Arnold Appointed New Director of Rosen Bioengineering Center

Now in its sixth year of exploring the intersection between biology and engineering, the Donna and Benjamin M. Rosen Bioengineering Center has chosen Caltech professor Frances Arnold as its new director. Arnold, the Dick and Barbara Dickinson Professor of Chemical Engineering, Bioengineering and Biochemistry began her tenure as director on June 1.

A recipient of the 2011 National Medal of Technology and Innovation, Arnold pioneered methods of "directed evolution" – processes now widely used to create biological catalysts that are important in the production of fuels from renewable resources. She was selected for the directorship because "of her demonstrated leadership in the field of bioengineering," says Stephen Mayo, William K. Bowes Jr. Foundation Chair of the Division of Biology and Biological Engineering.

The Rosen Center supports bioengineering research through the funding of fellows and faculty from many disciplines, including applied physics, chemical engineering, synthetic biology, and computer science.

"Bioengineering is an incredibly exciting field right now," Arnold says. "Solutions to some of the biggest problems in science, medicine, and sustainability will come from the interface between biology and engineering, and Caltech is well positioned to be at the forefront. The Rosen Center will help make that happen with innovative programs for bioengineering research and education."

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A Secret to Making Macrophages

Caltech researchers find a key in cell-cycle duration

Biologists at the California Institute of Technology (Caltech) have worked out the details of a mechanism that leads undifferentiated blood stem cells to become macrophages—immune cells that attack bacteria and other foreign pathogens. The process involves an unexpected cycle in which cell division slows, leading to an increased accumulation of a particular regulatory protein that in turn slows cell division further. The finding provides new insight into how stem cells are guided to generate one cell type as opposed to another.

Previous research has shown that different levels of a key regulatory protein called PU.1, which is involved in the new cycle, are important for the production of at least four different kinds of differentiated blood cells. For example, levels of PU.1 need to increase in order for macrophages to form, but must decrease during the development of another type of white blood cell known as the B cell. Precisely how such PU.1-level changes occur and are maintained in the cells has been unclear. But by observing differentiation in both macrophages and B cells, the Caltech team discovered something unusual in the feedback loop that produces macrophages. Their findings appear in the current issue of Science Express.

"Our results explain how blood stem cells and related progenitor cells can differentiate into macrophages and slow down their cell cycle, coordinating these two processes at the same time," says lead author Hao Yuan Kueh, a postdoctoral scholar at Caltech who works with biologists Michael Elowitz and Ellen Rothenberg, who were both principal investigators on the study. "We are excited about this because it means other systems could also use this mechanism to coordinate cell proliferation with differentiation."

In the study, the researchers captured movies of blood stem cells taken from transgenic mice. The cells expressed a green fluorescent protein that serves as an indicator of PU.1 levels in the cell: the brighter the cells appeared in the movies, the more PU.1 was present. By measuring PU.1 levels over time using this indicator, the scientists were able to monitor changes in the rate of PU.1's synthesis.

PU.1 can work through a positive feedback loop, binding to its own DNA regulatory sequence to stimulate its own production in a self-reinforcing manner. This type of loop is thought to be a general mechanism that allows a stem cell to switch into a differentiated state. In the case of PU.1, the process cranks up to produce macrophages, for example, and turns down to produce B cells.

And, indeed, when the researchers looked at B cell development, they saw what they expected: developing B cells decreased PU.1 levels by putting the brakes on the production of the protein.

The surprise came when they observed macrophages. Although the amount of PU.1 in the cells increased when the stem cells became macrophages, the researchers saw no change in the rate of PU.1 synthesis.

So where was the increase coming from? Upon investigation, the researchers observed that cells increased their PU.1 levels simply by slowing down their rate of division. With fewer cells being produced as the rate of PU.1 production marched steadily on, higher levels of the PU.1 protein were able to accumulate in the cells. Indeed, by slowing down the cell cycle, the researchers found that they could raise PU.1 levels enough to prompt the generation of macrophages. This result suggested that a different type of positive feedback loop might be responsible for the decisive final increase in PU.1 levels during macrophage differentiation.

"This work shows the amazing power of movies of individual cells in deciphering the dynamics of gene circuits," says Elowitz, who is a professor of biology and bioengineering at Caltech and an investigator with the Howard Hughes Medical Institute. "Just by following how the amount of PU.1 protein changed over time in a single cell, one can see directly that cells use a very different kind of feedback architecture than we usually associate with cellular differentiation."

Time-lapse movie of blood progenitor cells dividing and differentiating in culture. The brightness of green fluorescence indicates the amount of the regulatory protein PU.1 present in each cell. Green fluorescence images are acquired at a lower frame rate compared to the gray bright-field images of the cells. Time is given in hours.

To test what kind of positive feedback loop might control these events, the researchers forced cells to express extra PU.1, and measured its effect on the cells' own PU.1. They found that the extra PU.1 did not boost the cell's own PU.1 synthesis rate any further, but instead slowed the rate of cell division, causing PU.1 to accumulate to higher levels in the cells—an effect that slowed the cell cycle further.

