Caltech Chemists Devise Chemical Reaction that Holds Promise for New Drug Development

PASADENA, Calif.—A team of researchers at the California Institute of Technology (Caltech) has devised a new method for making complex molecules. The reaction they have come up with should enable chemists to synthesize new varieties of a whole subclass of organic compounds called nitrogen-containing heterocycles, thus opening up new avenues for the development of novel pharmaceuticals and natural products ranging from chemotherapeutic compounds to bioactive plant materials such as morphine.

The team—led by Brian Stoltz, the Ethel Wilson Bowles and Robert Bowles Professor of Chemistry, and Doug Behenna, a scientific researcher—used a suite of specialized robotic tools in the Caltech Center for Catalysis and Chemical Synthesis to find the optimal conditions and an appropriate catalyst to drive this particular type of reaction, known as an alkylation, because it adds an alkyl group (a group of carbon and hydrogen atoms) to the compound. The researchers describe the reaction in a recent advance online publication of a paper in Nature Chemistry.

"We think it's going to be a highly enabling reaction, not only for preparing complex natural products, but also for making pharmaceutical substances that include components that were previously very challenging to make," Stoltz says. "This has suddenly made them quite easy to make, and it should allow medicinal chemists to access levels of complexity they couldn't previously access."

The reaction creates compounds called heterocycles, which involve cyclic groups of carbon and nitrogen atoms. Such nitrogen-containing heterocycles are found in many natural products and pharmaceuticals, as well as in many synthetic polymers. In addition, the reaction manages to form carbon-carbon bonds at sites where some of the carbon atoms are essentially hidden, or blocked, by larger nearby components.

"Making carbon-carbon bonds is hard, but that's what we need to make the complicated structures we're after," Stoltz says. "We're taking that up another notch by making carbon-carbon bonds in really challenging scenarios. We're making carbon centers that have four other carbon groups around them, and that's very hard to do."

The vast majority of pharmaceuticals being made today do not include such congested carbon centers, Stoltz says—not so much because they would not be effective compounds, but because they have been so difficult to make. "But now," he says, "we've made it very easy to make those very hindered centers, even in compounds that contain nitrogen. And that should give pharmaceutical companies new possibilities that they previously couldn't consider."

Perhaps the most important feature of the reaction is that it yields almost 100 percent of just one version of its product. This is significant because many organic compounds exist in two distinct versions, or enantiomers, each having the same chemical formula and bond structure as the other, but with functional groups in opposite positions in space, making them mirror images of each other. One version can be thought of as right-handed, the other as left-handed.

The problem is that there is often a lock-and-key interaction between our bodies and the compounds that act upon them—only one of the two possible hands of a compound can "shake hands" and fit appropriately. In fact, one version will often have a beneficial effect on the body while the other will have a completely different and sometimes detrimental effect. Therefore, it is important to be able to selectively produce the compound with the desired handedness. For this reason, the FDA has increasingly required that the molecules in a particular drug be present in just one form.

"So not only are we making tricky carbon-carbon bonds, we're also making them such that the resulting products have a particular, desired handedness," Stoltz says. "This was the culmination of six years of work. There was essentially no way to make these compounds before, so to all of a sudden be able to do it and with perfect selectivity… that's pretty awesome."

In addition to Stoltz and Behenna, other authors on the paper, "Enantioselective construction of quaternary N-heterocycles by palladium-catalysed decarboxylative allylic alkylation of lactams," include Yiyang Liu, Jimin Kim, David White, and Scott Virgil of Caltech, and Taiga Yurino, who visited the Stoltz lab on a fellowship supported by the Japan Society for the Promotion of Science. The work was supported by the King Abdullah University of Science and Technology, the NIH-NIGMS, the Gordon and Betty Moore Foundation, Amgen, Abbott, and Boehringer Ingelheim. 

