Oka Awarded Grant for "Exceptional Young Scientists"

Yuki Oka, an assistant professor of biology, has been named a 2015 Searle Scholar. The Searle Scholars Program provides grants to young faculty to support research in the biomedical sciences and chemistry. Fifteen scholars are named annually, each receiving $100,000 per year for three years.

"I'm very excited and honored by this award," says Oka, who studies how the brain compiles both internal and external sensory information in order to maintain homeostasis, or internal stability of the body. In particular, Oka's group studies how the brain controls the feeling of thirst, and how that feeling drives us to drink water. There are multiple processes involved in regulating thirst in the brain.  

"Our research group aims to understand how these thirst signals are processed in the brain and how they ultimately drive specific behavioral outputs," Oka says. "We recently identified two distinct neural populations controlling drinking behavior in two opposite directions: driving and suppressing thirst." By manipulating these neural populations in animals, the group found that it could artificially create or suppress the desire to drink water.

Before joining the faculty at Caltech, Oka was a postdoctoral scholar at Columbia University. He received his PhD from the University of Tokyo. He is the 18th current Caltech faculty member to be named a Searle Scholar.

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Microbes Help Produce Serotonin in Gut

Although serotonin is well known as a brain neurotransmitter, it is estimated that 90 percent of the body's serotonin is made in the digestive tract. In fact, altered levels of this peripheral serotonin have been linked to diseases such as irritable bowel syndrome, cardiovascular disease, and osteoporosis. New research at Caltech, published in the April 9 issue of the journal Cell, shows that certain bacteria in the gut are important for the production of peripheral serotonin.

"More and more studies are showing that mice or other model organisms with changes in their gut microbes exhibit altered behaviors," explains Elaine Hsiao, research assistant professor of biology and biological engineering and senior author of the study. "We are interested in how microbes communicate with the nervous system. To start, we explored the idea that normal gut microbes could influence levels of neurotransmitters in their hosts."

Peripheral serotonin is produced in the digestive tract by enterochromaffin (EC) cells and also by particular types of immune cells and neurons. Hsiao and her colleagues first wanted to know if gut microbes have any effect on serotonin production in the gut and, if so, in which types of cells. They began by measuring peripheral serotonin levels in mice with normal populations of gut bacteria and also in germ-free mice that lack these resident microbes.

The researchers found that the EC cells from germ-free mice produced approximately 60 percent less serotonin than did their peers with conventional bacterial colonies. When these germ-free mice were recolonized with normal gut microbes, the serotonin levels went back up—showing that the deficit in serotonin can be reversed.

"EC cells are rich sources of serotonin in the gut. What we saw in this experiment is that they appear to depend on microbes to make serotonin—or at least a large portion of it," says Jessica Yano, first author on the paper and a research technician working with Hsiao.

The researchers next wanted to find out whether specific species of bacteria, out of the diverse pool of microbes that inhabit the gut, are interacting with EC cells to make serotonin.

After testing several different single species and groups of known gut microbes, Yano, Hsiao, and colleagues observed that one condition—the presence of a group of approximately 20 species of spore-forming bacteria—elevated serotonin levels in germ-free mice. The mice treated with this group also showed an increase in gastrointestinal motility compared to their germ-free counterparts, and changes in the activation of blood platelets, which are known to use serotonin to promote clotting.

Wanting to home in on mechanisms that could be involved in this interesting collaboration between microbe and host, the researchers began looking for molecules that might be key. They identified several particular metabolites—products of the microbes' metabolism—that were regulated by spore-forming bacteria and that elevated serotonin from EC cells in culture. Furthermore, increasing these metabolites in germ-free mice increased their serotonin levels.

Previous work in the field indicated that some bacteria can make serotonin all by themselves. However, this new study suggests that much of the body's serotonin relies on particular bacteria that interact with the host to produce serotonin, says Yano. "Our work demonstrates that microbes normally present in the gut stimulate host intestinal cells to produce serotonin," she explains.

