A Changing View of Bone Marrow Cells

Caltech researchers show that the cells are actively involved in sensing infection

In the battle against infection, immune cells are the body's offense and defense—some cells go on the attack while others block invading pathogens. It has long been known that a population of blood stem cells that resides in the bone marrow generates all of these immune cells. But most scientists have believed that blood stem cells participate in battles against infection in a delayed way, replenishing immune cells on the front line only after they become depleted.

Now, using a novel microfluidic technique, researchers at Caltech have shown that these stem cells might be more actively involved, sensing danger signals directly and quickly producing new immune cells to join the fight.

"It has been most people's belief that the bone marrow has the function of making these cells but that the response to infection is something that happens locally, at the infection site," says David Baltimore, president emeritus and the Robert Andrews Millikan Professor of Biology at Caltech. "We've shown that these bone marrow cells themselves are sensitive to infection-related molecules and that they respond very rapidly. So the bone marrow is actually set up to respond to infection."

The study, led by Jimmy Zhao, a graduate student in the UCLA-Caltech Medical Scientist Training Program, will appear in the April 3 issue of the journal Cell Stem Cell.

In the work, the researchers show that blood stem cells have all the components needed to detect an invasion and to mount an inflammatory response. They show, as others have previously, that these cells have on their surface a type of receptor called a toll-like receptor. The researchers then identify an entire internal response pathway that can translate activation of those receptors by infection-related molecules, or danger signals, into the production of cytokines, signaling molecules that can crank up immune-cell production. Interestingly, they show for the first time that the transcription factor NF-κB, known to be the central organizer of the immune response to infection, is part of that response pathway.

To examine what happens to a blood stem cell once it is activated by a danger signal, the Baltimore lab teamed up with chemists from the lab of James Heath, the Elizabeth W. Gilloon Professor and professor of chemistry at Caltech. They devised a microfluidic chip—printed in flexible silicon on a glass slide, complete with input and output ports, control valves, and thousands of tiny wells—that would enable single-cell analysis. At the bottom of each well, they attached DNA molecules in strips and introduced a flow of antibodies—pathogen-targeting proteins of the immune system—that had complementary DNA. They then added the stem cells along with infection-related molecules and incubated the whole sample. Since the antibodies were selected based on their ability to bind to certain cytokines, they specifically captured any of those cytokines released by the cells after activation. When the researchers added a secondary antibody and a dye, the cytokines lit up. "They all light up the same color, but you can tell which is which because you've attached the DNA in an orderly fashion," explains Baltimore. "So you've got both visualization and localization that tells you which molecule was secreted." In this way, they were able to measure, for example, that the cytokine IL-6 was secreted most frequently—by 21.9 percent of the cells tested.

"The experimental challenges here were significant—we needed to isolate what are actually quite rare cells, and then measure the levels of a dozen secreted proteins from each of those cells," says Heath. "The end result was sort of like putting on a new pair of glasses—we were able to observe functional properties of these stem cells that were totally unexpected."

The team found that blood stem cells produce a surprising number and variety of cytokines very rapidly. In fact, the stem cells are even more potent generators of cytokines than other previously known cytokine producers of the immune system. Once the cytokines are released, it appears that they are able to bind to their own cytokine receptors or those on other nearby blood stem cells. This stimulates the bound cells to differentiate into the immune cells needed at the site of infection.

"This does now change the view of the potential of bone marrow cells to be involved in inflammatory reactions," says Baltimore.

Heath notes that the collaboration benefited greatly from Caltech's support of interdisciplinary work. "It is a unique and fertile environment," he says, "one that encourages scientists from different disciplines to harness their disparate areas of expertise to solve tough problems like this one."

Additional coauthors on the paper, "Conversion of danger signals into cytokine signals by hematopoietic stem and progenitor cells for regulation of stress-induced hematopoiesis," are Chao Ma, Ryan O'Connell, Arnav Mehta, and Race DiLoreto. The work was supported by grants from the National Institute of Allergy and Infectious Diseases, the National Institutes of Health, a National Research Service Award, the UCLA-Caltech Medical Scientist Training Program, a Rosen Fellowship, a Pathway to Independence Award, and an American Cancer Society Research Grant.

Kimm Fesenmaier
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Friday, March 14, 2014
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Caltech's "Secrets" to Success

Everyone who really knows Caltech understands that it is unique among universities around the world. But just what makes Caltech so special? We've asked that question before, and the numbers don't tell the full story. So, is it our focus? Our culture? Our people?

The UK's Times Higher Education magazine recently tackled the topic, asking more specifically, "How does a tiny institution create such an outsized impact?" Caltech faculty share their perspectives in the cover story of the magazine's latest issue.