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Caltech Faculty Receive Gates Foundation Grants for Global Health Initiatives

On December 15, the Gates Foundation and Grand Challenge Canada announced over $31 million in new grants to help advance healthcare in the developing world. James Heath, Gilloon Professor and professor of chemistry, and Axel Scherer, Neches Professor of Electrical Engineering, Applied Physics, and Physics, were among the 12 grant recipients who will be funded by the Bill & Melinda Gates Foundation. Caltech was the only organization to receive more than one award.  

The grants are part of the Point-of-Care Diagnostics (POC Dx) Initiative, which aims to create high-quality, low-cost diagnostic platforms to improve the quality and efficacy of healthcare in the world's poorest countries. POC Dx is the 14th program of the Grand Challenges in Global Health initiative, launched in 2003 to create new healthcare tools across a range of disciplines.   

"New and improved diagnostics to use at the point of care can help health workers around the world save countless lives," said Chris Wilson, director of global health discovery at the Bill & Melinda Gates Foundation, in a press release. "Our hope is that these bold ideas lead to affordable, easy-to-use tools that can rapidly diagnose diseases, trigger timelier treatment and thereby reduce death, disability and transmission of infections in resource-poor communities."

Heath was awarded a grant to develop HIV diagnostic tools that use synthetically created peptides instead of antibodies in diagnostic assays. Their chemical structure would allow them to be transported, stored, and used more easily than antibodies. Scherer will work with collaborators at Dartmouth to develop a prototype technology to detect a wide range of pathogens that is low-cost, low-power, and easy to use.

For more information on the Grand Challenges in Global Health program, visit the program's website

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Caltech Chemists Propose Explanation for Superconductivity at High Temperatures

Could lead to dramatic improvements in superconductor performance

PASADENA, Calif.—It has been 25 years since scientists discovered the first high-temperature superconductors—copper oxides, or cuprates, that conduct electricity without a shred of resistance at temperatures much higher than other superconducting metals. Yet no one has managed to explain why these cuprates are able to superconduct at all. Now, two Caltech chemists have developed a hypothesis to explain the strange behavior of these materials, while also pointing the way to a method for making even higher-temperature superconductors. 

Superconductors are invaluable for applications such as MRI machines because they conduct electricity perfectly, without losing any energy to heat—a necessary capability for creating large magnetic fields. The problem is that most superconductors can only function at extremely low temperatures, making them impractical for most applications because of the expense involved in cooling them.

A value known as the maximum Tc indicates the highest temperature at which a material can superconduct. The superconductor used in MRI—the metal alloy niobium tin—has a maximum Tc of -248ËšC. Cooling this material to such a frigid temperature requires liquid helium, a scarce and extremely expensive commodity.

But the cuprates are different. They still operate well below freezing (the highest of the high-temperature superconductors, a cuprate created in 1993, has a maximum Tc of about -135ËšC), but some can be cooled using liquid nitrogen. This makes them much more practical, since liquid nitrogen is plentiful and its cost is about a hundredth that of liquid helium.

The ultimate goal, however, is the creation of superconductors that could operate near room temperature. These could improve cell-phone tower signaling and the robustness of the electrical grid, and could one day enable the operation of levitating trains at dramatically reduced fuel costs.

"But to take superconductors to the next level, we need to understand how the known high-temperature superconductors work," says William Goddard III, the Charles and Mary Ferkel Professor of Chemistry, Materials Science, and Applied Physics at Caltech. "After the publication of more than 100,000 refereed papers on the topic, there is still no acceptable explanation, and indeed, there has been no increase in Tc for the last 18 years."

All superconducting cuprates start as magnetic insulators and are transformed into superconductors through "doping," a process that involves removing electrons from the parent compound, either by substituting certain atoms for others or by adding or removing oxygen atoms. Still, no one knows what it is about doping that makes these cuprates superconduct.

