Gilmartin Named Dean of Undergraduate Students

On July 1, 2016, Kevin Gilmartin, professor of English, will begin serving as Caltech's dean of undergraduate students.

In announcing Gilmartin's appointment, Joseph E. Shepherd, vice president for student affairs and the C. L. Kelly Johnson Professor of Aeronautics and Mechanical Engineering, described him as "an accomplished scholar and author who brings to this position twenty-five years of experience in teaching and mentoring our students, and who has shown a keen interest in the welfare of our undergraduate students in and outside of the classroom."

In his new role as dean of undergraduate students, Gilmartin will work on fostering academic and personal growth through counseling and support for student activities as well as acting as a liaison between students and faculty, says Shepherd.

A recipient the Feynman Prize, Caltech's highest teaching award, Gilmartin says he was attracted to the job of dean because "I have always found our students to be so interesting, and engaging. They are extraordinarily optimistic. They seem to have a positive attitude toward the world—they're curious, and they're open to new things. What more could you ask for?"

He says he sees his role as helping undergraduates develop and thrive. "I'm excited to work with students to help foster their intellectual and academic growth and their development as individuals," he says. "Our students are remarkably diverse and they have diverse interests. The Caltech curriculum is demanding, and focused, no doubt. But within it, and through it, our students do find so many opportunities."

He adds, "The dean's office provides essential support. But we can also encourage our students to do more than they are inclined to do, to challenge themselves, to try new things."

Gilmartin received his undergraduate degree in English from Oberlin College in 1985. He received both his MS ('86) and PhD ('91) in English from the University of Chicago, joining the faculty of Caltech in 1991.

Barbara Green, who has served as the interim dean over the past year will return to her regular position as associate dean in July. In his announcement, Shepherd thanked Green "for her work with our students and service to the Institute [and for] being so willing and committed to the success of our undergraduate student body."

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Gilmartin Named Dean of Undergraduates
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On July 1, 2016, Kevin Gilmartin, professor of English, will begin serving as Caltech's dean of undergraduate students.

Ditch Day? It’s Today, Frosh!

Today we celebrate Ditch Day, one of Caltech's oldest traditions. During this annual spring rite—the timing of which is kept secret until the last minute—seniors ditch their classes and vanish from campus. Before they go, however, they leave behind complex, carefully planned out puzzles and challenges—known as "stacks"—designed to occupy the underclassmen and prevent them from wreaking havoc on the seniors' unoccupied rooms.

Follow the action on Caltech's Facebook, Twitter, and Instagram pages as the undergraduates tackle the puzzles left for them to solve around campus. Join the conversation by sharing your favorite Ditch Day memories and using #CaltechDitchDay in your tweets and postings.

          

 

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Frances Arnold Wins 2016 Millennium Technology Prize

Frances Arnold, the Dick and Barbara Dickinson Professor of Chemical Engineering, Bioengineering and Biochemistry, has been awarded the Millennium Technology Prize for her "directed evolution" method, which creates new and better proteins in the laboratory using principles of evolution. The Millennium Technology Prize, worth one million euros (approximately $1.1 million), is the world's most prominent award for technological innovations that enhance the quality of people's lives.

Directed evolution, first pioneered in the early 1990s, is a key factor in green technologies for a wide range of products, from biofuels to pharmaceuticals, agricultural chemicals, paper products, and more.

The technique enlists the help of nature's design process—evolution—to come up with better enzymes, which are molecules that catalyze, or facilitate, chemical reactions. In the same way that breeders mate cats or dogs to bring out desired traits, scientists use directed evolution to create desired enzymes.

"We can do what nature takes millions of years to do in a matter of weeks," says Arnold, who is also director of the Donna and Benjamin M. Rosen Bioengineering Center at Caltech. "The most beautiful, complex, and functional objects on the planet have been made by evolution. We can now use evolution to make things that no human knows how to design. Evolution is the most powerful engineering method in the world, and we should make use of it to find new biological solutions to problems."

