Bar-Coding Technique Opens Up Studies Within Single Cells

All of the cells in a particular tissue sample are not necessarily the same—they can vary widely in terms of genetic content, composition, and function. Yet many studies and analytical techniques aimed at understanding how biological systems work at the cellular level treat all of the cells in a tissue sample as identical, averaging measurements over the entire cellular population. It is easy to see why this happens. With the cell's complex matrix of organelles, signaling chemicals, and genetic material—not to mention its miniscule scale—zooming in to differentiate what is happening within each individual cell is no trivial task.

"But being able to do single-cell analysis is crucial to understanding a lot of biological systems," says Long Cai, assistant professor of chemistry at Caltech. "This is true in brains, in biofilms, in embryos . . . you name it."

Now Cai's lab has developed a method for simultaneously imaging and identifying dozens of molecules within individual cells. This technique could offer new insight into how cells are organized and interact with each other and could eventually improve our understanding of many diseases.

The imaging technique that Cai and his colleagues have developed allows researchers not only to resolve a large number of molecules—such as messenger RNA species (mRNAs)—within a single cell, but also to systematically label each type of molecule with its own unique fluorescent "bar code" so it can be readily identified and measured without damaging the cell.

"Using this technique, there is essentially no limit on how many different types of molecules you can detect within a single cell," explains Cai.

The new method uses an innovative sequential bar-coding scheme that takes fluorescence in situ hybridization (FISH), a well-known procedure for detecting specific sequences of DNA or RNA in a sample, to the next level. Cai and his colleagues have dubbed their technique FISH Sequential Coding anALYSis (FISH SCALYS). 

FISH makes use of molecular probes—short fragments of DNA bound to fluorescent dyes, or fluorophores. These probes bind, or hybridize, to DNA or RNA with complementary sequences. When a hybridized sample is imaged with microscopy, the fluorophore lights up, pinpointing the target molecule's location.

There are a handful of fluorophores that can be used in these probes, and researchers typically use them to identify only a few different genes. For example, they will use a red dye to label all of the probes that target a specific type of mRNA. And when they image the sample, they will see a bunch of red dots in the cell. Then they will take another set of probes that target a different type of mRNA, label them with a blue fluorophore, and see glowing blue spots. And so on.

But what if a researcher wants to image more types of molecules than there are fluorophores? In the past, they have tried to mix the dyes together, making both red and blue probes for a particular gene, so that when both probes bind to the gene, the resulting dot would look purple. It was an imperfect solution and could still only label about 30 different types of molecules.

Cai's team realized that the same handful of fluorophores could be used in sequential rounds of hybridization to create thousands of unique fluorescent bar codes that could clearly identify many types of molecules (see graphic at right).

"With our technique, each tagged molecule remains just one single color in each round but we build up a bar code through multiple rounds, so the colors remain distinguishable. Using additional colors and extra rounds of hybridization, you can scale up easily to identify tens of thousands of different molecules," says Cai.

The number of bar codes available is potentially immense: FN, where F is the number of fluorophores and N is the number of rounds of hybridization. So with four dyes and eight rounds of hybridization, scientists would have more than enough bar codes (48=65,536) to cover all of the approximately 20,000 RNA molecules in a cell.

Cai says FISH SCALYS could be used to determine molecular identities of various types of cells, including embryonic stem cells. "One subset of genes will be turned on for one type of cell and off for another," he explains. It could also provide insight into the way that diseases alter cells, allowing researchers to compare the expression differences for a large number of genes in normal tissue versus diseased tissue.

Cai has recently been funded by the McKnight Endowment Fund for Neuroscience to adapt the technique to identify different types of neurons in samples from the hippocampus, a part of the brain associated with memory and learning.

Cai is also leading a program through Caltech's Beckman Institute that is helping other researchers on campus apply the imaging method to diverse biological questions.

Cai and his team describe the technique in a Nature Methods paper titled "Single-cell in situ RNA profiling by sequential hybridization." Caltech graduate student Eric Lubeck and postdoctoral scholar Ahmet Coskun are lead authors on the paper. Additional coauthors include Timur Zhiyentayev, a former Caltech graduate student, and Mubhij Ahmad, a former research technician in the Cai lab. The work has been funded by the National Institutes of Health's Single Cell Analysis Program.

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Partnership with Heritage Medical Research Institute Will Augment Translational Medicine Research

A new partnership will support translational sciences and health technology at Caltech thanks to a three-year commitment from Heritage Medical Research Institute (HMRI), a nonprofit founded and led by Caltech trustee Richard N. Merkin.

With this gift, the Institute and HMRI have created the Heritage Research Institute for the Advancement of Medicine and Science at Caltech. Eight Caltech faculty members from three academic divisions have been selected for the inaugural cohort of Heritage researchers, with a ninth yet to be named. These scientists and engineers—who will hold the title of Heritage Principal Investigators—will receive salary and research support as well as opportunities to learn from and collaborate with each other and with practicing physicians in the local community.