"The key to this mechanism is that PU.1 is a very stable protein," says Rothenberg, the Albert Billings Ruddock Professor of Biology at Caltech. "Its central role in blood cell development has come from the fact that it collaborates with different regulatory protein partners to guide stem cells to make different cell types. We've known for some time that the exact ratios between PU.1 and its partners are important in these decisions, but it has been hard to see how the cells can manage to control the balance between so many of these different regulators with such precision. The beauty of this mechanism is that this ratio can be controlled simply by altering cell-cycle length. This shows us a new tool that factors like PU.1 and its collaborators can use to guide stem cells into precise developmental paths."

The team also used mathematical modeling to test the properties of a feedback loop that relies on the length of the cell cycle. They were able to show that a system that incorporated both the new loop and the PU.1-production feedback loop was able to account for three distinct levels of PU.1—one corresponding to B cells, one to progenitor cells, and one to macrophages.

"That was a proof-of-principle that this type of architecture can work," Kueh says. "The modeling will also help us to generate predictions for future studies."

In addition to Kueh, Elowitz, and Rothenberg, the paper, titled "Positive feedback between PU.1 and the cell cycle controls myeloid differentiation," is also coauthored by Ameya Champhekar, a postdoctoral scholar at Caltech, and Stephen Nutt, head of the Division of Molecular Immunology at the Walter and Eliza Hall Institute of Medical Research in Parkville, Victoria, Australia. The work was supported by a CRI Irvington Postdoctoral Fellowship, an Australian Research Council Future Fellowship, the Victorian State Government Operational Infrastructure Support, the National Health and Medical Research Council of Australia, the National Institutes of Health, the Albert Billings Ruddock Professorship, the Al Sherman Foundation, and the Louis A. Garfinkle Memorial Laboratory Fund.

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Thursday, September 26, 2013
Ramo Auditorium

Graduate TA Orientation & Teaching Conference

New Research Sheds Light on M.O. of Unusual RNA Molecules

The genes that code for proteins—more than 20,000 in total—make up only about 1 percent of the complete human genome. That entire thing—not just the genes, but also genetic junk and all the rest—is coiled and folded up in any number of ways within the nucleus of each of our cells. Think, then, of the challenge that a protein or other molecule, like RNA, faces when searching through that material to locate a target gene.

Now a team of researchers led by newly arrived biologist Mitchell Guttman of the California Institute of Technology (Caltech) and Kathrin Plath of UCLA, has figured out how some RNA molecules take advantage of their position within the three-dimensional mishmash of genomic material to home in on targets. The research appears in the current issue of Science Express.

The findings suggest a unique role for a class of RNAs, called lncRNAs, which Guttman and his colleagues at the Broad Institute of MIT and Harvard first characterized in 2009. Until then, these lncRNAs—short for long, noncoding RNAs and pronounced "link RNAs"—had been largely overlooked because they lie in between the genes that code for proteins. Guttman and others have since shown that lncRNAs scaffold, or bring together and organize, key proteins involved in the packaging of genetic information to regulate gene expression—controlling cell fate in some stem cells, for example.

In the new work, the researchers found that lncRNAs can easily locate and bind to nearby genes. Then, with the help of proteins that reorganize genetic material, the molecules can pull in additional related genes and move to new sites, building up a "compartment" where many genes can be regulated all at once.

"You can now think about these lncRNAs as a way to bring together genes that are needed for common function into a single physical region and then regulate them as a set, rather than individually," Guttman says. "They are not just scaffolds of proteins but actual organizers of genes."

The new work focused on Xist, a lncRNA molecule that has long been known to be involved in turning off one of the two X chromosomes in female mammals (something that must happen in order for the genome to function properly). Quite a bit has been uncovered about how Xist achieves this silencing act. We know, for example, that it binds to the X chromosome; that it recruits a chromatin regulator to help it organize and modify the structure of the chromatin; and that certain distinct regions of the RNA are necessary to do all of this work. Despite this knowledge, it had been unknown at the molecular level how Xist actually finds its targets and spreads across the X chromosome.

To gain insight into that process, Guttman and his colleagues at the Broad Institute developed a method called RNA Antisense Purification (RAP) that, by sequencing DNA at high resolution, gave them a way to map out exactly where different lncRNAs go. Then, working with Plath's group at UCLA, they used their method to watch in high resolution as Xist was activated in undifferentiated mouse stem cells, and the process of X-chromosome silencing proceeded.

"That's where this got really surprising," Guttman says. "It wasn't that somehow this RNA just went everywhere, searching for its target. There was some method to its madness. It was clear that this RNA actually used its positional information to find things that were very far away from it in genome space, but all of those genes that it went to were really close to it in three-dimensional space."

Before Xist is activated, X-chromosome genes are all spread out. But, the researchers found, once Xist is turned on, it quickly pulls in genes, forming a cloud. "And it's not just that the expression levels of Xist get higher and higher," Guttman says. "It's that Xist brings in all of these related genes into a physical nuclear structure. All of these genes then occupy a single territory."