Directed evolution works by inducing mutations to the DNA, or gene, that encodes a particular enzyme. An array of thousands of mutated enzymes is produced, and then tested for a desired trait. The top-performing enzymes are selected and the process is repeated to further enhance the enzyme's performance. For instance, in 2009, Arnold and her team engineered enzymes that break down cellulose, the main component of plant-cell walls, creating better catalysts for turning agricultural wastes into fuels and chemicals.

"It's redesign by evolution," says Arnold. "This method can be used to improve any enzyme, and make it do something new it doesn't do in nature." 

Today, directed evolution is at work in hundreds of laboratories and companies that make everything from laundry detergent to medicines, including a drug for treating type 2 diabetes. Enzymes created using the technique have replaced toxic chemicals in many industrial processes.

"My entire career I have been concerned about the damage we are doing to the planet and each other," says Arnold. "Science and technology can play a major role in mitigating our negative influences on the environment. Changing behavior is even more important. However, I feel that change is easier when there are good, economically viable alternatives to harmful habits."

"Frances is a distinguished engineer, a pioneering researcher, a great role model for young men and women, and a successful entrepreneur who has had a profound impact on the way we think about protein engineering and the biotechnology industry," says David Tirrell, the Ross McCollum-William H. Corcoran Professor of Chemistry and Chemical Engineering at Caltech. "The Millenium Technology Prize provides wonderful recognition of her extraordinary contributions to science, technology, and society."

Arnold received her undergraduate degree in mechanical and aerospace engineering at Princeton University in 1979. She earned her graduate degree in chemical engineering from UC Berkeley in 1985. She arrived at Caltech as a visiting associate in 1986 and became an assistant professor in 1987, associate professor in 1992, professor in 1996, and Dickinson Professor in 2000.

She is the recipient of numerous awards, including in 2011 both the Charles Stark Draper Prize, the engineering profession's highest honor, and the National Medal of Technology and Innovation. Arnold is one of a very small number of individuals to be elected to all three branches of the National Academies—the National Academy of Engineering (2000), the Institute of Medicine (2004), and the National Academy of Sciences (2008)—and the first woman elected to all three branches.

"I certainly hope that young women can see themselves in my position someday. I hope that my getting this prize will highlight the fact that yes, women can do this, they can do it well, and that they can make a contribution to the world and be recognized for it," says Arnold.

The Millennium Technology Prize is awarded every two years by Technology Academy Finland (TAF) to "groundbreaking technological innovations that enhance the quality of people's lives in a sustainable manner," according to the prize website. The prize was first awarded in 2004. Past recipients include Sir Tim Berners-Lee, creator of the World Wide Web; Shuji Nakamura, the inventor of bright blue and white LEDs; and ethical stem cell pioneer Shinya Yamanaka. Arnold is the first woman to win the prize.

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Chemical Engineer Wins Top Tech Prize
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Innovator Frances Arnold has been awarded the Millennium Technology Prize for her "directed evolution" method.
Monday, June 6, 2016
Guggenheim 101 (Lees-Kubota Lecture Hall) – Guggenheim Aeronautical Laboratory

Resnick Sustainability Institute Battery Symposium

Signed, Sealed, Delivered: How Proteins Get Where They’re Supposed to Go

Proteins are only synthesized at specialized cellular locations, but are destined for delivery to all corners of the cell—and beyond. A key step in this delivery process is the efficient transport, or translocation, of the newly synthesized proteins across cell membranes. Protein translocation involves a delicate balance of processes that range from atomic-level interactions to macromolecule-scale rearrangements.

On Wednesday, May 11, at 8 p.m. in Beckman Auditorium, Caltech professor of chemistry Thomas Miller will explain how his group is simulating the protein translocation process and predicting ways to control the targeting and delivery of proteins for therapeutic and biotechnological applications. Admission is free.

What do you do?