"Dick Merkin's insights into the changing landscape of modern medicine, his devotion to supporting young talent, and his exceptional generosity have come together to create an innovative program to advance translational research," says President Thomas F. Rosenbaum, holder of the Sonja and William Davidow Presidential Chair and professor of physics. "The generous support of HMRI, through Dick's vision, will provide the freedom and resources for faculty from across the divisions to tackle difficult science and engineering problems for the betterment of the human condition."

As a physician and a healthcare executive, Merkin has witnessed the rapid evolution of medicine and patient care in recent decades—and says he sees monumental changes on the horizon.

"I think some of the greatest breakthroughs this century will occur in biology, and I think Caltech is particularly positioned to be a leader in this area," Merkin says. "Our biggest problems are our biggest opportunities, and Caltech is gifted in looking at the world not as it is, but as it could be."

Caltech is uniquely suited to accelerating progress due to its highly collaborative environment, Merkin adds. The convergence of multidisciplinary science and technology, he says, is driving innovation at an exponential rate, particularly in the areas of implantable sensors and precision medicine.

Many of Caltech's new Heritage Principal Investigators have already deepened our understanding of how the human body works—from the microbes in our gut to the chemicals in our brain—and are advancing the study of diseases such as diabetes, autism, and cancer. As a trustee and benefactor, Merkin has been energized by the potential impact of their investigations.

"The most imaginative scientists on the globe are concentrated at Caltech," Merkin says. "They are dedicated to understanding the world around us. Just being able to interact with so many passionate, hardworking, and brilliant people is inspiring. I'm very grateful to be part of the Institute." 

Adds Stephen Mayo, the William K. Bowes Jr. Leadership Chair of the Division of Biology and Biological Engineering and Bren Professor of Biology and Chemistry: "As a valued friend of the Institute and a physician, Richard Merkin knows that the treatments of tomorrow begin in the lab today. This gift will embolden the Heritage Principal Investigators—some of whom are in the early stages of their careers—to pursue their most promising ideas and, in turn, quicken the pace of discovery in the biosciences."

A graduate of the University of Miami, Merkin began his career as a physician before creating what is now known as Heritage Provider Network (HPN) in 1979. Merkin serves as HPN's president and chief executive officer and has overseen its growth into one of California's largest healthcare provider networks. In 2012, Fast Company magazine named HPN one of the most innovative healthcare companies for embracing techniques such as data mining and predictive modeling to better the well-being of patients and improve the nation's healthcare system.

Merkin's philanthropy focuses on medical research, the arts, and children, with a special emphasis on the people of Southern California. He has served on the Caltech Board of Trustees since 2007 and also sits on the boards of the Los Angeles County Museum of Art and United Friends of the Children, as well as educational institutions, including the Keck School of Medicine of USC and Alliance College-Ready Public Schools. The latter runs 27 charter schools in the greater Los Angeles area, including one site named after him—the Richard Merkin Middle School. 

In 2003, Merkin founded HMRI, a nonprofit that also has supported the Dana Farber Cancer Institute and the Prostate Cancer Foundation. In deciding where to direct HMRI's research funds, making a pledge to Caltech made sense for Merkin.

"Watching the Institute's stewardship of resources as a trustee makes me very comfortable investing as a benefactor," Merkin says. "Supporting Caltech and its faculty and students is a much broader investment in a better future—not just for the local community, not just for the United States, but, really, for the world."

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Artificial Leaf Harnesses Sunlight for Efficient Fuel Production

Generating and storing renewable energy, such as solar or wind power, is a key barrier to a clean-energy economy. When the Joint Center for Artificial Photosynthesis (JCAP) was established at Caltech and its partnering institutions in 2010, the U.S. Department of Energy (DOE) Energy Innovation Hub had one main goal: a cost-effective method of producing fuels using only sunlight, water, and carbon dioxide, mimicking the natural process of photosynthesis in plants and storing energy in the form of chemical fuels for use on demand. Over the past five years, researchers at JCAP have made major advances toward this goal, and they now report the development of the first complete, efficient, safe, integrated solar-driven system for splitting water to create hydrogen fuels.

"This result was a stretch project milestone for the entire five years of JCAP as a whole, and not only have we achieved this goal, we also achieved it on time and on budget," says Caltech's Nate Lewis, George L. Argyros Professor and professor of chemistry, and the JCAP scientific director.

The new solar fuel generation system, or artificial leaf, is described in the August 27 online issue of the journal Energy and Environmental Science. The work was done by researchers in the laboratories of Lewis and Harry Atwater, director of JCAP and Howard Hughes Professor of Applied Physics and Materials Science.

"This accomplishment drew on the knowledge, insights and capabilities of JCAP, which illustrates what can be achieved in a Hub-scale effort by an integrated team," Atwater says. "The device reported here grew out of a multi-year, large-scale effort to define the design and materials components needed for an integrated solar fuels generator."


Solar Fuels Prototype in Operation
A fully integrated photoelectrochemical device performing unassisted solar water splitting for the production of hydrogen fuel. Credit: Erik Verlage and Chengxiang Xiang/Caltech

The new system consists of three main components: two electrodes—one photoanode and one photocathode—and a membrane. The photoanode uses sunlight to oxidize water molecules, generating protons and electrons as well as oxygen gas. The photocathode recombines the protons and electrons to form hydrogen gas. A key part of the JCAP design is the plastic membrane, which keeps the oxygen and hydrogen gases separate. If the two gases are allowed to mix and are accidentally ignited, an explosion can occur; the membrane lets the hydrogen fuel be separately collected under pressure and safely pushed into a pipeline.