The researchers found that a specific region of Xist, known as the A-repeat domain, that is known to be vital for the lncRNA's ability to silence X-chromosome genes is also needed to pull in all the genes that it needs to silence. When the researchers deleted the domain, the X chromosome did not become inactivated, because the silencing compartment did not form.

One of the most exciting aspects of the new research, Guttman says, is that it has implications beyond just explaining how Xist works. "In our paper, we talk a lot about Xist, but these results are likely to be general to other lncRNAs," he says. He adds that the work provides one of the first direct pieces of evidence to explain what makes lncRNAs special. "LncRNAs, unlike proteins, really can use their genomic information—their context, their location—to act, to bring together targets," he says. "That makes them quite unique."  

The new paper is titled "The Xist lncRNA exploits three-dimensional genome architecture to spread across the X-chromosome." Along with Guttman and Plath, additional coauthors are Jesse M. Engreitz, Patrick McDonel, Alexander Shishkin, Klara Sirokman, Christine Surka, Sabah Kadri, Jeffrey Xing, Along Goren, and Eric Lander of the Broad Institute of Harvard and MIT; as well as Amy Pandya-Jones of UCLA. The work was funded by an NIH Director's Early Independence Award, the National Human Genome Research Institute Centers of Excellence in Genomic Sciences, the California Institute for Regenerative Medicine, and funds from the Broad Institute and from UCLA's Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research. 

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Kimm Fesenmaier
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Biology Commencement 2013

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Julie Boucher
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Caltech Seniors Receive Fulbright Fellowships

Three graduating Caltech seniors, Alex Wang, Joy Xie, and Philip Kong, have been selected to receive 2013–2014 Fulbright scholarships to pursue graduate studies abroad.

The Fulbright Program is the U.S. government's premier scholarship program. Set up by Congress in 1946 to foster mutual understanding among nations through educational and cultural exchanges, Fulbright grants enable U.S. students and artists to benefit from unique resources in every corner of the world. Each year more than 800 Americans study or conduct research in more than 140 nations through the Fulbright Program.

"It was a pleasure to work with these students," says Lauren Stolper, director of Fellowships Advising and Study Abroad and Caltech's Fulbright Program advisor. "They each had a well-thought-out research idea based at a host university abroad that will provide the resources and supervision needed to ensure a successful outcome. Our Fulbright Scholars are excellent representatives for the Institute as well as for the U.S.—and part of their role as a Fulbright Scholar is an ambassadorial one."

 

Chemical engineering major Alex Wang, from Dallas, Texas, will be spending a year at Imperial College London in the laboratory of professor Molly Stevens, who specializes in biomedical materials and their application to regenerative medicine. "My topic of study will be how the external stem-cell environment may be able to influence stem-cell behavior and differentiation," Wang says. In particular, he says, "I would be looking at the influence of the protein laminin on differentiation within an artificial hydrogel scaffold. This way, we can look at how these cells can potentially be better controlled in vitro. I chose this topic due to its potential applications in medicine, as well as the opportunity to apply the engineering principles I have learned at Caltech.

"I always wanted to see the UK and experience a brand new culture for an extended period of time. I have never been to Europe," he adds, "so this should be a very eye-opening experience. I am very thankful that Fulbright has given me this honor."

Upon his return, Wang will attend graduate school at MIT, studying biological engineering.

 

Joy Xie, a chemical engineering major from Troy, Michigan, will travel to Switzerland for a research project in bioengineering and protein chemistry, working with Jeffrey Hubbell at the École Polytechnique Fédérale de Lausanne.

"Hubbell has done some very translational work in tissue engineering and drug delivery," Xie explains. The goal of her project is to create protein therapeutics that can be used to induce immune tolerance to certain antigens, such as self-antigens, to help treat autoimmune diseases. "I picked this project because I have always been interested in medicine and how it is possible to combine knowledge from several different fields to create something that has the potential to be used in the medical industry," she says.

"Switzerland seems like an incredibly scenic and exciting place, and I have always wanted to visit it," adds Xie, who will attend Northwestern University to study chemical and biological engineering upon her return to the States. "I'm really grateful for this opportunity and excited to be able to be abroad!"

 

Philip Kong, a biology major from Philadelphia, will be headed this summer to Seoul National University in South Korea to work with professor Sunyoung Kim. Kong, who has been doing immunology research in David Baltimore's lab for the past two years, will be studying how to identify medically meaningful bioactive compounds used in Korea's traditional botanical medicines, with a particular emphasis on screening for activities that control the Th1 and Th2 pathways of the human immune system. Various immune diseases, such as rheumatoid arthritis and allergic diseases, will be considered in the work. "I wanted to try a different type of research than my undergraduate research had been. My new project gives me more opportunity to gain access to patient samples and have more immediate impact when it comes to treating autoimmune diseases like rheumatoid arthritis," says Kong, who plans to go to medical school to pursue an MD/PhD after his year abroad.

"There are many reasons why I wanted to go to Korea," he says, "but the main reason had to do with my project, which involves data from herbal medicine. South Korea is one of the two or three places where the practice of botanical medicine has a rich database regarding botanical medicines, including literature hundreds of years old with lists of plants and their clinical effects and safety profiles. In addition, only specific plants grow in South Korea due to the unique climate of the peninsula."