I am a theoretical chemist. We develop mathematical models and computational algorithms for the simulation and understanding of chemical processes. We use this approach to study a range of problems, including electrolyte performance and degradation in batteries, solar energy conversion, and the cellular targeting and synthesis of proteins. An important aspect of this challenge is that many systems exhibit dynamics that couple vastly different timescales and lengthscales. A primary goal of our research is thus to develop new computational strategies to accurately and efficiently simulate complex molecular systems.

Why is this important?

Many of the urgent problems facing our society—including the generation and storage of renewable energy, the development of improved medicines, and the design of new materials—are fundamentally related to molecular processes (i.e., chemistry). Theoretical chemistry provides the tools to understand the underlying molecular behavior, to help interpret experimental measurements, and to predict new properties and phenomena. Just like computer simulations have dramatically impacted the fields of weather and climate prediction, traffic flow, and demographics—so too have they become central to the way in which we understand and study chemical problems. Theoretical chemistry is the field that makes this possible.

How did you get into this line of work?

I have always enjoyed chemistry, physics, and math, as well as the challenge of getting to the bottom of complicated problems. So the thing that "seduced" me into becoming a theoretical chemist was the realization that those interests coincided in the description of molecules. A major turning point in my career came in my freshman year, when I learned the way in which the Schrödinger Equation provided a simple, clear, and essentially exact mathematical description of chemical bonding. The idea that all of chemistry rests upon this equation from physics and the mathematical challenge of solving it was simply too intriguing to pass up. I immediately began participating in undergraduate research in a theoretical chemistry lab, and I have since enjoyed the myriad directions in which this pursuit has led.

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Signed, Sealed, Delivered
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Signed, Sealed, Delivered: How Proteins Get Where They’re Supposed to Go
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Professor Tom Miller discusses how proteins get where they're supposed to go in his upcoming Watson lecture.
Wednesday, May 11, 2016
Noyes 147 (J. Holmes Sturdivant Lecture Hall) – Arthur Amos Noyes Laboratory of Chemical Physics

Administrative Contact Information Session

Resnick Sustainability Institute Boosts Caltech's Earth Day Celebration

The Resnick Sustainability Institute—Caltech's hub for projects aimed at tackling some of the toughest sustainability-focused problems our society faces—played a key role in Caltech's Earth Week celebration, during which various events were held to show support for environmental protection and achieving a sustainable future.

For example, on April 19, Resnick fellow Bryan Hunter gave a talk on "The 21st Century Solar Army," which focused on his volunteer work with Caltech's NSF Center for Chemical Innovation in Solar Fuels. Among CCI Solar's volunteers are Resnick postdoctoral scholars Bradley Brennan and Sonja Francis, whose efforts have included working with school teachers to show them how to build and test simple and cheap solar cells; the teachers then take these activities back to their classrooms.

The Resnick Sustainability Institute's 17 graduate student fellows and 10 postdoctoral scholars are actively engaged in research involving everything from solar fuels and photovoltaics to improved catalysts for greener industrial processes, carbon capture and storage, greenhouse gas assessment, wastewater treatment, and more.

Recently, postdoctoral scholar Christopher Prier and his colleagues in Frances Arnold's laboratory described a method for the synthesis of valuable amines using engineered variants of cytochrome P450, a common iron-containing enzyme, in the journal Angewandte Chemie. Because enzymatic processes are typically environmentally benign, Prier notes, his work contributes to the greening of chemical synthesis.

Francis and colleagues described in the journal ACS Catalysis a new catalyst made of two metals, nickel and gallium, which can be used for converting carbon dioxide and water into hydrocarbons like methane, ethane, and ethylene. Currently, no electro-catalyst exists that can convert carbon dioxide with both high efficiency and selectivity to hydrocarbons or even alcohols, Francis notes.

Additionally, in an upcoming issue, the Journal of the American Chemical Society will spotlight an improved catalyst for sustainable fertilizer production developed by Resnick fellow Niklas Thompson and others from Resnick Institute director Jonas Peters' research group. This same research also won the 2016 Dow Sustainability Innovation Student Challenge Award at Caltech.