Semiconductors such as silicon or gallium arsenide absorb light efficiently and are therefore used in solar panels. However, these materials also oxidize (or rust) on the surface when exposed to water, so cannot be used to directly generate fuel. A major advance that allowed the integrated system to be developed was previous work in Lewis's laboratory, which showed that adding a nanometers-thick layer of titanium dioxide (TiO2)—a material found in white paint and many toothpastes and sunscreens—onto the electrodes could prevent them from corroding while still allowing light and electrons to pass through. The new complete solar fuel generation system developed by Lewis and colleagues uses such a 62.5-nanometer-thick TiO2 layer to effectively prevent corrosion and improve the stability of a gallium arsenide–based photoelectrode.

Another key advance is the use of active, inexpensive catalysts for fuel production. The photoanode requires a catalyst to drive the essential water-splitting reaction. Rare and expensive metals such as platinum can serve as effective catalysts, but in its work the team discovered that it could create a much cheaper, active catalyst by adding a 2-nanometer-thick layer of nickel to the surface of the TiO2. This catalyst is among the most active known catalysts for splitting water molecules into oxygen, protons, and electrons and is a key to the high efficiency displayed by the device.

The photoanode was grown onto a photocathode, which also contains a highly active, inexpensive, nickel-molybdenum catalyst, to create a fully integrated single material that serves as a complete solar-driven water-splitting system.

A critical component that contributes to the efficiency and safety of the new system is the special plastic membrane that separates the gases and prevents the possibility of an explosion, while still allowing the ions to flow seamlessly to complete the electrical circuit in the cell. All of the components are stable under the same conditions and work together to produce a high-performance, fully integrated system. The demonstration system is approximately one square centimeter in area, converts 10 percent of the energy in sunlight into stored energy in the chemical fuel, and can operate for more than 40 hours continuously.

"This new system shatters all of the combined safety, performance, and stability records for artificial leaf technology by factors of 5 to 10 or more ," Lewis says.

"Our work shows that it is indeed possible to produce fuels from sunlight safely and efficiently in an integrated system with inexpensive components," Lewis adds, "Of course, we still have work to do to extend the lifetime of the system and to develop methods for cost-effectively manufacturing full systems, both of which are in progress."

Because the work assembled various components that were developed by multiple teams within JCAP, coauthor Chengxiang Xiang, who is co-leader of the JCAP prototyping and scale-up project, says that the successful end result was a collaborative effort. "JCAP's research and development in device design, simulation, and materials discovery and integration all funneled into the demonstration of this new device," Xiang says.

These results are published in a paper titled "A monolithically integrated, intrinsically safe, 10% efficient, solar-driven water-splitting system based on active, stable earth-abundant electrocatalysts in conjunction with tandem III-V light absorbers protected by amorphous TiO2 films." In addition to Lewis, Atwater, and Xiang, other Caltech coauthors include graduate student Erik Verlage, postdoctoral scholars Shu Hu and Ke Sun, material processing and integration research engineer Rui Liu, and JCAP mechanical engineer Ryan Jones. Funding was provided by the Office of Science at the U.S. Department of Energy, and the Gordon and Betty Moore Foundation.

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Caltech Chemists Solve Major Piece of Cellular Mystery

Team determines the architecture of a second subcomplex of the nuclear pore complex

Not just anything is allowed to enter the nucleus, the heart of eukaryotic cells where, among other things, genetic information is stored. A double membrane, called the nuclear envelope, serves as a wall, protecting the contents of the nucleus. Any molecules trying to enter or exit the nucleus must do so via a cellular gatekeeper known as the nuclear pore complex (NPC), or pore, that exists within the envelope.

How can the NPC be such an effective gatekeeper—preventing much from entering the nucleus while helping to shuttle certain molecules across the nuclear envelope? Scientists have been trying to figure that out for decades, at least in part because the NPC is targeted by a number of diseases, including some aggressive forms of leukemia and nervous system disorders such as a hereditary form of Lou Gehrig's disease. Now a team led by André Hoelz, assistant professor of biochemistry at Caltech, has solved a crucial piece of the puzzle.

In February of this year, Hoelz and his colleagues published a paper describing the atomic structure of the NPC's coat nucleoporin complex, a subcomplex that forms what they now call the outer rings (see illustration). Building on that work, the team has now solved the architecture of the pore's inner ring, a subcomplex that is central to the NPC's ability to serve as a barrier and transport facilitator. In order to the determine that architecture, which determines how the ring's proteins interact with each other, the biochemists built up the complex in a test tube and then systematically dissected it to understand the individual interactions between components. Then they validated that this is actually how it works in vivo, in a species of fungus.

For more than a decade, other researchers have suggested that the inner ring is highly flexible and expands to allow large macromolecules to pass through. "People have proposed some complicated models to explain how this might happen," says Hoelz. But now he and his colleagues have shown that these models are incorrect and that these dilations simply do not occur.