Over the last four years, Goddard has published three papers with Jamil Tahir-Kheli, a senior staff scientist at Caltech, building a hypothesis that explains what makes cuprates superconduct. They have been working with a cuprate in which strontium (Sr) atoms are the "dopant atoms," replacing lanthanum (La) atoms. Based on modern quantum-mechanical calculations, Goddard and Tahir-Kheli found that each dopant atom creates a four-center hole on the copper atoms surrounding the strontium, a unit they refer to as a "plaquette." Electrons within the plaquettes form tiny pieces of metal, while those outside the plaquettes are insulating and behave like magnets. This result was completely contrary to the assumptions made by most other scientists about what happens when dopant atoms are added. The problem was, the researchers still did not know how the holes in the plaquettes led to superconductivity.

It took Goddard and Tahir-Kheli five years to figure that out. Their hypothesis is that when enough dopant atoms are added, the plaquettes are able to create a percolating pathway that allows electrons to flow all the way through the material. The magnetic electrons outside the plaquettes can interact with the electrons traveling through the plaquette pathway, and "it is this interaction that leads to the electron pairing—the slight attraction between electrons—that in turn results in superconductivity," Tahir-Kheli says.

The researchers' latest paper, published earlier this year in the Journal of Physical Chemistry Letters, takes the hypothesis a step further by accounting for a mysterious phase seen in cuprate superconductors called the pseudogap. In all superconductors, there is a superconducting energy gap, which is the amount of energy required to excite an electron from the superconducting state into a higher energy level not associated with superconductivity. This energy gap vanishes at temperatures above which a material no longer superconducts—in other words, above Tc. But in cuprate superconductors, there is a huge energy gap that persists at temperatures far higher than Tc. This is the pseudogap.

Among scientists, there are two camps on the pseudogap issue. One says that the pseudogap is connected somehow to superconductivity. The other insists that it is not connected, and in fact may be a phase that is competing with superconductivity. Goddard and Tahir-Kheli's theory lands them in this latter camp. "We believe that the pseudogap is decreasing the material's superconductivity," Tahir-Kheli says. "And, once again, its origin is related to the location of the plaquettes."

Goddard and Tahir-Kheli explain the pseudogap by pointing to plaquettes that do not contribute to superconductivity. These plaquettes are isolated; they do not have any other plaquettes directly next to them. The researchers found that there are two distinct quantum states with equal energy within these isolated plaquettes. These two states can interact with nearby isolated plaquettes, at which point the two distinct quantum states become unequal in energy. That difference in energy is the pseudogap. Therefore, to determine the size of the pseudogap, all you need to do is count the number of isolated plaquettes and determine how far away they are from one another.

"The electrons involved in the pseudogap are wasted electrons because they do not contribute to superconductivity," Goddard says. "What is important about them is knowing that, since the pseudogap comes from isolated plaquettes, if we were to control dopant locations to eliminate isolated plaquettes, we should be able to increase the superconducting temperature."

Goddard and Tahir-Kheli predict that by carefully managing the placement of dopant atoms, it might be possible to make materials that superconduct at temperatures as high as -73ËšC. They note that such an improvement after 18 years of stagnation would mark a significant step toward the creation of truly high-temperature superconductors with practical implications for the energy and health sectors.

The pseudogap paper, "Origin of the Pseudogap in High-Temperature Cuprate Superconductors" was published by The Journal of Physical Chemistry Letters

 

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New Professor Uses Chemistry and Chemical Engineering to Make a Difference

Rustem Ismagilov, the new John W. and Herberta M. Miles Professor of Chemistry and Chemical Engineering at Caltech, believes in the ability of science and technology to address significant societal problems—from the spread of HIV and drug resistance to bacterial imbalances in the gut.

There's always a lot happening in the Ismagilov lab. Some people are working on fundamental science to enable the development of new microfluidic devices—tools that control the flow of very small volumes of fluids through miniscule channels. Meanwhile, others are applying these technologies to answer questions related to the nature of complex biological systems and to address problems such as global-health issues, applications which often demand them to push the frontiers of chemistry and chemical engineering.  