Learn more about the Resnick Sustainability Institute at Caltech at http://resnick.caltech.edu.

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Monday, September 12, 2016

The Resnick Young Investigators Symposium

Rerouting Cancer

Cancer is capable of rapidly developing resistance to therapeutic drugs, rendering those drugs harmless—often before they have a chance to work. Now, researchers at Caltech and their colleagues have identified how at least one brain cancer, called glioblastoma multiforme (GBM), adapts so fast—and they show that by formulating the right combination of drugs, doctors could potentially overcome this resistance and stop a tumor in its tracks.

The work appears in the April 12 issue of the journal Cancer Cell.

Some cancer drugs are designed to target a cell's chemical circuitry. This network of signaling pathways controls how a healthy cell functions, but in many cancers, the pathways are hyperactivated, directly leading to the aggressive nature of the disease. By blocking a key pathway, a drug can, in principle, stop the tumor from growing.

"The concept is that if you block a key node in the pathway, then the communication can't proceed and the cells can't get the signals to divide and multiply," explains Jim Heath, the Elizabeth W. Gilloon Professor of Chemistry and co-corresponding author on the paper.

In reality, however, tumors can become resistant to a drug even if the drug works exactly as designed. With GBM, such resistance develops in almost every patient. "In some patients, you can treat with a drug that does everything you could want it to do, but you would never know that the drug hit the target because the tumor adapts so quickly," Heath says.

Some scientists have suspected that the cancer becomes resistant through Darwinian-type evolution, in a process similar to how bacteria develop resistance to antibiotics. That is, the genetic differences of certain cancer cells may make those cells resistant to a drug. Nonresistant cells are killed by the drug and their death leaves room for the naturally resistant cells—and tumors—to grow and multiply.

However, this mechanism was not what Heath and his colleagues found in studies of tissue from glioblastoma patients. Instead, the researchers discovered that the cancer cells that developed resistance to a drug were the same cells that had responded to the drug. When the drug blocks a signaling pathway in a cancer cell, they realized, the cell simply finds a detour, like a GPS navigator that reroutes to avoid traffic.

"You can block a key part," Heath says, "and the cells will respond to route around that part you blocked."

This notion of shifting pathways is not new, but the work is the first to show that the process can happen in as little as two days. In particular, the researchers found that the changes occur with a specific drug (CC214‑2) that targets a central GBM signaling-protein called mTOR. When mTOR is inhibited, certain GBM signaling pathways are repressed, but others are activated.

To map the detours, the researchers separated individual GBM cells from patient tumors and measured the levels of several key proteins in the cells. These proteins—called phosphoproteins because they are activated by the addition of a phosphoryl group to a molecule—carry signals throughout the cell. Measurements of the abundance of the proteins showed that the drug was effective.

The story was different at the single-cell level, at which Heath and his colleagues not only measured the levels of proteins in individual cells, but also the signaling between those proteins. For example, if protein A signals protein B, then the levels of A, as measured across many single cells, will correlate with the levels of B.  By measuring the presence of several such proteins, the researchers could infer the structure of the protein signaling network.

They discovered that after the drug was introduced, the cell activated new pathways that previously had been dormant. This drug-induced pathway activation suggested several combination therapies that might halt the development of drug resistance, as well as drugging strategies that would have no effect.

In mice, Heath and his team tested seven therapies or therapy combinations that they predicted would—or would not—halt resistance development. The four that they predicted would not work were, indeed, ineffectual; the three they thought would work, did. The researchers then showed that they could see similar effects in GBM patient tissues, as well as in melanoma tumor models. This kind of rapid drug adaptation by tumors may occur in many cancer types, and helps explain how cancers can develop resistance to targeted drugs so quickly, Heath says.