The Fulbright Program, Kong says, is an "exciting opportunity, and I feel that everyone at Caltech at least deserves a chance to study abroad and enjoy the new air of a different country. Any future Fulbright applicants should not hesitate to contact me if they would like to know more about the program."

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Kathy Svitil
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Beauty and the Brain: Electrical Stimulation of the Brain Makes You Perceive Faces as More Attractive

Findings may lead to promising ways to treat and study neuropsychiatric disorders

Beauty is in the eye of the beholder, and—as researchers have now shown—in the brain as well.

The researchers, led by scientists at the California Institute of Technology (Caltech), have used a well-known, noninvasive technique to electrically stimulate a specific region deep inside the brain previously thought to be inaccessible. The stimulation, the scientists say, caused volunteers to judge faces as more attractive than before their brains were stimulated.

Being able to effect such behavioral changes means that this electrical stimulation tool could be used to noninvasively manipulate deep regions of the brain—and, therefore, that it could serve as a new approach to study and treat a variety of deep-brain neuropsychiatric disorders, such as Parkinson's disease and schizophrenia, the researchers say.

"This is very exciting because the primary means of inducing these kinds of deep-brain changes to date has been by administering drug treatments," says Vikram Chib, a postdoctoral scholar who led the study, which is being published in the June 11 issue of the journal Translational Psychiatry. "But the problem with drugs is that they're not location-specific—they act on the entire brain." Thus, drugs may carry unwanted side effects or, occasionally, won't work for certain patients—who then may need invasive treatments involving the implantation of electrodes into the brain.

So Chib and his colleagues turned to a technique called transcranial direct-current stimulation (tDCS), which, Chib notes, is cheap, simple, and safe. In this method, an anode and a cathode are placed at two different locations on the scalp. A weak electrical current—which can be powered by a nine-volt battery—runs from the cathode, through the brain, and to the anode. The electrical current is a mere 2 milliamps—10,000 times less than the 20 amps typically available from wall sockets. "All you feel is a little bit of tingling, and some people don't even feel that," he says.

"There have been many studies employing tDCS to affect behavior or change local neural activity," says Shinsuke Shimojo, the Gertrude Baltimore Professor of Experimental Psychology and a coauthor of the paper. For example, the technique has been used to treat depression and to help stroke patients rehabilitate their motor skills. "However, to our knowledge, virtually none of the previous studies actually examined and correlated both behavior and neural activity," he says. These studies also targeted the surface areas of the brain—not much more than a centimeter deep—which were thought to be the physical limit of how far tDCS could reach, Chib adds.

The researchers hypothesized that they could exploit known neural connections and use tDCS to stimulate deeper regions of the brain. In particular, they wanted to access the ventral midbrain—the center of the brain's reward-processing network, and about as deep as you can go. It is thought to be the source of dopamine, a chemical whose deficiency has been linked to many neuropsychiatric disorders.

The ventral midbrain is part of a neural circuit that includes the dorsolateral prefrontal cortex (DLPFC), which is located just above the temples, and the ventromedial prefrontal cortex (VMPFC), which is behind the forehead. Decreasing activity in the DLPFC boosts activity in the VMPFC, which in turn bumps up activity in the ventral midbrain. To manipulate the ventral midbrain, therefore, the researchers decided to try using tDCS to deactivate the DLPFC and activate the VMPFC.

To test their hypothesis, the researchers asked volunteers to judge the attractiveness of groups of faces both before and after the volunteers' brains had been stimulated with tDCS. Judging facial attractiveness is one of the simplest, most primal tasks that can activate the brain's reward network, and difficulty in evaluating faces and recognizing facial emotions is a common symptom of neuropsychiatric disorders. The study participants rated the faces while inside a functional magnetic resonance imaging (fMRI) scanner, which allowed the researchers to evaluate any changes in brain activity caused by the stimulation.

A total of 99 volunteers participated in the tDCS experiment and were divided into six stimulation groups. In the main stimulation group, composed of 19 subjects, the DLPFC was deactivated and the VMPFC activated with a stimulation configuration that the researchers theorized would ultimately activate the ventral midbrain. The other groups were used to test different stimulation configurations. For example, in one group, the placement of the cathode and anode were switched so that the DLPFC was activated and the VMPFC was deactivated—the opposite of the main group. Another was a "sham" group, in which the electrodes were placed on volunteers' heads, but no current was run.

Those in the main group rated the faces presented after stimulation as more attractive than those they saw before stimulation. There were no differences in the ratings from the control groups. This change in ratings in the main group suggests that tDCS is indeed able to activate the ventral midbrain, and that the resulting changes in brain activity in this deep-brain region are associated with changes in the evaluation of attractiveness.

In addition, the fMRI scans revealed that tDCS strengthened the correlation between VMPFC activity and ventral midbrain activity. In other words, stimulation appeared to enhance the neural connectivity between the two brain areas. And for those who showed the strongest connectivity, tDCS led to the biggest change in attractiveness ratings. Taken together, the researchers say these results show that tDCS is causing those shifts in perception by manipulating the ventral midbrain via the DLPFC and VMPFC.