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Theodor Agapie Wins Presidential Early Career Award

Theodor Agapie, assistant professor of chemistry at the California Institute of Technology (Caltech), is a 2014 recipient of a Presidential Early Career Award for Scientists and Engineers (PECASE). Agapie will receive the award from President Barack Obama at a ceremony in the nation's capital later this year.

The Presidential Early Career Awards are given each year as encouragement to scientists and engineers to help advance the nation's technological goals, solve major problems, and contribute to the American economy. PECASE is the highest honor bestowed by the United States Government on science and engineering professionals in the early stages of their independent research careers. Recipients are employed or funded by government departments and agencies such as the Department of Defense, the Department of Energy, NASA, and the National Science Foundation (NSF).

The NSF recognized Agapie for his early career contributions to the chemistry field, particularly in the areas of inorganic, organometallic, and bioinorganic chemistry. Inspired by chemistry occurring in the natural world, Agapie guides researchers in his laboratory at Caltech in the development and investigation of a variety of chemical processes that promise to provide benefits in fields including energy, materials, and health.

The Agapie group has designed ways to synthesize inorganic clusters that model the active sites of catalysts for oxygen-oxygen bond cleavage and formation, transformations relevant to renewable energy conversion and artificial photosynthesis. In particular, they have made molecular models of the complicated metal species responsible for oxygen evolution in plants. Their studies have provided a better understanding of the photosynthetic mechanism and have offered potential strategies for the development of better catalysts. Other projects in the Agapie group focus on fundamental studies of carbon-oxygen bond activation relevant to biomass conversion, the design of catalysts for the synthesis of advanced materials, and transformations of small molecules such carbon dioxide and hydrogen relevant to sustainable technologies.

"I am honored to have been selected to receive a Presidential Early Career Award," says Agapie. "I am delighted to see that the research done by my group at Caltech is appreciated by the NSF and President Obama."

Agapie, a native of Romania, received his bachelor's degree from MIT in 2001 and his PhD from Caltech in 2007. He has been an assistant professor at Caltech since early 2009. Since joining Caltech's faculty, Agapie has been named a Cottrell Scholar, a Searle Scholar, and a Sloan Research Fellow. He is a recipient of a National Science Foundation CAREER Award, and he has received the Award in Pure Chemistry from the American Chemical Society.

Brian Bell
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Probiotic Therapy Alleviates Autism-like Behaviors in Mice

Autism spectrum disorder (ASD) is diagnosed when individuals exhibit characteristic behaviors that include repetitive actions, decreased social interactions, and impaired communication. Curiously, many individuals with ASD also suffer from gastrointestinal (GI) issues, such as abdominal cramps and constipation.

Using the co-occurrence of brain and gut problems in ASD as their guide, researchers at the California Institute Technology (Caltech) are investigating a potentially transformative new therapy for autism and other neurodevelopmental disorders.

The gut microbiota—the community of bacteria that populate the human GI tract—previously has been shown to influence social and emotional behavior, but the Caltech research, published online in the December 5 issue of the journal Cell, is the first to demonstrate that changes in these gut bacteria can influence autism-like behaviors in a mouse model.

"Traditional research has studied autism as a genetic disorder and a disorder of the brain, but our work shows that gut bacteria may contribute to ASD-like symptoms in ways that were previously unappreciated," says Professor of Biology Sarkis K. Mazmanian. "Gut physiology appears to have effects on what are currently presumed to be brain functions."

To study this gut–microbiota–brain interaction, the researchers used a mouse model of autism previously developed at Caltech in the laboratory of Paul H. Patterson, the Anne P. and Benjamin F. Biaggini Professor of Biological Sciences. In humans, having a severe viral infection raises the risk that a pregnant woman will give birth to a child with autism. Patterson and his lab reproduced the effect in mice using a viral mimic that triggers an infection-like immune response in the mother and produces the core behavioral symptoms associated with autism in the offspring.

In the new Cell study, Mazmanian, Patterson, and their colleagues found that the "autistic" offspring of immune-activated pregnant mice also exhibited GI abnormalities. In particular, the GI tracts of autistic-like mice were "leaky," which means that they allow material to pass through the intestinal wall and into the bloodstream. This characteristic, known as intestinal permeability, has been reported in some autistic individuals. "To our knowledge, this is the first report of an animal model for autism with comorbid GI dysfunction," says Elaine Hsiao, a senior research fellow at Caltech and the first author on the study.

To see whether these GI symptoms actually influenced the autism-like behaviors, the researchers treated the mice with Bacteroides fragilis, a bacterium that has been used as an experimental probiotic therapy in animal models of GI disorders.