"Using an interdisciplinary approach, we solved the architecture of this subcomplex and showed that it cannot change shape significantly," says Hoelz. "It is a relatively rigid scaffold that is incorporated into the pore and basically just sits as a decoration, like pom-poms on a bicycle. It cannot dilate."

The new paper appears online ahead of print on August 27 in Science Express. The four co-lead authors on the paper are Caltech postdoctoral scholars Tobias Stuwe, Christopher J. Bley, and Karsten Thierbach, and graduate student Stefan Petrovic.


Crystal Structure of Fungal Channel Nucleoporin Complex
This video features a rotating three-dimensional crystal structure of the fungal channel nucleoporin complex bound to the adaptor nucleoporin Nic96. This interaction is the complex's sole site of attachment to the rest of the inner ring of the NPC. The channel nucleoporin complex borders the central transport channel and fills it with filamentous structures (phenylalanine-glycine repeats) that form a diffusion barrier and provide docking sites for proteins that ferry molecules across the nuclear envelope. Credit: Andre Hoelz/Caltech and Science

Together, the inner and outer rings make up the symmetric core of the NPC, a structure that includes 21 different proteins. The symmetric core is so named because of its radial symmetry (the two remaining subcomplexes of the NPC are specific to either the side that faces the cell's cytoplasm or the side that faces the nucleus and are therefore not symmetric). Having previously solved the structure of the coat nucleoporin complex and located it in the outer rings, the researchers knew that the remaining components that are not membrane anchored must make up the inner ring.

They started solving the architecture by focusing on the channel nucleoporin complex, or channel, which lines the central transport channel and is made up of three proteins, accounting for about half of the inner ring. This complex produces filamentous structures that serve as docking sites for specific proteins that ferry molecules across the nuclear envelope.

The biochemists employed bacteria to make the proteins associated with the inner ring in a test tube and mixed various combinations until they built the entire subcomplex. Once they had reconstituted the inner ring subcomplex, they were able to modify it to investigate how it is held together and which of its components are critical, and to determine how the channel is attached to the rest of the pore.

Hoelz and his team found that the channel is attached at only one site. This means that it cannot stretch significantly because such shape changes require multiple attachment points. Hoelz notes that a new electron microscopy study of the NPC published in 2013 by Martin Beck's group at the European Molecular Biology Laboratory (EMBL) in Heidelberg, Germany, indicated that the central channel is bigger than previously thought and wide enough to accommodate even the largest cargoes known to pass through the pore.

When the researchers introduced mutations that effectively eliminated the channel's single attachment, the complex could no longer be incorporated into the inner ring. After proving this in the test tube, they also showed this to be true in living cells.

"This whole complex is a very complicated machine to assemble. The cool thing here is that nature has found an elegant way to wait until the very end of the assembly of the nuclear pore to incorporate the channel," says Hoelz. "By incorporating the channel, you establish two things at once: you immediately form a barrier and you generate the ability for regulated transport to occur through the pore." Prior to the channel's incorporation, there is simply a hole through which macromolecules can freely pass.

Next, Hoelz and his colleagues used X-ray crystallography to determine the structure of the channel nucleoporin subcomplex bound to the adaptor nucleoporin Nic96, which is its only nuclear pore attachment site. X-ray crystallography involves shining X-rays on a crystallized sample and analyzing the pattern of rays reflected off the atoms in the crystal. Because the NPC is a large and complex molecular machine that also has many moving parts, they used an engineered antibody to essentially "superglue" many copies of the complex into place to form a nicely ordered crystalline sample. Then they analyzed hundreds of samples using Caltech's Molecular Observatory—a facility developed with support from the Gordon and Betty Moore Foundation that includes an automated X-ray beam line at the Stanford Synchrotron Radiation Laboratory that can be controlled remotely from Caltech—and the GM/CA beam line at the Advanced Photon Source at the Argonne National Laboratory. Eventually, they were able to determine the size, shape, and position of all the atoms of the channel nucleoporin subcomplex and its location within the full NPC.

"The crystal structure nailed it," Hoelz says. "There is no way that the channel is changing shape. All of that other work that, for more than 10 years, suggested it was dilating was wrong."

The researchers also solved a number of crystal structures from other parts of the NPC and determined how they interact with components of the inner ring. In doing so they demonstrated that one such interaction is critical for positioning the channel in the center of the inner ring. They found that exact positioning is needed for the proper export from the nucleus of mRNA and components of ribosomes, the cell's protein-making complexes, rendering it critical in the flow of genetic information from DNA to mRNA to protein.

Hoelz adds that now that the architectures of the inner and outer rings of the NPC are known, getting an atomic structure of the entire symmetric core is "a sprint to the summit."

"When I started at Caltech, I thought it might take another 10, 20 years to do this," he says. "In the end, we have really only been working on this for four and a half years, and the thing is basically tackled. I want to emphasize that this kind of work is not doable everywhere. The people who worked on this are truly special, talented, and smart; and they worked day and night on this for years."