"The fact that we haven't had a way to noninvasively manipulate a functional circuit in the brain has been a fundamental bottleneck in human behavioral neuroscience," Shimojo says. This new work, he adds, represents a big first step in removing that bottleneck.

Using tDCS to study and treat neuropsychiatric disorders hinges on the assumption that the technique directly influences dopamine production in the ventral midbrain, Chib explains. But because fMRI can't directly measure dopamine, this study was unable to make that determination. The next step, then, is to use methods that can—such as positron emission tomography (PET) scans.

More work also needs to be done to see how tDCS may be used for treating disorders and to precisely determine the duration of the stimulation effects—as a rule of thumb, the influence of tDCS lasts for twice the exposure time, Chib says. Future studies will also be needed to see what other behaviors this tDCS method can influence. Ultimately, clinical tests will be needed for medical applications.

In addition to Chib and Shimojo, the other authors of the paper are Kyongsik Yun, a former postdoctoral scholar at Caltech who is now at the Korea Advanced Institute of Science and Technology (KAIST), and Hidehiko Takahashi of the Kyoto University Graduate School of Medicine. The title of the Translational Psychiatry paper is "Noninvasive remote activation of the ventral midbrain by transcranial direct current stimulation of prefrontal cortex." This work was funded by the Exploratory Research for Advanced Technology (ERATO) and CREST programs of the Japan Science and Technology Agency (JST); the Caltech-Tamagawa gCOE (Global Center of Excellence) program; and a Japan-U.S. Brain Research Cooperative Program grant.

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Keeping Stem Cells Strong

Caltech biologists show that an RNA molecule protects stem cells during inflammation

When infections occur in the body, stem cells in the blood often jump into action by multiplying and differentiating into mature immune cells that can fight off illness. But repeated infections and inflammation can deplete these cell populations, potentially leading to the development of serious blood conditions such as cancer. Now, a team of researchers led by biologists at the California Institute of Technology (Caltech) has found that, in mouse models, the molecule microRNA-146a (miR-146a) acts as a critical regulator and protector of blood-forming stem cells (called hematopoietic stem cells, or HSCs) during chronic inflammation, suggesting that a deficiency of miR-146a may be one important cause of blood cancers and bone marrow failure.

The team came to this conclusion by developing a mouse model that lacks miR-146a. RNA is a polymer structured like DNA, the chemical that makes up our genes. MicroRNAs, as the name implies, are a class of very short RNAs that can interfere with or regulate the activities of particular genes. When subjected to a state of chronic inflammation, mice lacking miR-146a showed a decline in the overall number and quality of their HSCs; normal mice producing the molecule, in contrast, were better able to maintain their levels of HSCs despite long-term inflammation. The researchers' findings are outlined in the May 21 issue of the new journal eLIFE.

"This mouse with genetic deletion of miR-146a is a wonderful model with which to understand chronic-inflammation-driven tumor formation and hematopoietic stem cell biology during chronic inflammation," says Jimmy Zhao, the lead author of the study and an MD/PhD student in the Caltech laboratory of David Baltimore, the Robert Andrews Millikan Professor of Biology. "It was surprising that a single microRNA plays such a crucial role. Deleting it produced a profound and dramatic pathology, which clearly highlights the critical and indispensable function of miR-146a in guarding the quality and longevity of HSCs."

The study findings provide, for the first time, a detailed molecular connection between chronic inflammation, and bone marrow failure and diseases of the blood. These findings could lead to the discovery and development of anti-inflammatory molecules that could be used as therapeutics for blood diseases. In fact, the researchers believe that miR-146a itself may ultimately become a very effective anti-inflammatory molecule, once RNA molecules or mimetics can be delivered more efficiently to the cells of interest.

The new mouse model, Zhao says, also mimics important aspects of human myelodysplastic syndrome (MDS)—a form of pre-leukemia that often causes severe anemia, can require frequent blood transfusions, and usually leads to acute myeloid leukemia. Further study of the model could lead to a better understanding of the condition and therefore potential new treatments for MDS.

"This study speaks to the importance of keeping chronic inflammation in check and provides a good rationale for broad use of safer and more effective anti-inflammatory molecules," says Baltimore, who is a coauthor of the study. "If we can understand what cell types and proteins are critically important in chronic-inflammation-driven tumor formation and stem cell exhaustion, we can potentially design better and safer drugs to intervene."

Funding for the research outlined in the eLIFE paper, titled "MicroRNA-146a acts as a guardian of the quality and longevity of hematopoietic stem cells in mice," was provided by the National Institute of Allergy and Infectious Disease; the National Heart, Lung, and Blood Institute; and the National Cancer Institute. Yvette Garcia-Flores, the lead technician in Baltimore's lab, also contributed to the study along with Dinesh Rao from UCLA and Ryan O'Connell from the University of Utah. eLIFE, a new open-access, high-impact journal, is backed by three of the world's leading funding agencies, the Howard Hughes Medical Institute, the Max Planck Society, and the Wellcome Trust. 