The result? The leaky gut was corrected.

In addition, observations of the treated mice showed that their behavior had changed. In particular, they were more likely to communicate with other mice, had reduced anxiety, and were less likely to engage in a repetitive digging behavior.

"The B. fragilis treatment alleviates GI problems in the mouse model and also improves some of the main behavioral symptoms," Hsiao says. "This suggests that GI problems could contribute to particular symptoms in neurodevelopmental disorders."

With the help of clinical collaborators, the researchers are now planning a trial to test the probiotic treatment on the behavioral symptoms of human autism. The trial should begin within the next year or two, says Patterson.

"This probiotic treatment is postnatal, which means that the mother has already experienced the immune challenge, and, as a result, the growing fetuses have already started down a different developmental path," Patterson says. "In this study, we can provide a treatment after the offspring have been born that can help improve certain behaviors. I think that's a powerful part of the story."

The researchers stress that much work is still needed to develop an effective and reliable probiotic therapy for human autism—in part because there are both genetic and environmental contributions to the disorder, and because the immune-challenged mother in the mouse model reproduces only the environmental component.

"Autism is such a heterogeneous disorder that the ratio between genetic and environmental contributions could be different in each individual," Mazmanian says. "Even if B. fragilis ameliorates some of the symptoms associated with autism, I would be surprised if it's a universal therapy—it probably won't work for every single case."

The Caltech team proposes that particular beneficial bugs are intimately involved in regulating the release of metabolic products (or metabolites) from the gut into the bloodstream. Indeed, the researchers found that in the leaky intestinal wall of the autistic-like mice, certain metabolites that were modulated by microbes could both easily enter the circulation and affect particular behaviors.

"I think our results may someday transform the way people view possible causes and potential treatments for autism," Mazmanian says.

Along with Patterson, Hsiao, and Mazmanian, additional Caltech coauthors on the paper, "Microbiota Modulate Behavioral and Physiological Abnormalities Associated with Neurodevelopmental Disorders," are Sara McBride, Sophia Hsien, Gil Sharon, Julian A. Codelli, Janet Chow, and Sarah E. Reisman. The work was supported by a Caltech Innovation Initiative grant, an Autism Speaks Weatherstone Fellowship, a National Institutes of Health/National Research Service Award Ruth L. Kirschstein Predoctoral Fellowship, a Human Frontiers Science Program Fellowship, a Department Of Defense Graduate Fellowship, a National Science Foundation Graduate Research Fellowship, an Autism Speaks Trailblazer Award, a Caltech Grubstake award, a Congressionally Directed Medical Research Award, a Weston Havens Foundation Award, several Callie McGrath Charitable Foundation awards, and the National Institute of Mental Health.

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Chemical Transformations for Food and Fuel: An Interview with Jonas Peters

Many science disciplines are dedicated to investigating naturally occurring curiosities that have yet to be explained. However, in the laboratory of Jonas Peters, researchers must first create the curiosities they'll study—in the form of new chemical compounds and molecular configurations. Peters's research with the Joint Center for Artificial Photosynthesis (JCAP) at Caltech is focused on finding chemical compounds that can turn sunlight and water into fuel—much like the photosynthetic processes used by plants. In addition, his laboratory's interest in nitrogen fixation—a chemical transformation that, ultimately, enables the delivery of nitrogen to the molecules of life (DNA, RNA, proteins)—could one day influence how fertilizer is produced and is used to feed the world.

Peters received his bachelor's degree from the University of Chicago in 1993 and a doctorate from the Massachusetts Institute of Technology in 1998. He joined the Caltech faculty as an assistant professor of chemistry in 1999, became an associate professor in 2004, a professor in 2006, and the Bren Professor of Chemistry in 2010.

Recently, Peters spoke with us about his research, his childhood, and how a stint as a college football player contributed to his career as an academic.

What are your main research interests?

Our group is interested in the chemical transformations that are relevant to feeding and fueling the planet. There are two efforts on this campus in artificial photosynthesis, and I participate in both. One is the National Science Foundation–funded Center for Chemical Innovation in Solar Fuels (CCI Solar), which we call "powering the planet." Our work here is at the fundamental level of developing the science and the concepts for artificial photosynthesis. In JCAP, our emphasis is more on taking those concepts and applying them to, ultimately, make real prototype devices that would accomplish the goal of delivering liquid fuels via artificial photosynthesis.

What role does your work play in "fueling the planet"?