"We love discovering new things on the science side," Ismagilov says, "but we also want to take those new things and do something with them that ultimately makes societal impact."

One project his lab has been working on is the development of a test to quantitatively diagnose disease almost anywhere—even "on a bicycle in Africa," as Ismagilov likes to say. The World Health Organization is pushing for the development of a viral-load test, which could accurately measure the concentration of viruses, such as HIV or hepatitis C, in the bloodstream, in resource-limited settings. Such an HIV viral-load test is important for monitoring the emergence of drug resistance and to curb its spread among the community. The problem is that the viral-load tests used in the United States require bulky and expensive equipment.

Ismagilov has come up with an alternative: a microfluidic device that he calls the SlipChip. Essentially, it turns a quantitative measurement, where the desired output is a specific number, into many qualitative, thumbs-up or thumbs-down questions. The basic idea is to split a sample into volumes small enough that each either contains a single viral RNA molecule or it doesn't, and to chemically test each volume for the presence of the virus.

The SlipChip is made up of two credit card–sized glass or plastic plates stacked atop one another. In the simplest set-up, the bottom plate includes a series of reagent-holding wells. The user injects a sample into a separate path, filling a set of wells and ducts. Then, with just a twist of the top plate, the sample gets separated into discrete volumes and brought into contact with the reagents, where reactions take place if specified concentrations of viral molecules are present. The plates can be made to have wells of different volumes, and the setup can be calibrated to test for different concentrations of viral molecules. 

"It's a really cool way of manipulating lots of small volumes in parallel," Ismagilov says. "What we are really trying to go for is the development of chemistries that will allow us to read things out with a cell phone," Ismagilov says.

The technique holds promise beyond its potential use in diagnostics in the developing world. "If we can make it robust enough to be used in the real world, I really also think it will revolutionize how we do many experiments in chemistry and biology," Ismagilov says. "Scientists are discovering that the world is complex and heterogeneous—many macromolecules are different, all cells are different. Being able to do these kinds of digital experiments for biology and chemistry would be pretty awesome."

For example, he says, think about running an experiment in a flask where a million cells are producing a million molecules of antibiotic. It could be that each cell is producing one molecule, or alternately, one cell could be in overdrive, producing a million molecules. "It's pretty hard and tedious right now to get a quantitative handle on things like that," Ismagilov says. "And scientists are discovering that in diagnostics and cancer, there are very critical subpopulations that control outcomes."

The SlipChip project is just one of several avenues of research currently being pursued in the Ismagilov lab. Another project aims to develop "microbiome-in-a-pill" particles, which could one day deliver spatially structured mixes of needed bacteria in order to prevent or treat conditions associated with microbial imbalance, such as inflammatory bowel disease and colitis. To read more about that new project, click here.

Microfluid technologies developed by Ismagilov's group have been licensed to Emerald BioStructures, Randance Technologies, and SlipChip LLC.

Before coming to Caltech, Ismagilov was a professor of chemistry at the University of Chicago, having worked his way up the ranks after joining the faculty there in 2001. He graduated from Higher Chemical College of the Russian Academy of Sciences in Moscow and earned his PhD in physical organic chemistry at the University of Wisconsin–Madison.

It might be hard to believe, but there was a time when chemistry was Ismagilov's most troubling subject. Growing up in the former Soviet Union, he was introduced to chemistry at an early age. After receiving failing grades on a couple homework assignments, he went home and read the entire textbook. Then he read the textbook for the next year and the next, eventually reading a college-level chemistry book. Yet he still found himself failing. Finally, perplexed, he went to speak with his teacher and found out that his was a different edition of the book, making his multiple-choice answers incorrect.

"By that time, I'd gone through the exercise of learning all of this stuff, and chemistry seemed pretty interesting," Ismagilov says. The rest, as they say, is history.

Click here, to watch animations of some SlipChip setups. 