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Katie Neith
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Fifty Years of Clearing the Skies

A Milestone in Environmental Science

Ringed by mountains and capped by a temperature inversion that traps bad air, Los Angeles has had bouts of smog since the turn of the 20th century. An outbreak in 1903 rendered the skies so dark that many people mistook it for a solar eclipse. Angelenos might now be living in a state of perpetual midnight—assuming we could live here at all—were it not for the work of Caltech Professor of Bio-organic Chemistry Arie Jan Haagen-Smit. How he did it is told here largely in his own words, excerpted from Caltech's Engineering & Science magazine between 1950 and 1962. (See "Related Links" for the original articles.)

Old timers, which in California means people who have lived here some 25 years, will remember the invigorating atmosphere of Los Angeles, the wonderful view of the mountains, and the towns surrounded by orange groves. Although there were some badly polluted industrial areas, it was possible to ignore them and live in more pleasant locations, especially the valleys . . . Just 20 years ago, the community was disagreeably surprised when the atmosphere was filled with a foreign substance that produced a strong irritation of the eyes. Fortunately, this was a passing interlude which ended with the closing up of a wartime synthetic rubber plant. (November 1962)

Alas, the "interlude" was an illusion. In the years following World War II, visibility often fell to a few blocks. The watery-eyed citizenry established the Los Angeles County Air Pollution Control District (LACAPCD) in 1947, the first such body in the nation. The obvious culprits—smoke-belching power plants, oil refineries, steel mills, and the like—were quickly regulated, yet the problem persisted. Worse, this smog was fundamentally different from air pollution elsewhere—the yellow, sulfur-dioxide-laced smog that killed 20 people in the Pennsylvania steel town of Donora in 1948, for example, or London's infamous pitch-black "pea-soupers," where the burning of low-grade, sulfur-rich coal added soot to the SO2. (The Great Smog of 1952 would carry off some 4,000 souls in four days.) By contrast, L.A.'s smog was brown and had an acrid odor all its own.

Haagen-Smit had honed his detective skills isolating and identifying the trace compounds responsible for the flavors of pineapples and fine wines, and in 1948 he began to turn his attention to smog.

Chemically, the most characteristic aspect of smog is its strong oxidizing action . . . The amount of oxidant can readily be determined through a quantitative measurement of iodine liberated from potassium iodide solution, or of the red color formed in the oxidation of phenolphthalin to the well-known acid-base indicator, phenolphthalein. To demonstrate these effects, it is only necessary to bubble a few liters of smog air through the colorless solutions. (December 1954)

His chief suspect was ozone, a highly reactive form of oxygen widely used as a bleach and a disinfectant. It's easy to make—a spark will suffice—and it's responsible for that crisp "blue" odor produced by an overloaded electric motor. But there was a problem:

During severe smog attacks, ozone concentrations of 0.5 ppm [parts per million], twenty times higher than in [clean] country air, have been measured. From such analyses the quantity of ozone present in the [Los Angeles] basin at that time is calculated to be about 500 tons.

Since ozone is subject to a continuous destruction in competition with its formation, we can estimate that several thousand tons of ozone are formed during a smog day. It is obvious that industrial sources or occasional electrical discharges do not release such tremendous quantities of ozone. (December 1954)

If ozone really was to blame, where was it coming from? An extraordinary challenge lay ahead:

The analysis of air contaminants has some special features, due to the minute amounts present in a large volume of air. The state in which these pollutants are present—as gases, liquids and solid particles of greatly different sizes—presents additional difficulties. The small particles of less than one micron diameter do not settle out, but are in a stable suspension and form so-called aerosols.

The analytical chemist has devoted a great deal of effort to devising methods for the collection of this heterogeneous material. Most of these methods are based on the principle that the particles are given enough speed to collide with each other or with collecting surfaces . . . A sample of Los Angeles' air shows numerous oily droplets of a size smaller than 0.5 micron, as well as crystalline deposits of metals and salts . . . When air is passed through a filter paper, the paper takes on a grey appearance, and extraction with organic solvents gives an oily material. (December 1950)

Haagen-Smit suspected that this oily material, a complex brew of organic acids and other partially oxidized hydrocarbons, was smog's secret ingredient. In 1950, he took a one-year leave of absence from Caltech to prove it, working full-time in a specially equipped lab set up for him by the LACAPCD. By the end of the year, he had done so.

