Bai, a former technician in the Bjorkman lab, also contributed to the work; they are currently at Google and Case Western Reserve University School of Medicine, respectively. Michael Seaman of Beth Israel Deaconess Medical Center and Michel Nussenzweig of the Rockefeller University in New York are also coauthors. The work was supported by the National Institutes of Health through a Director's Pioneer Award and a grant from the HIV Vaccine Research and Design Program, as well as grants from the Collaboration for AIDS Vaccine Discovery and the Bill and Melinda Gates Foundation. Nussenzweig is also an investigator with the Howard Hughes Medical Institute.

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Getting a Better Grip on HIV
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Friday, February 13, 2015
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Backpocket Barnburner: A Lightning Quick Overview of Educational Theory

Why Do We Feel Thirst? An Interview with Yuki Oka

To fight dehydration on a hot summer day, you instinctively crave the relief provided by a tall glass of water. But how does your brain sense the need for water, generate the sensation of thirst, and then ultimately turn that signal into a behavioral trigger that leads you to drink water? That's what Yuki Oka, a new assistant professor of biology at Caltech, wants to find out.

Oka's research focuses on the study of how the brain and body work together to maintain a healthy ratio of salt to water as part of a delicate form of biological balance called homeostasis.

Recently, Oka came to Caltech from Columbia University. We spoke with him about his work, his interests outside of the lab, and why he's excited to be joining the faculty at Caltech.

 

Can you tell us a bit more about your research?

The goal of my research is to understand the mechanisms by which the brain and body cooperate to maintain our internal environment's stability, which is called homeostasis. I'm especially focusing on fluid homeostasis, the fundamental mechanism that regulates the balance of water and salt. When water or salt are depleted in the body, the brain generates a signal that causes either a thirst or a salt craving. And that craving then drives animals to either drink water or eat something salty.

I'd like to know how our brain generates such a specific motivation simply by sensing internal state, and then how that motivation—which is really just neural activity in the brain—goes on to control the behavior.

 

Why did you choose to study thirst?

After finishing my Ph.D. in Japan, I came to Columbia University where I worked on salt sensing mechanisms in the mammalian taste system. We found that the peripheral taste system has a key function for salt homeostasis in the body by regulating our salt intake behavior. But of course, the peripheral sensor does not work by itself.  It requires a controller, the brain, which uses information from the sensor. So I decided to move on to explore the function of the brain; the real driver of our behaviors.

I was fascinated by thirst because the behavior it generates is very robust and stereotyped across various species. If an animal feels thirst, the behavioral output is simply to drink water. On the other hand, if the brain triggers salt appetite, then the animal specifically looks for salt—nothing else. These direct causal relations make it an ideal system to study the link between the neural circuit and the behavior.

 

You recently published a paper on this work in the journal Nature. Could you tell us about those findings?

In the paper, we linked specific neural populations in the brain to water drinking behavior. Previous work from other labs suggested that thirst may stem from a part of the brain called the hypothalamus, so we wanted to identify which groups of neurons in the hypothalamus control thirst. Using a technique called optogenetics that can manipulate neural activities with light, we found two distinct populations of neurons that control thirst in two opposite directions. When we activated one of those two populations, it evoked an intense drinking behavior even in fully water-satiated animals. In contrast, activation of a second population drastically suppressed drinking, even in highly water-deprived thirsty animals.  In other words, we could artificially create or erase the desire for drinking water.

Our findings suggest that there is an innate brain circuit that can turn an animal's water-drinking behavior on and off, and that this circuit likely functions as a center for thirst control in the mammalian brain. This work was performed with support from Howard Hughes Medical Institute and National Institutes of Health [for Charles S. Zuker at Columbia University, Oka's former advisor].

 

You use a mouse model to study thirst, but does this work have applications for humans?

There are many fluid homeostasis-associated conditions; one example is dehydration. We cannot specifically say a direct application for humans since our studies are focused on basic research. But if the same mechanisms and circuits exist in mice and humans, our studies will provide important insights into human physiologies and conditions.

 

Where did you grow up—and what started your initial interest in science?

I grew up in Japan, close to Tokyo, but not really in the center of the city. It was a nice combination between the big city and nature. There was a big park close to my house and when I was a child, I went there every day and observed plants and animals. That's pretty much how I spent my childhood. My parents are not scientists—neither of them, actually. It was just my innate interest in nature that made me want to be a scientist.

 

What drew you to Caltech?

I'm really excited about the environment here and the great climate. That's actually not trivial; I think the climate really does affect the people. For example, if you compare Southern California to New York, it's just a totally different character. I came here for a visit last January, and although it was my first time at Caltech I kind of felt a bond. I hadn't even received an offer yet, but I just intuitively thought, "This is probably the place for me."

I'm also looking forward to talking to my colleagues here who use fMRI for human behavioral research. One great advantage about using human subjects in behavioral studies is that they can report back to you about how they feel. There are certainly advantages of using an animal model, like mice. But they cannot report back. We just observe their behavior and say, "They are drinking water, so they must be thirsty." But that is totally different than someone telling you, "I feel thirsty." I believe that combining advantages of animal and human studies should allow us to address important questions about brain functions.

 

Do you have any hobbies?

I play basketball in my spare time, but my major hobby is collecting fossils. I have some trilobites and, actually, I have a complete set of bones from a type of herbivorous dinosaur. It is being shipped from New York right now and I may put it in my new office.

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