Ultimately, Hoelz says he would like to understand how the NPC works in great detail so that he might be able to generate therapies for diseases associated with the dysfunction of the complex. He also dreams of building up an entire pore in the test tube so that he can fully study it and understand what happens as it is modified in various ways. "Just as they did previously when I said that I wanted to solve the atomic structure of the nuclear pore, people will say that I'm crazy for trying to do this," he says. "But if we don't do it, it is likely that nobody else will."

The paper, "Architecture of the fungal nuclear pore inner ring complex," had a number of additional Caltech authors: Sandra Schilbach (now of the Max Planck Institute of Biophysical Chemistry), Daniel J. Mayo, Thibaud Perriches, Emily J. Rundlet, Young E. Jeon, Leslie N. Collins, Ferdinand M. Huber, and Daniel H. Lin. Additional coauthors include Marcin Paduch, Akiko Koide, Vincent Lu, Shohei Koide, and Anthony A. Kossiakoff of the University of Chicago; and Jessica Fischer and Ed Hurt of Heidelberg University.

 

 

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High School Students Visit for Women in STEM Preview Day

On Friday, August 7, 104 female high school seniors and their families visited Caltech for the fourth annual Women in STEM (WiSTEM) Preview Day, hosted by the undergraduate admissions office. The event was designed to explore the accomplishments and continued contributions of Caltech women in the disciplines of science, technology, engineering, and mathematics (STEM).

The day opened with a keynote address by Marianne Bronner, the Albert Billings Ruddock Professor of Biology and executive officer for neurobiology. Bronner, who studies the development of the central nervous system, spoke about her experiences in science and at Caltech.

"Caltech is an exciting place to be. It's a place where you can be creative and think outside the box," she said. "My advice to you would be to try different things, play around, and do what makes you happy." Bronner ended her address by noting the pleasure she takes in mentoring young scientists, and especially young women. "I was just like you," she said.

Over the course of the day, students and their families attended panels on undergraduate research opportunities and participated in social events where current students shared their experiences of Caltech life. They also listened to presentations from female scientists and engineers of the Jet Propulsion Laboratory.

"I really love science, and it's so exciting to be around all of these other people who share that," says Sydney Feldman, a senior from Maryland. "I switched around my whole summer visit schedule to come to this event and I'm having such a great time."

The annual event began four years ago with the goal of encouraging interest in STEM in high school women and ultimately increasing applications to Caltech by female candidates. In 2009, a U.S. Department of Commerce study showed that women make up 24 percent of the STEM workforce and hold a disproportionately low share of undergraduate degrees in STEM fields.

"Women are seriously underrepresented in these fields," says Caltech admissions counselor and WiSTEM coordinator Abeni Tinubu. "Our event really puts emphasis on how Caltech supports women on campus, and we want to show prospective students that."

This year, the incoming freshman class is a record 47 percent female students. "This is hugely exciting," says Jarrid Whitney, the executive director of admissions and financial aid. "We've been working hard toward our goal of 50 percent women, and it is clearly paying off thanks to the support of President Rosenbaum and the overall Caltech community."

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Science for the Community

On the grounds of San Marino's Huntington Library, Art Collections, and Botanical Gardens—to the north of the Chinese Gardens, in the private, half-acre Huntington Ranch area—nearly two dozen middle- and high-school students have been spending this summer measuring the levels of nitrogen in the soils around them to help the ranch determine whether its soil is up to the challenge of growing an urban garden.

This hands-on research experience is part of the Community Science Academy @ Caltech, which is affiliated with Caltech's Center for Teaching, Learning, and Outreach (CTLO). The 23 first-timers in what is called CSA 1 are studying biological systems at the ranch; a similar number of continuing students, in CSA 2, are studying engineering and programming, and are building their own scientific instruments.

The program runs three days a week for six weeks. For CSA 1 students, it began on June 15 with soil sampling; by July 24, when it ends, students will have designed and performed their own experiments.

CSA@Caltech is now in its second year. It initially was funded with support from a National Institutes of Health Director's Pioneer Award to Caltech Professor of Biology Bruce Hay. In addition, the Pasadena Educational Foundation and the Siemens Foundation currently provide support for scholarships that allow all students from the Pasadena Unified School District to attend the program free of charge.

The students start most days with lectures by members of the Caltech staff. Every student is issued an iPad and keyboard for note taking and fieldwork. This technology allows the lectures to become interactive presentations using software that allows constant feedback between teacher and student. They spend much of their time at the CTLO on the Caltech campus, for talks on topics including soil and water quality, pest control, environmental monitoring, and remote sensing. They also work in the undergraduate teaching labs in Caltech's Divisions of Chemistry and Chemical Engineering and Biology and Biological Engineering for lessons on plant processing and bacterial detection, respectively.

At the Huntington Library, students apply in an outdoor setting what they have learned and practiced in Caltech classrooms and labs. For example, they gather soil samples from gardens and water samples from lily ponds for nitrate and ammonia testing; they conduct experiments on ant behavior; and they design and build sensor-carrying remote-controlled powered kites, which they fly over the Library grounds.