Through investigations initiated at Caltech, we know that the main source of this smog is due to the release of two types of material. One is organic material—mostly hydrocarbons from gasoline—and the other is a mixture of oxides of nitrogen. Each one of these emissions by itself would be hardly noticed. However, in the presence of sunlight, a reaction occurs, resulting in products which give rise to the typical smog symptoms. The photochemical oxidation is initiated by the dissociation of NO2 into NO and atomic oxygen. This reactive oxygen attacks organic material, resulting in the formation of ozone and various oxidation products . . . The oxidation reactions are generally accompanied by haze or aerosol formation, and this combination aggravates the nuisance effects of the individual components of the smog complex. (November 1962)

Professor of Plant Physiology Frits Went was also on the case. Went ran Caltech's Earhart Plant Research Laboratory, which he proudly called the "phytotron," by analogy to the various "trons" operated by particle physicists. (Phyton is the Greek word for plant.) "Caltech's plant physiologists happen to believe that the phytotron is as marvellously complicated as any of the highly-touted 'atom-smashing' machines," Went wrote in E&S in 1949. "[It] is the first laboratory in the world in which plants can be grown under every possible climatic condition. Light, temperature, humidity, gas content of the air, wind, rain, and fog—all these factors can be simultaneously and independently controlled. The laboratory can create Sacramento Valley climate in one room and New England climate in another." Most of Los Angeles was still orchards and fields instead of tract houses, and the smog was hurting the produce. Went, the LACAPCD, and the UC Riverside agricultural station tested five particularly sensitive crops in the phytotron, Haagen-Smit wrote.

The smog indicator plants include spinach, sugar beet, endive, alfalfa and oats. The symptoms on the first three species are mainly silvering or bronzing of the underside of the leaf, whereas alfalfa and oats show bleaching effects. Some fifty compounds possibly present in the air were tested on their ability to cause smog damage—without success. However, when the reaction products of ozone with unsaturated hydrocarbons were tried, typical smog damage resulted. (December 1950)

And yet a third set of experiments was under way. Rubber tires were rotting from the smog at an alarming rate, cracking as they flexed while rolling along the road. Charles E. Bradley, a research associate in biology, turned this distressing development into a cheap and effective analytical tool by cutting rubber bands by the boxful into short segments. The segments—folded double, secured with a twist of wire, and set outside—would start to fall apart almost before one could close the window. "During severe smog initial cracking appears in about four minutes, as compared to an hour or more required on smog-free days, or at night," Haagen-Smit wrote in the December 1954 E&S.

The conclusion that airborne gasoline and nitrogen oxides (another chief constituent of automobile exhaust) were to blame for smog was not well received by the oil refineries, who hired their own expert to prove him wrong. Abe Zarem (MS '40, PhD '44), the manager and chairman of physics research for the Stanford Research Institute, opined that stratospheric ozone seeping down through the inversion layer was to blame. But seeing (or smelling) is believing, so Haagen-Smit fought back by giving public lectures in which he would whip up flasks full of artificial smog before the audience's eyes, which would soon be watering—especially if they were seated in the first few rows. By the end of his talk, the smog would fill the hall, and he became known throughout the Southland as Arie Haagen-Smog.

By 1954, he and Frits Went had carried the day.

[Plant] fumigations with the photochemical oxidation products of gasoline and nitrogen dioxide (NO2) was the basis of one of the most convincing arguments for the control of hydrocarbons by the oil industry. (December 1954)

It probably didn't hurt that an outbreak that October closed schools and shuttered factories for most of the month, and that angry voters were wearing gas masks to protest meetings. By then, there were some two million cars on the road in the metropolitan area, spewing a thousand tons of hydrocarbons daily.

Incomplete combustion of gasoline allows unburned and partially burned fuel to escape from the tailpipe. Seepage of gasoline, even in new cars, past piston rings into the crankcase, is responsible for 'blowby' or crankcase vent losses. Evaporation from carburetor and fuel tank are substantial contributions, especially on hot days. (November 1962)

Haagen-Smit was a founding member of California's Motor Vehicle Pollution Control Board, established in 1960. One of the board's first projects was testing positive crankcase ventilation (PCV) systems, which sucked the blown-by hydrocarbons out of the crankcase and recirculated them through the engine to be burned on the second pass. PCV systems were mandated on all new cars sold in California as of 1963. The blowby problem was thus easily solved—but, as Haagen-Smit noted in that same article, it was only the second-largest source, representing about 30 percent of the escaping hydrocarbons.

The preferred method of control of the tailpipe hydrocarbon emission is a better combustion in the engine itself. (The automobile industry has predicted the appearance of more efficiently burning engines in 1965. It is not known how efficient these will be, nor has it been revealed whether there will be an increase or decrease of oxides of nitrogen.) Other approaches to the control of the tailpipe gases involve completing the combustion in muffler-type afterburners. One type relies on the ignition of gases with a sparkplug or pilot-burner; the second type passes the gases through a catalyst bed which burns the gases at a lower temperature than is possible with the direct-flame burners. (November 1962)

Installing an afterburner in the muffler has some drawbacks, not the least of which is that the notion of tooling around town with an open flame under the floorboards might give some people the willies. Instead, catalytic converters became required equipment on California cars in 1975.