"While the connections between the microbiome and the immune and metabolic systems are well appreciated, research into the role gut microbes play in shaping the nervous system is an exciting frontier in the biological sciences," says Sarkis K. Mazmanian, Luis B. and Nelly Soux Professor of Microbiology and a coauthor on the study. "This work elegantly extends previous seminal research from Caltech in this emerging field".

Additional coauthor Rustem Ismagilov, the Ethel Wilson Bowles and Robert Bowles Professor of Chemistry and Chemical Engineering, adds, "This work illustrates both the richness of chemical interactions between the hosts and their microbial communities, and Dr. Hsiao's scientific breadth and acumen in leading this work."

Serotonin is important for many aspects of human health, but Hsiao cautions that much more research is needed before any of these findings can be translated to the clinic.

"We identified a group of bacteria that, aside from increasing serotonin, likely has other effects yet to be explored," she says. "Also, there are conditions where an excess of peripheral serotonin appears to be detrimental."

Although this study was limited to serotonin in the gut, Hsiao and her team are now investigating how this mechanism might also be important for the developing brain. "Serotonin is an important neurotransmitter and hormone that is involved in a variety of biological processes. The finding that gut microbes modulate serotonin levels raises the interesting prospect of using them to drive changes in biology," says Hsiao.

The work was published in an article titled "Indigenous Bacteria from the Gut Microbiota Regulate Host Serotonin Biosynthesis." In addition to Hsiao, Yano, Mazmanian, and Ismagilov, other Caltech coauthors include undergraduates Kristie Yu, Gauri Shastri, and Phoebe Ann; graduate student Gregory Donaldson; postdoctoral scholar Liang Ma. Additional coauthor Cathryn Nagler is from the University of Chicago.

This work was funded by an NIH Director's Early Independence Award and a Caltech Center for Environmental Microbial Interactions Award, both to Hsiao. The study was also supported by NSF, NIDDK, and NIMH grants to Mazmanian, NSF EFRI and NHGRI grants to Ismagilov, and grants from the NIAID and Food Allergy Research and Education and University of Chicago Digestive Diseases Center Core to Nagler.

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Thursday, July 2, 2015
Athenaeum, Main Lounge

Ray and June Owen Memorial

Wednesday, April 29, 2015

At the Intersection of Art and Science: A Conversation with Joyce Carol Oates and Charlie Gross

A Molecular Arms Race: The Immune System Versus HIV

Watson Lecture Preview

It is now more than 30 years after the first AIDS epidemic, and an effective vaccine against HIV does not yet exist—partly because the virus quickly mutates to evade the vaccine's antibodies. On Wednesday, April 1, at 8 p.m. in Caltech's Beckman Auditorium, Pamela J. Bjorkman, Caltech's Max Delbrück Professor of Biology and an investigator with the Howard Hughes Medical Institute, will describe ways to neutralize that mutational advantage. Admission is free.

 

What do you do?

We are structural biologists who use various imaging techniques to look at biological macromolecules and assemblies, sometimes in purified forms and sometimes in tissues. For example, we study HIV proteins alone, on viruses, and on viruses in tissues during an infection. Utilizing high-resolution structures of individual proteins, we are trying to apply our knowledge of the chemistry of protein-protein interactions to understanding what makes some antibodies produced by HIV-infected people good at neutralizing viruses and other antibodies less effective. We then try to reengineer good antibodies to make them even better in hopes that they could be used therapeutically to prevent or treat HIV infection.

 

What's the neatest thing about what you do?

Using imaging techniques such as X-ray crystallography and electron microscopy, we can visualize structures in three dimensions, sometimes even localizing all of the atoms in a protein structure. This feels a bit like spying on nature—forcing her to reveal secrets that we can hopefully use to combat HIV/AIDS.

 

How did you get into this line of work?

I was hooked after taking chemistry in high school. I knew then that I wanted to use chemistry to understand biology. I became interested in HIV about 10 years ago when I started teaching the Caltech freshman biology class and used HIV as a model system to understand basic principles of biology, especially evolution. HIV is an amazing example of successful evolution against which the human immune system loses, but I hope that we can win the war against HIV through a fundamental understanding of how it works.