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Cheating Nature for Secrets

André Hoelz, Caltech's newest assistant professor of chemistry, recalls the exhilaration he felt when he solved his first biological structure. At the time, he was a grad student at Rockefeller University and had been working for years to make crystals of a large brain enzyme known as CaMKII that would capture the macromolecular complex in just the right way, enabling him to resolve its atomic structure using X-ray crystallography.

"With crystallography there's this one moment where you know exactly how something looks," Hoelz says. "It's sort of a grand prize. You're the first one who can think about how it works and then generate experiments. It's like you cheated nature for a big secret."

Hoelz thinks structural biologists are born to seek that feeling and that once they've experienced it, they're hooked and will strive to experience it again and again. He puts himself squarely in that category of born structural biologists. "I'm lucky because I do what I really love to do," he says. "It's not really work."

Hoelz, originally from Lüdenscheid, Germany, comes to Caltech following a long association with Rockefeller University, where he was first a graduate student, then a postdoc, a research associate, and finally a research assistant professor. He has started an ambitious study to fully characterize the nuclear pore complex, a cellular component made up of many copies of about 30 different proteins—perhaps 1,000 proteins in all and 10 million atoms—which forms a transport channel in the membrane of the nuclear envelope. Hoelz calls the complex "the gatekeeper of the nucleus" because the pore provides a means for the cell to regulate which proteins and other molecules can access the genetic material stored within the nucleus.

The nuclear pore complex is a particularly challenging target for study with X-ray crystallography. The technique generally involves shining X-rays of a certain wavelength on a crystal and analyzing the pattern created by the reflections off of the atoms in the sample. But the nuclear pore complex is big—about 30 times larger than the ribosome, a cellular component that is itself considered large and whose structure wasn't solved until the year 2000. The nuclear pore complex is also very flexible and dynamic, making it difficult to capture in individual snapshots, as X-ray crystallography aims to do.

Hoelz's approach is to divide the nuclear-pore-complex problem into more manageable chunks. During cell division, the nuclear envelope falls apart, and as a result, the nuclear pore complex also breaks into smaller subcomplexes. "We try to understand these subcomplexes with the idea that if we solve the structures of these subcomplexes, we can ultimately piece together the entire pore," Hoelz says. "We think of it as a three-dimensional jigsaw puzzle."

So far, his group has solved the structure of the first four-protein unit and aims to do the same for all of the remaining subcomplexes. The crystallographic task before them is enormous. Biochemists estimate that anywhere from 500 to 1,000 individual pieces make up the three-dimensional jigsaw puzzle of the nuclear pore complex.

"You don't really know how the pore is built if you don't have all of the structures, but for every new structure that you solve, you can formulate a structurally informed hypothesis of how it may work, and you can test those ideas," Hoelz says. His goal is to understand how the nuclear pore complex normally works so he can tackle the problem of what happens when mutations or other defects change its operation in ways that are associated with disease, such as some kinds of leukemia.

"The bigger the problem, the more crystallography becomes a dark art," Hoelz says. "We need essentially unlimited access to an X-ray source, because a lot of the process is trying to squeeze structural information out of less-than-ideal crystals, and that involves a lot of empirical trial." Indeed, Hoelz says one of the key reasons he came to Caltech was the Institute's Molecular Observatory, which includes a completely automated radiation beam line at the Stanford Synchrotron Radiation Laboratory, which Caltech researchers control remotely. "This project is really pushing the envelope of what's possible by X-ray crystallography, but it's only possible if you have a certain infrastructure."

He hopes that he'll one day "cheat nature" out of its secret of the full structure of the nuclear pore complex so that he can begin structurally informed biochemical and in vivo experiments related to its function and to problems associated with its dysfunction.

"If you look at details in nature on the level that you can look at with your eyes, it's incredible. If you look at a flower or a tree, there's a lot of detail that's very beautiful, very intricate," Hoelz says. "That sort of detail and beauty goes down all the way to the atomic resolution. Looking at what nature came up with to solve particular problems is just amazing. But it's something that most of the time is not obvious before you solve the structure."