The good news is that, by identifying the drug-activated signaling pathways, one may be able to find drug combinations that will suppress resistance, Heath says. Eventually, he says, clinicians may be able to analyze a patient's tumor at the single-cell level to determine the best therapy strategy.

These kinds of drug combinations would likely remain a secondary therapy against cancer—used when treatments like chemotherapy, radiation, and surgery fail. But, Heath says, they are essential for staving off the resistance that has severely limited the benefits that patients currently receive from targeted therapies.

The first authors of the Cancer Cell paper, titled "Single cell phosphoproteomics resolves adaptive signaling dynamics and informs targeted combination therapy in glioblastoma," are Wei Wei (PhD '14), a visitor in chemistry at Caltech and assistant professor at UCLA, and Young Shik Shin (MS '06, PhD '11), who now works at a biotech startup. Both are former graduate students of Heath's. A third key contributor to the work was Beatrice Gini, formerly a member of the UC San Diego (UCSD) laboratory of co-corresponding author Paul Mischel and now at UC San Francisco. Other Caltech authors include Min Xue and Kiwook Hwang (PhD '13) and graduate students Jungwoo Kim and Yapeng Su. Authors also include researchers from UCSD, the University of Verona in Italy, Northwestern University, and the Celgene Corporation. Heath is board member of and holds a financial interest in IsoPlexis, a company that is commercializing a microchip technology similar to what was used for single-cell analyses in the research described. 

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A new strategy may help overcome cancer cells' drug resistance.

Biochemists Solve the Structure of Cell's DNA Gatekeeper

Caltech scientists have produced the most detailed map yet of the massive protein machine that controls access to the DNA-containing heart of the cell.

In a new study, a team led by André Hoelz, an assistant professor of biochemistry, reports the successful mapping of the structure of the symmetric core of the nuclear pore complex (NPC), a cellular gatekeeper that determines what molecules can enter and exit the nucleus, where a cell's genetic information is stored.

The study appears in the April 15, 2016 issue of the journal Science, featured on the cover.

The findings are the culmination of more than a decade of work by Hoelz's research group and could lead to new classes of medicine against viruses that subvert the NPC in order to hijack infected cells and that could treat various diseases associated with NPC dysfunction.

"The methods that we have been developing for the last 12 years open the door for tackling other large and flexible structures like this," says Hoelz. "The cell is full of such machineries but they have resisted structural characterization at the atomic level."

The NPC is one of the largest and most complex structures inside the cells of eukaryotes, the group of organisms that includes humans and other mammals, and it is vital for the survival of cells. It is composed of approximately 10 million atoms that together form the symmetric core as well as surrounding asymmetric structures that attach to other cellular machineries. The NPC has about 50 times the number of atoms as the ribosome—a large cellular component whose structure was not solved until the year 2000. Because the NPC is so big, it jiggles like a large block of gelatin, and this constant motion makes it difficult to get a clear snapshot of its structure.

In 2004, Hoelz laid out an ambitious plan for mapping the structure of the NPC: Rather than trying to image the entire assembly at once, he and his group would determine the crystal structures of each of its 34 protein subunits and then piece them together like a three-dimensional jigsaw puzzle. "A lot of people told us we were really crazy, that it would never work, and that it could not be done," Hoelz says.

Last year, the team published two papers in Science that detailed the structures of key pieces of the NPC's inner and outer rings, which are the two primary components of the NPC's symmetric core. The donut-shaped core is embedded in the nuclear envelope, a double membrane that surrounds the nucleus, creating a selective barrier for molecules entering and leaving the nucleus.

By being able to piece these crystal structures into a reconstruction of the intact human NPC obtained through a technique called electron cryotomography—in which entire isolated nuclei are instantaneously frozen, with all of their structures and molecules locked into place, and then probed with a transmission electron microscope to produce 2-D images that can be reassembled into a 3-D structure—"we bridged for the first time the resolution gap between low-resolution electron microscopy reconstructions that provide overall shape and high-resolution crystal structures that provide the precise positioning of all atoms," Hoelz says.