 

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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Friday, April 10, 2015
Noyes 147 (J. Holmes Sturdivant Lecture Hall) – Arthur Amos Noyes Laboratory of Chemical Physics

Transforming Chemistry Education

Research Suggests Brain's Melatonin May Trigger Sleep

If you walk into your local drug store and ask for a supplement to help you sleep, you might be directed to a bottle labeled "melatonin." The hormone supplement's use as a sleep aid is supported by anecdotal evidence and even some reputable research studies. However, our bodies also make melatonin naturally, and until a recent Caltech study using zebrafish, no one knew how—or even if—this melatonin contributed to our natural sleep. The new work suggests that even in the absence of a supplement, naturally occurring melatonin may help us fall and stay asleep.

The study was published online in the March 5 issue of the journal Neuron.

"When we first tell people that we're testing whether melatonin is involved in sleep, the response is often, 'Don't we already know that?'" says Assistant Professor of Biology David Prober. "This is a reasonable response based on articles in newspapers and melatonin products available on the Internet. However, while some scientific studies show that supplemental melatonin can help to promote sleep, many studies failed to observe this, so the effectiveness of melatonin supplements is controversial. More importantly, these studies don't tell you anything about what naturally occurring melatonin normally does in the body."

There are several factors at play when you are starting to feel tired. Sleep is thought to be regulated by two mechanisms: a homeostatic mechanism, which responds to the body's internal cues for sleep, and a circadian mechanism that responds to external cues such as darkness and light, signaling appropriate times for sleep and wakefulness.

For years, researchers have known that melatonin production is regulated by the circadian clock, and that animals produce more of the hormone at night than they do during the day. However, this fact alone is not enough to prove that melatonin promotes sleep. For example, although nocturnal animals sleep during the day and are active at night, they also produce the most melatonin at night.

In the hopes of determining, once and for all, what role the hormone actually plays in sleep, Prober and his team at Caltech designed an experiment using the larvae of zebrafish, an organism commonly used in research studies because of its small size and well-characterized genome. Like humans, zebrafish are also diurnal—awake during the day and asleep at night—and produce melatonin at night.

But how exactly can you tell if a young zebrafish has fallen asleep? There are behavioral criteria—including how long a zebrafish takes to respond to a stimulus, like a knock on the tank, for example. "Based on these criteria, we found that if the zebrafish larvae don't move for one or more minutes, they are in a sleep-like state," Prober says.

To test the effect of naturally occurring melatonin on sleep, the researchers first compared the sleep patterns of normal, or "wild-type," zebrafish larvae to those of zebrafish larvae that are unable to produce the hormone because of a mutation in a gene called aanat2. They found that fish with the mutation slept only half as long as normal fish. And although a normal zebrafish begins to fall asleep about 10 minutes after "lights out"—about the same amount of time it takes a human to fall asleep—it took the aanat2 mutant fish about twice as long.

"This result was surprising because it suggests that almost half of the sleep that the larvae are getting at night is due to the effects of melatonin," Prober says. "That suggests that melatonin normally plays an important role in sleep and that you need this natural melatonin both to fall asleep and to stay asleep."

In both humans and zebrafish, melatonin is produced in a part of the brain called the pineal gland. To confirm that the mutation-induced reduction in sleep was actually due to a lack of melatonin, the researchers next used a drug to specifically kill the cells of the pineal gland, thus halting the hormone's production. The drug-treated fish showed the same reduction in sleep as fish with mutated aanat2. When the drug treatment stopped, allowing pineal gland cells to regenerate, the fish returned to a normal sleep pattern.

Sleep patterns, like many other biological and behavioral processes, are known to be regulated by the circadian clock. In an organism, the circadian clock aligns these processes with daily changes in the environment, such as daylight and darkness at night. However, while a great deal is known about how the circadian clock works, it was not known how the clock regulates sleep. Because the researchers had determined that melatonin is involved in promoting natural sleep, they next asked whether melatonin mediates the circadian regulation of sleep.