On the fueling-the-planet side of things, our group is interested in using protons and electrons derived from water for the production of fuel. That fuel could be hydrogen, generated by combining the protons and electrons, or a liquid fuel that instead can be made by adding the protons and electrons to carbon dioxide to make a carbon fuel source like methanol, for example. Our specific interest is in the design of metal complexes that have a high affinity for the substances like CO2—these metal complexes could then facilitate putting the CO2 through a desirable transformation instead of an undesirable one.

And how about "feeding the planet"?

To make fertilizer to feed the planet, you need to understand how to redirect those protons and electrons to other really important substances, like the element nitrogen. Industry currently does this using hydrogen and very high pressures and temperatures with a catalyst. And so another big interest in our group is trying to understand and also discover systems that mediate nitrogen fixation [the process by which some soil microorganisms turn nitrogen from the air into ammonia—an essential transformation for all life]. Elsewhere in our lab we are interested in catalyzing reactions that could be important to organic chemists—and ultimately the pharmaceutical industry. One such example is using copper and light to catalyze molecular-bond constructions.

What makes your research unique?

In all of our projects, we try to advance new concepts for catalysis, and to test these concepts. For us, it is the conceptual advance that is intellectually most exciting, rather than the longer-term possible applications. But on a day to day basis, we are also excited about making cool, fundamentally new types of molecules—ones that are just interesting in and of themselves—so that we characterize them and use them to ask interesting chemistry questions. So it's fair to say that while catalysis drives the problems we work on, we're also very interested in making new molecules that push the boundaries of what we know can be made, what we know cannot be made, and why. This has been the essence of chemistry as a discipline for a long time.

What excites you most about your research?

I think what I find most interesting is when my coworkers discover fundamentally new molecules, or an unexpected chemical transformation, that represents a whole new set of possibilities for us to think about and explore.

Something that distinguishes chemistry from a lot of other disciplines is that often chemists create—via the synthesis of new molecules—the problems that they then study. That's certainly true of my research. You can make molecules that are similar to other things you've made, but once in a while a student or a postdoc will come in with something that is fundamentally new and conceptually different, and these moments inspire a ton of ideas that can pave the way for literally years' worth of interesting work. Probably the most exciting moments for me are when students and postdocs open up brand new territory that sort of gets us past a logjam in thinking and instead swimming in an exciting new current.

Can you tell us a little bit about your background?

I grew up in Chicago. My parents have had a remarkably wide range of jobs through the years, but when I was a kid the most memorable was when we had a small diner in the city. I washed a lot of "glassware" there and helped out in various ways. I grew up in the city's North Side, went to Chicago Public Schools, and then went to the University of Chicago for college. So I actually didn't leave the city until I was 22. I played football in high school and for my freshman year in college, and I was really awful.

Ironically though, sports provided a means for me into higher education. I only applied to the University of Chicago because their football coach contacted me, which in retrospect was incredible, given just how bad at football I really was. Without that encouragement, I wouldn't have applied there, because I would have assumed that I wouldn't have been accepted on academic merit. In fact, the dean of admissions there eventually confided to me that I just barely was accepted into their college—just by the skin of my teeth.

What happened with your football career?

I fortunately had some injuries that helped me quit football after my first year, but around that time, I had started to get really excited about lab work. I was not very focused in high school—at least not to the extent that would be helpful if one is going to go the academic route in science—but I managed to clean up my act in college. In addition to getting really excited about what I was learning in my courses and also the lab, what probably made me focus on schoolwork in college more than anything else was the shocking sum of money I knew my parents were forking out for me to go to the University of Chicago. Guilt is powerfully motivating. It was not at all easy for them to pay those bills, but they were willing to do it and rarely complained. I was very lucky, and after a year or so that luck translated into innate interest and excitement about science, and chemistry in particular.

How did you get interested in chemistry?

That's an interesting story, because my first chemistry class in high school was a disaster. I was 15, and was too preoccupied with other things at the time. When I got to college and took the core chemistry classes, I discovered that I had an aptitude for them that I didn't realize I had. Once I realized that, I began to get a lot more confident and excited about chemistry. What drew me irreversibly into chemical research was linking up as an undergraduate with a wonderful research mentor who helped me realize how exciting research is, and what a wonderful community was there to embrace me if I just made the effort.

Do you have any interests outside of your research?

For a few years, I had a bit of a baseball career here in L.A. I was a member of two teams in the Los Angeles Baseball League called the Mudskippers and the Christmas Bail Bonds Cardinals. I'm on temporary retirement until my son finishes his baseball years, but I fully expect to return as a player/manager some day; right now, I'm coaching my son's T-ball team. I really enjoy gardening; that's probably one of my favorite things to do day to day, in addition to going for runs in the area.

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