"These hands-on methods are critical for teaching students about the collaborative nature of science, the system of trial and error, and the importance of following protocols in scientific experimentation and analysis," says James Maloney (MS '06), one of the two codirectors of the CSA@Caltech program. Even while the students are getting what may well be their first exposure to research, they are also making a serious contribution to the Huntington's understanding of the ranch's viability as an urban garden. The ranch was originally a gravel parking lot, notes ranch coordinator Kyra Saegusa. It took six years for the soil to be rebuilt with sheets of mulch. The question now is whether it is ready for growing fruits and vegetables.

If the shouts of "I got a worm!" from one 13-year-old field worker are any indication, the soil restoration is certainly moving in the right direction.

The ultimate goal of CSA@Caltech—to promote STEM (science, technology, engineering, and mathematics) in secondary education and to help create the next generation of scientists—is further buttressed by tours of Caltech labs, where researchers such as Sarah Reisman, professor of chemistry, talked to the CSA@Caltech students about life as a scientist. Some of the students have already chosen areas in which they think they would like to specialize: for instance, Eris, a ninth grader from Blair High School in CSA 2, wants to study engineering and chemistry; Brandon, a CSA 2 ninth grader from Pasadena High School, wants to go into theoretical physics; and CSA 1 student Connor, an eighth grader from Sierra Madre Middle School, wants to be an aerospace engineer.

Building on this success, CSA@Caltech plans to add a third year of study next summer and continue their development of new educational technologies. "Our goal is to make high-quality science accessible to all," says CSA@Caltech codirector Julius Su (BS '98, BS '99, PhD '07).

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$100 Million Gift from Gordon and Betty Moore Will Bolster Graduate Fellowships

Trustees Gordon (PhD '54) and Betty Moore have pledged $100 million to Caltech, the second-largest single contribution in the Institute's history. With this gift, they have created a permanent endowment and entrusted the choice of how to direct the funds to the Institute's leadership—providing lasting resources coupled with uncommon freedom.

"Those within the Institute have a much better view of what the highest priorities are than we could have," Intel Corporation cofounder Gordon Moore explains. "We'd rather turn the job of deciding where to use resources over to Caltech than try to dictate it from outside."

Applying the Moores' donation in a way that will strengthen the Institute for generations to come, Caltech's president and provost have decided to dedicate the funds to fellowships for graduate students.

"Gordon and Betty Moore's incredibly generous gift will have a transformative effect on Caltech," says President Thomas F. Rosenbaum, holder of the Institute's Sonja and William Davidow Presidential Chair and professor of physics. "Our ultimate goal is to provide fellowships for every graduate student at Caltech, to free these remarkable young scholars to pursue their interests wherever they may lead, independent of the vicissitudes of federal funding. The fellowships created by the Moores' gift will help make the Institute the destination of choice for the most original and creative scholars, students and faculty members alike."

Further multiplying the impact of the Moores' contribution, the Institute has established a program that will inspire others to contribute as well. The Gordon and Betty Moore Graduate Fellowship Match will provide one additional dollar for every two dollars pledged to endow Institute-wide fellowships. In this way, the Moores' $100 million commitment will increase fellowship support for Caltech by a total of $300 million.

Says Provost Edward M. Stolper, the Carl and Shirley Larson Provostial Chair and William E. Leonhard Professor of Geology: "Investigators across campus work with outstanding graduate students to advance discovery and to train the next generation of teachers and researchers. By supporting these students, the Moore Match will stimulate creativity and excellence in perpetuity all across Caltech. We are grateful to Gordon and Betty for allowing us the flexibility to devote their gift to this crucial priority."

The Moores describe Caltech as a one-of-a-kind institution in its ability to train budding scientists and engineers and conduct high-risk research with world-changing results—and they are committed to helping the Institute maintain that ability far into the future.

"We appreciate being able to support the best science," Gordon Moore says, "and that's something that supporting Caltech lets us do."

The couple's extraordinary philanthropy already has motivated other benefactors to follow their example, notes David L. Lee, chair of the Caltech Board of Trustees.

"The decision that Gordon and Betty made—to give such a remarkable gift, to make it perpetual through an endowment, and to remove any restrictions as to how it can be used—creates a tremendous ripple effect," Lee says. "Others have seen the Moores' confidence in Caltech and have made commitments of their own. We thank the Moores for their leadership."

The Moores consider their gift a high-leverage way of fostering scientific research at a place that is close to their hearts. Before he went on to cofound Intel, Gordon Moore earned a PhD in chemistry from Caltech.

"It's been a long-term association that has served me well," he says.

Joining him in Pasadena just a day after the two were married, Betty Moore became active in the campus community as well. A graduate of San Jose State College's journalism program, she secured a job at the Ford Foundation's new Pasadena headquarters and also made time to come to campus to participate in community activities, including the Chem Wives social club.

"We started out at Caltech," she recalls. "I had a feeling that it was home away from home. It gives you a down-home feeling when you're young and just taking off from family. You need that connection somehow."

After earning his PhD from Caltech in 1954, Gordon Moore took a position conducting basic research at the Applied Physics Laboratory at Johns Hopkins University. Fourteen years and two jobs later, he and his colleague Robert Noyce cofounded Intel Corp. Moore served as executive vice president of the company until 1975, when he took the helm. Under his leadership—as chief executive officer (1975 to 1987) and chairman of the board (1987 to 1997)—Intel grew from a Mountain View-based startup to a giant of Silicon Valley, worth more than $140 billion today.