They first raised both wild-type and aanat2 mutant zebrafish larvae in a normal light/dark cycle—14 hours of light followed by 10 hours of darkness—to entrain their circadian clocks. Then, when the larvae were 5 days old, they switched both populations to an environment of constant darkness. In this "free running" condition, the circadian clock continues to function in the absence of daily light and dark signals from the environment. As expected, the wild-type fish maintained their regular circadian sleep cycle. The melatonin-lacking aanat2 mutants, however, showed no cyclical sleep patterns.  

"This was really surprising," says Prober. "For years, people have been looking in rodents for a factor that's required for the circadian regulation of sleep and have found a few other candidate molecules that, like melatonin, are regulated by the circadian clock and can induce sleep when given as supplements. However, mutants that lack these factors had normal circadian sleep cycles," says Prober. "One thought was that maybe all of these molecules work together and that you'd have to make mutations in multiple genes to see an effect. But we found that eliminating one molecule, melatonin, is the whole show. It's one of those rare and surprisingly clear results."

After finding that melatonin is necessary for the circadian regulation of sleep, Prober next wanted to ask how it does this. To find out, Prober and his colleagues looked to a neuromodulator called adenosine—part of the homeostatic mechanism that promotes sleep. As an animal expends energy throughout the day, adenosine accumulates in the brain causing the animal to feel more and more tired—a pressure that is relieved through sleep.

The researchers treated both wild-type and melatonin-deficient aanat2 mutant fish with drugs that activate adenosine signaling. They found that although the drugs had no effect on the wild-type fish, they restored normal sleep amounts in aanat2 mutants. This result suggests that melatonin may be promoting sleep, in part, by turning on adenosine—providing a long sought-after link between the homeostatic and circadian processes that regulate sleep.

Prober and his colleagues hypothesize that the circadian clock drives the production of melatonin, which then promotes sleep through yet-to-be-determined mechanisms while also stimulating adenosine production, thus promoting sleep through the homeostatic pathway. Although more experiments are needed to confirm this model, Prober says that the preliminary results may offer insights about human sleep as well.

"Zebrafish are vertebrates and their brain is structurally similar to ours. All of the markers that we and others have tested are expressed in the same regions of the zebrafish brain as in the mammalian brain," he says. "Zebrafish sleep and human sleep are likely different in some ways, but all of our drug and genetic data indicate that the same factors—working through the same mechanisms—have similar effects on sleep in zebrafish and mammals. "

Prober's work with the circadian regulation of sleep follows in the conceptual—and physical—footsteps of late Caltech geneticist Seymour Benzer, who founded genetic studies of the circadian clock. In experiments in fruit flies, Benzer and his graduate student, the late Ronald Konopka (PhD '72), discovered the first circadian-rhythm mutants. Benzer passed away in 2007, and when Prober came to Caltech in 2009, he was offered Benzer's former office and lab space. "Seymour Benzer's work in fruit flies launched the beginning of our understanding of the molecular circadian clock," Prober says, "so it's really special to be in this space, and it's gratifying that we're taking the next step based on his work."

The results of Prober's study are published in the journal Neuron in an article titled, "Melatonin is required for the circadian regulation of sleep." Other Caltech coauthors on the paper are graduate student Avni Gandhi and postdoctoral scholars Eric Mosser and Grigorios Oikonomou. This work was funded by grants from the National Institutes of Health, the Mallinckrodt Foundation, the Rita Allen Foundation, the Brain and Behavior Research Foundation as well as a Della Martin Postdoctoral Fellowship to Mosser.

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Feeling Sleepy? Might be the Melatonin
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Tuesday, April 7, 2015
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Caltech Roundtable: Writing Popular Books about Science

Fighting a Worm with Its Own Genome

Tiny parasitic hookworms infect nearly half a billion people worldwide—almost exclusively in developing countries—causing health problems ranging from gastrointestinal issues to cognitive impairment and stunted growth in children. By sequencing and analyzing the genome of one particular hookworm species, Caltech researchers have uncovered new information that could aid the fight against these parasites.  

The results of their work were published online in the March 2 issue of the journal Nature Genetics.

"Hookworms infect a huge percentage of the human population. Getting clean water and sanitation to the most affected regions would help to ameliorate hookworms and a number of other parasites, but since these are big, complicated challenges that are difficult to address, we need to also be working on drugs to treat them," says study lead Paul Sternberg, the Thomas Hunt Morgan Professor of Biology at Caltech and a Howard Hughes Medical Institute investigator.