With these structures known, the mapping of the rest of the NPC's symmetric core came quickly. "It is just like when solving a puzzle," he says. "By placing the first piece confidently, we knew that we would eventually be able to place all of them."

As described in the new paper, Hoelz's research group now has solved the crystal structures of the last remaining components of the symmetric core's inner ring and determined where all of the rings' pieces fit in the NPC's overall structure.

To do this, the team had to first generate a complete "biochemical interaction map" of the entire symmetric core. Akin to a blueprint, this map describes the interconnections and interactions of all of the proteins, as part of a larger cellular machine. The process involved genetically modifying bacteria to produce purified samples of each of the 19 different protein subunits of the NPC's symmetric core and then combining the fragments two at a time inside a test tube to see which adhered to each other.

The team then used the completed interaction map as a guide for identifying the inner ring's key proteins and employed X-ray crystallography to determine the size, shape, and position of all of their atoms. X-ray crystallography involves shining X-rays on a crystallized sample and analyzing the pattern of rays reflected off the atoms in the crystal. The team analyzed thousands of samples at 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.

"We now had a clear picture of what the key jigsaw pieces of the NPC looked like and how they fit together," says Daniel Lin, a graduate student in Hoelz's lab and one of two first authors on the study.

The next step was to determine how the individual pieces fit into the larger puzzle of the NPC's overall structure. To do this, the team took advantage of an electron microscopy reconstruction of the entire human NPC published in 2015 by Martin Beck's group at the European Molecular Biology Laboratory (EMBL) in Heidelberg, Germany. The images from Beck's group were relatively low resolution and revealed only a rough approximation of the NPC's shape, but they still provided a critical framework onto which Hoelz's team could overlay their atomic high-resolution images, captured using X-ray crystallography. The NPC is the largest cellular structure ever pieced together using such an approach.

"We were able to use the biochemical interaction map we created to solve the puzzle in an unbiased way," Hoelz says. "This not only ensured that our pieces fit in the electron microscopy reconstruction, but that they also fit together in a way that made sense in the context of the interaction map."

Hoelz said his team is committed to solving the remaining asymmetric parts of the NPC, which include filamentous structures that serve as docking sites for so-called transport factors that ferry molecules safely through the pore and other cellular machineries that are critical for the flow of genetic information from DNA to RNA to protein.

"I suspect that things are going to move very quickly now," Hoelz says. "We know exactly what we need to do. It's like we're climbing Mount Everest for the first time, and we've made it to Camp 4. All that's left is the sprint to the summit."

Along with Hoelz and Lin, additional Caltech authors on the paper, "Architecture of the symmetric core of the nuclear pore," include research technician Emily Rundlet; Thibaud Perriches, George Mobbs, and Karsten Thierbach, all postdoctoral scholars in chemistry working in the Hoelz lab; and graduate students Ferdinand Huber and Leslie Collins. Other coauthors on the paper include former Hoelz lab member Tobias Stuwe—the second cofirst author of the paper—as well as former lab members Sandra Schilbach, Yanbin Fan, Andrew Davenport (PhD '15), and Young Jeon.

The work was supported by the National Institute of General Medical Sciences; the Caltech-Amgen Research Collaboration; the German Research Foundation; the Boehringer Ingelheim Fonds; the China Scholarship Council; Caltech startup funds; an Albert Wyrick V Scholar Award from the V Foundation for Cancer Research; a Mallinckrodt Scholar Award from the Edward Mallinckrodt Jr. Foundation; a Kimmel Scholar Award from the Sidney Kimmel Foundation; and a Camille Dreyfus Teacher-Scholar Award from the Camille & Henry Dreyfus Foundation. Hoelz is also an inaugural Heritage Principal Investigator of the Heritage Medical Research Institute for the Advancement of Medicine and Science at Caltech.

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Solved: Structure of the Cell's DNA Gatekeeper
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The detailed map is the first to determine the structure of a massive protein machine with near-atomic resolution.

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