Moore is widely known for "Moore's Law," his 1965 prediction that the number of transistors that can fit on a chip would double every year. Still relevant 50 years later, this principle pushed Moore and his company—and the tech industry as a whole—to produce continually more powerful and cheaper semiconductor chips.

Gordon Moore joined the Caltech Board of Trustees in 1983 and served as chair from 1993 to 2000. That same year, he and his wife established the Gordon and Betty Moore Foundation, an organization dedicated to creating positive outcomes for future generations in the San Francisco Bay Area and around the world.

Among numerous other honors, Gordon Moore is a member of the National Academy of Engineering, a fellow of the Institute of Electrical and Electronics Engineers, and a recipient of the National Medal of Technology and the Presidential Medal of Freedom. 

The Gordon and Betty Moore Graduate Fellowship Match is available for new gifts and pledges to endow graduate fellowships. For more information about the match and how to support graduate education at Caltech, please email give@caltech.edu or call (626) 395-4863.

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Clean Water For Nepal

On the steep, tea-covered hillsides of Ilam in eastern Nepal, where 25 percent of households live below the poverty level and electricity is scarce, clean running water is scarcer still. What comes out of the region's centralized distribution systems is unfiltered, untreated, and teeming with nitrates, viruses, and E. coli. Purifying it is the consumer's responsibility.

But wood and yak dung, the only available fuels for boiling water, are precious, and purification tablets impart an unpleasant chlorine taste. The result? During the rainy season, local hospitals overflow with typhoid and gastrointestinal cases, mostly involving children and tainted runoff.

That may change, thanks to a gravity flow and slow-sand filtration system designed by Caltech undergraduates. They represent EWB-Caltech, one of the newest chapters of Engineers Without Borders USA, a nongovernmental organization (NGO) whose mission is to design and implement sustainable engineering projects in underprivileged communities.

Founded in 2012 by Sarah Wright (BS '13, bioengineering), EWB-Caltech already has about 30 members. This summer, a half dozen of the chapter's members are traveling to Ilam, where they are staying with local villagers while helping to oversee and implement the system's construction. The hillside will be partly excavated and then reconstructed. Layers of rock, gravel, sand, polyethylene sheeting, and soil will soak up rainfall, filtering and purifying it as it trickles into underground water. Pipes tapping into the underground water will run downhill to a small communal enclosure made of poured concrete, providing a reliable supply of clean water for about 100 households, with another 200 indirectly affected.

The students will not be working alone, says their mentor, environmental engineering consultant Gordon Treweek (MS '71, PhD '75) who is partnering with Caltech engineering students for the first time. "All EWB projects are community-driven, with the local workforce providing much of the labor. And we've received tremendous logistical support, including interpreters, from the Namsaling Community Development Center, an NGO in Ilam that had previously worked with an EWB chapter from the University of Colorado, Boulder."

According to EWB requirements the Nepalese must contribute 5 percent of the project's budget. EWB-Caltech copresidents Jihoon Lee (a senior in bioengineering) and Nauman Javed (a senior in physics) acknowledge that successfully coming up with the remainder—over $20,000—involved nearly continuous fund-raising. "We've been applying for grants, soliciting private donations, partnering with companies, especially water-related and environmental corporations, and we held a benefit dinner in January that was largely attended by Caltech faculty and friends," says Lee.

Both a 10-day on-site assessment trip last summer and this summer's trip were covered by individual donations and grants. The assessment trip took Treweek, Javed, and fellow Caltech senior Webster Guan (chemical engineering) to Ilam to meet with the NGO; to survey the local community of about 100 families to ascertain their needs and willingness to assist in the construction and ongoing maintenance of the water tap stand; and to gather predesign data for planning construction and estimating costs.

"The support we have received from Caltech alumni directly and through their networks of contacts at Northrop Grumman and Boeing has been invaluable in helping to keep this project moving forward," Treweek says.

After the assessment trip, the students spent the 2014–15 school year preparing detailed engineering documents using computer-aided design techniques. In this, they were assisted by the water-resource engineering firms Carollo Engineers and Montgomery Watson Harza, whose pro bono involvement did not surprise Treweek. "Consulting engineering firms frequently donate resources for projects like this," he says. "It's socially responsible, and it gives them a chance to observe future engineers addressing the four traditional phases of engineering: planning, design, fund-raising, and construction."

With preventable infectious diseases a leading component of Ilam's one-in-three infant mortality rate, the project includes a public-education component. "Besides training the local villagers who will maintain our spring-water source protection system," says Javed, "we plan to visit local schools, demonstrate how the system works, teach a little germ theory."

But no amount of careful planning can guarantee success. Similar projects have failed due to engineering problems, misaligned long-term governance strategies, eleventh-hour reprioritizations by the community, even simple miscommunication. "We've drafted plenty of contingency plans," affirms Lee, "with great support from EWB-USA. Their stringent review procedures covered every engineering and social aspect of the project, and they've given us detailed feedback on our drawings, schedules, and rationales."