Medicines have been developed to treat hookworm infections, but the parasites have begun to develop resistance to these drugs. As part of the search for effective new drugs, Sternberg and his colleagues investigated the genome of a hookworm species known as Ancylostoma ceylanicum. Other hookworm species cause more disease among humans, but A. ceylanicum piqued the interest of the researchers because it also infects some species of rodents that are commonly used for research. This means that the researchers can easily study the parasite's entire infection process inside the laboratory.

The team began by sequencing all 313 million nucleotides of the A. ceylanicum genome using the next-generation sequencing capabilities of the Millard and Muriel Jacobs Genetics and Genomics Laboratory at Caltech. In next-generation sequencing, a large amount of DNA—such as a genome—is first reproduced as many very short sequences. Then, computer programs match up common sequences in the short strands to piece them into much longer strands.

"Assembling the short sequences correctly can be a relatively difficult analysis to carry out, but we have experience sequencing worm genomes in this way, so we are quite successful," says Igor Antoshechkin, director of the Jacobs Laboratory. 

Their sequencing results revealed that although the A. ceylanicum genome is only about 10 percent of the size of the human genome, it actually encodes at least 30 percent more genes—about 30,000 in total, compared to approximately 20,000-23,000 in the human genome. However, of these 30,000 genes, the essential genes that are turned on specifically when the parasite is wreaking havoc on its host are the most relevant to the development of potential drugs to fight the worm.

Sternberg and his colleagues wanted to learn more about those active genes, so they looked not to DNA but to RNA—the genetic material that is generated (or transcribed) from the DNA template of active genes and from which proteins are made. Specifically, they examined the RNA generated in an A. ceylanicum worm during infection. Using this RNA, the team found more than 900 genes that are turned on only when the worm infects its host—including 90 genes that belong to a never-before-characterized family of proteins called activation-associated secreted protein related genes, or ASPRs.

"If you go back and look at other parasitic worms, you notice that they have these ASPRs as well," Sternberg says. "So basically we found this new family of proteins that are unique to parasitic worms, and they are related to this early infection process." Since the worm secretes these ASPR proteins early in the infection, the researchers think that these proteins might block the host's initial immune response—preventing the host's blood from clotting and ensuring a free-flowing food source for the blood-sucking parasite.

If ASPRs are necessary for this parasite to invade the host, then a drug that targets and destroys the proteins could one day be used to fight the parasite. Unfortunately, however, it is probably not that simple, Sternberg says.

"If we have 90 of these ASPRs, it might be that a drug would get rid of just a few of them and stop the infection, but maybe you'd have to get rid of all 90 of them for it to work. And that's a problem," he says. "It's going to take a lot more careful study to understand the functions of these ASPRs so we can target the ones that are key regulatory molecules."

Drugs that target ASPRs might one day be used to treat these parasitic infections, but these proteins also hold the potential for anti-A. ceylanicum vaccines—which would prevent these parasites from infecting a host in the first place, Sternberg adds. For example, if a person were injected with an ASPR protein vaccine before travelling to an infection-prone region, their immune system might be more prepared to successfully fend off an infection.

"A parasitic infection is a balance between the parasites trying to suppress the immune system and the host trying to attack the parasite," says Sternberg. "And we hope that by analyzing the genome, we can uncover clues that might help us alter that balance in favor of the host."

These findings were published in a paper titled, "The genome and transcriptome of the zoonotic hookworm Ancylostoma ceylanicum identify infection-specific gene families." In addition to Sternberg and Antoshechkin, other coauthors include Erich M. Schwarz of Cornell University; and Yan Hu, Melanie Miller, and Raffi V. Aroian from UC San Diego. Sternberg's work was funded by the National Institutes of Health and the Howard Hughes Medical Institute.

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Knocking Out Parasites with Their Own Genetic Code
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Knocking Out Parasites with Their Own Genetic Code
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Tuesday, March 31, 2015 to Thursday, April 16, 2015
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