In 1968, the Motor Vehicle Pollution Control Board became the California Air Resources Board, with Haagen-Smit as its chair. He was a member of the 1969 President's Task Force on Air Pollution, and the standards he helped those two bodies develop would eventually be adopted by the Environmental Protection Agency, established in 1970—the year that also saw the first celebration of Earth Day. It was also the year when ozone levels in the Los Angeles basin peaked at 0.58 parts per million, nearly five times in excess of the 0.12 parts per million that the EPA would declare to be safe for human health. This reading even exceeded the 0.5 ppm that Haagen-Smit had measured back in 1954, but it was a triumph nonetheless—the number of cars in L.A. had doubled, yet the smog was little worse than it had always been. That was the year we turned the corner, in fact, and our ozone levels have been dropping ever since—despite the continued influx of cars and people to the region.

Haagen-Smit retired from Caltech in 1971 as the skies began to clear, but continued to lead the fight for clean air until his death in 1977—of lung cancer, ironically, after a lifetime of cigarettes. Today, his intellectual heirs, including professors Richard Flagan, Mitchio Okumura, John Seinfeld, and Paul Wennberg, use analytical instruments descended from ones Haagen-Smit would have recognized and computer models sophisticated beyond his wildest dreams to carry the torch—a clean-burning one, of course—forward.

Writer: 
Douglas Smith
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Caltech Senior Wins Gates Cambridge Scholarship

Catherine Bingchan Xie, a senior bioengineering major and English minor at Caltech, has been selected to receive a Gates Cambridge Scholarship, which will fund her graduate studies at the University of Cambridge for the next academic year. Xie, a Canadian citizen, is one of 51 new international recipients selected from a pool of more than 4,000 applicants based not only on intellectual ability, but also on leadership capacity and a commitment to improving the lives of others.

As a Gates Cambridge Scholar, Xie, 20, will pursue a Master of Philosophy in translational medicine and therapeutics. "The research program and the knowledge that I'm going to gain will provide me with an essential foundation for becoming a physician-scientist, translating research findings in the lab into revolutionary therapies," she says. "I'm really excited to join the Gates Cambridge community and be surrounded by people like me who want to make an impact on other people by taking on important roles and issues in society. I think the energy and enthusiasm of rising toward this common goal will be really invigorating."

Having lived in China, Australia, Canada, and the United States, Xie has been exposed to a variety of cultures—something that she says motivated her to want to become a highly involved leader in a diverse and multicultural society.

As an undergraduate student, Xie has taken full advantage of opportunities to pursue research projects in the laboratory with outstanding scientists. During her freshman year, she began working in the lab of Frances Arnold, the Dick and Barbara Dickinson Professor of Chemical Engineering, Bioengineering and Biochemistry, engineering ways to improve the thermostability of enzymes used to make biofuels. The summer following her sophomore year, Xie joined the lab of C. Garrison Fathman, professor of medicine and chief of the Division of Immunology and Rheumatology at the Stanford School of Medicine, to study a novel transcription factor regulator involved in the pathogenesis of Type I diabetes. When she returned to Caltech, she immediately joined the lab of David Baltimore, the Robert Andrews Millikan Professor of Biology, where she is currently working. There, her research focuses on microRNAs—tiny snippets of RNA that are only about 20 nucleotides long—and the regulatory role they play in the development of leukemia. 

"Catherine is a student with broad interests, an engaging personal style, and great effectiveness," Baltimore says. "She has been a pleasure to have in the laboratory, and I am not surprised that she has won this prestigious scholarship and chosen to broaden her knowledge by focusing on public health issues while she is at Cambridge."

Xie says her ultimate goal in life "is to be able to not only improve our understanding of disease mechanisms, but also to be able to use that understanding to create novel, innovative therapies in order to help people battle their diseases."

Xie's desire to help others was clear during her time at Caltech—she led Caltech Y service trips, during which she and other students helped to rebuild houses for low-income families, assisted in beach and riverbed cleanups, and worked at a homeless shelter. As a freshman, she started the annual Caltech Student Health Fair to make students more aware of the physical, mental, and emotional health resources on campus and throughout the community. She has also served on campus as the vice chair of the Academics and Research Committee and as a member of the Caltech Y Student Executive Committee.

"I'm so excited that Catherine has been chosen to receive this fellowship," says Athena Castro, executive director of the Caltech Y. "I just love her. She's enthusiastic, dedicated, positive, thoughtful, and committed."

In the summer of 2012, Xie broadened her horizons even more when she traveled to Switzerland as a recipient of Caltech's SanPietro Travel Prize. "Catherine demonstrated her ability to adapt quickly and truly engage in another culture on that trip," says Lauren Stolper, director of fellowships advising and study abroad. "She will represent Caltech well as a Gates Cambridge Scholar."

Xie says she is thankful to everyone who has contributed to her experience at Caltech. "My achievements wouldn't have been possible without people giving me opportunities, encouraging me, and providing me with feedback, allowing me to grow as a scientist and as an individual," she says. "Caltech has shown me that intellectual curiosity and passion are vital driving forces behind finding innovative solutions that will have a profound and meaningful impact on solving issues that confront society."

The 51 newly announced international scholars will join 39 new American Gates Cambridge Scholars. The Gates Cambridge Scholarship program was established in 2000 through a donation from the Bill and Melinda Gates Foundation to the University of Cambridge. Xie is the sixth Caltech undergraduate student to receive the fellowship. 

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Kimm Fesenmaier
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