After the implementation phase—which ends just one week before classes resume back in Pasadena—EWB-Caltech will continue to monitor the site for five to six years. By then the current members will have moved on and a new group of student leaders will have taken over this project. But for now, they are spending their summer trying to build a better world, drop by drop.

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New VP for Student Affairs Named

Joseph Shepherd (PhD '81), the C. L. "Kelly" Johnson Professor of Aeronautics and professor of mechanical engineering, is leaving his post as dean of graduate studies to succeed Anneila Sargent (MS '67, PhD '78), the Ira S. Bowen Professor of Astronomy, as vice president for student affairs. Shepherd's new role is effective September 15.

Sargent, who served the campus as the leader of student affairs the last eight years, announced in March that she was leaving the post to return to research and teaching full time. Shepherd, who joined the Caltech faculty in 1993, has served the last six years as the dean of graduate studies.

We recently sat down with Shepherd to talk about his past role and his new one, his strengths and goals, and his experience at Caltech.

 

Q: What does the vice president for student affairs do?

A: Student Affairs includes the offices of the undergraduate and graduate deans as well as obvious things like the registrar, undergraduate admissions, fellowships and study abroad, the career center, the health center, and the counseling center. It also includes things you might not think of—athletics; performing and visual arts, which includes the music programs, the theater program, the various arts programs, and all of the faculty and instructors that make these programs possible; and a whole group of organizations lumped under "auxiliaries."

The term "auxiliaries" is misleading, because they're central to student life. Housing and dining are the biggest parts, but there are services like the C-Store, the Red Door Café, the Caltech Store and Wired.

 

Q: What makes this role exciting for you?

A:  People speculate about what it is that makes Caltech a great school. A lot of folks say, "Well, it's because it's so small." But I think it's also because we work with people instead of creating some bureaucratic mechanism to solve problems. We say, "All right, what's the issue here? How can we resolve this?" instead of, "We need to create a rule. And then we need to create a group to enforce the rule." My approach is to ask, "What do we want the outcome to be?" In Student Affairs, you want the outcome to be something that supports the students, supports the faculty, and then you make sure that it's not going to adversely affect the Institute.

 

Q: Are there any changes coming, any initiatives you want to establish?

A: We need to think about how we build on the strengths we have and improve the things that we're weakest at. Before you make any changes to an organization, you need to understand those two things. There are a lot of parts to Student Affairs, so I need to understand the strong points of those organizations, and then get them to help me formulate what's important to do.

You always have to be careful of unintended consequences. As they say in chess, you want to think several moves deep. All right, suppose we do that. What will it mean for different parts of our population? Do we make this choice based on the data we have, or do we need more data? Will there be effects on people we haven't thought about? Maybe we need to go talk to those people.

When you have the authority to change things, you also have the responsibility to ask, "Are these the right changes?" Nothing happens in isolation. Anything you do is invariably going to wind up touching quite a few people.

 

Q: You've been dean of graduate studies since 2009. Did you consider taking a breather before jumping into this?

A: Well, much to my surprise, I found that being the dean of graduate studies was rewarding in many different ways. Sometimes you had to do some difficult things, but I actually liked being the dean. I was able, to some extent, to continue my research. I did some teaching—although last year I taught a major course all three terms, and I had my research group—and I was the dean of graduate studies. That taught me a lesson: a man's got to know his limitations.

So when I was asked if I would take this position, I did think about taking a break and not doing it. I enjoy my research and I enjoy teaching. I enjoy working with students, but I also enjoy trying to help the Institute as a whole. Here at Caltech, we pride ourselves on the notion that we have this very special environment. We have this small school, and we have dedicated professionals that work together with faculty to nurture that environment—having faculty who are invested in participating in the key administrative roles is essential.

When I was a graduate student here, my adviser was Brad Sturtevant [MS '56, PhD '60, and a lifelong faculty member thereafter]. Brad was the executive officer for aeronautics [1972-76]. He was in charge of the committee that built the Sherman Fairchild Library and he was on the faculty board. He emphasized to me that being involved in administration was just as valuable as all the other aspects of being a faculty member. He was a dedicated researcher, but he also felt strongly that you should be a good citizen. You should contribute.

 

Q: It seems like this is more than just a duty to you, though.

A: I'm looking forward to it. I'm also very conscious of the responsibility. I think it's going to be important for us all to think about how we maintain the excellence of the Institute and that we imagine how this place is going to evolve. As society evolves around us, we will naturally wind up changing. We need to do that in a thoughtful way so that we continue to be the special organization that we are.

At the end of the day, I'm counting on help from the faculty and staff. Caltech works because of the committed individuals within our organizations, the personal connections we form as we work together and the cooperation across the campus that these connections enable.  It's a collective enterprise.

I think administration is not something that's done to people. It's being responsible for making sure that folks have the right work environment, the right job assignments, and the right resources. It's making sure we're doing the right things with the finite resources we have. One of our former presidents said something that's always stuck with me: an administrator's goals are not about their own career so much as helping the careers of others. You need to think about how you're helping the people working for you, because they have goals and aspirations. That's where you take your satisfaction.

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Thursday, September 24, 2015
Beckman Institute, Glanville Courtyard – Beckman Institute

3rd Annual Caltech Teaching Conference

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