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Caltech Nobel Laureate Named One of the Top Leaders in America

PASADENA, Calif.— Ahmed Zewail, the Linus Pauling Professor of Chemistry and professor of physics at the California Institute of Technology (Caltech), has been named one of the Top American Leaders of 2011 by The Washington Post and Harvard Kennedy School's Center for Public Leadership. Six other people, including New Jersey governor Chris Christie and New York Times columnist Nicholas Kristof, were chosen to receive the distinction, which recognizes "outstanding leadership" in any area of interest.

"Ahmed's exceptional achievements as pioneering scientist, an extraordinary professor, and a regarded statesman of the world make him an ideal candidate to receive this honor," says Caltech president Jean-Lou Chameau. "We at Caltech are, as always, extremely proud of him."

The selection committee included many prominent leadership experts and considered more than a hundred finalists from a variety of sectors and walks of life.

"I am pleased with this special recognition to be named among the top leaders in America," says Zewail, "It comes at a special time, when Egypt, my native country, is going through democratic changes, and to those who have died in the struggle against oppression, I dedicate this award."

In 1999, Zewail was awarded the Nobel Prize in Chemistry for his research that established the field of femtochemistry by enabling chemical reactions to be studied in real time, at the scale of quadrillionths of a second. More recently, he and his group have developed four-dimensional electron microscopy for direct imaging of matter in the three dimensions of space and in time, with applications spanning the physical and biological sciences.

Zewail completed his early education in Egypt, receiving his Bachelor of Science and Master of Science degrees in chemistry from Alexandria University. He obtained a PhD in chemical physics from the University of Pennsylvania in 1974. He joined Caltech's faculty in 1976 as an assistant professor, becoming associate professor in 1978, professor in 1982, and Pauling Professor in 1990. He is currently the director of the Moore Foundation's Center for Physical Biology at Caltech.

In 2009, Zewail was appointed to President Obama's Council of Advisors on Science and Technology. That same year, he was named the first U.S. Science Envoy to the Middle East as part of a program sponsored by the White House and the State Department to foster science and technology collaborations between the United States and nations throughout the Middle East, North Africa, and South and Southeast Asia. Since the January 25 revolution in Egypt, he has played a critical role in the development of his native country and its transition to a democratic state.

Zewail has a long-standing interest in global affairs, particularly as they relate to science, education, and world peace. His commentaries on these global issues have appeared in the International Herald Tribune, the New York Times, the Los Angeles Times, and the Wall Street Journal, among other publications. He has written more than 500 articles and a dozen books and has given public addresses all over the world.

Among other honors, Zewail has received the Albert Einstein World Award of Science, the Benjamin Franklin Medal, the Robert A. Welch Award, the Leonardo da Vinci Award, the Wolf Prize, the Priestley Medal, and the King Faisal International Prize. He is a recipient of the Grand Collar of the Order of the Nile, Egypt's highest state honor, and has been featured on postage stamps issued to honor his contributions to science and humanity. Zewail holds honorary degrees from 40 universities around the world and is an elected member of many professional academies and societies, including the National Academy of Sciences, the American Philosophical Society, The Royal Society of London, and the Swedish, Russian, Chinese, and French Academies.  

Zewail will receive the Top American Leaders award at a public forum at Ford's Theatre in Washington, D.C., on December 5.

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Caltech Professors Mark E. Davis and David A. Tirrell Elected to the Institute of Medicine

Caltech Now Has Three of the 13 Living Members of All Three Branches of the National Academies

PASADENA, Calif.—Mark E. Davis and David A. Tirrell of the California Institute of Technology (Caltech) have been elected to the Institute of Medicine (IOM), an honor that is considered among the highest in the fields of health and medicine. Both Davis and Tirrell are already members of the National Academy of Sciences and the National Academy of Engineering, making them two of only 13 living individuals who have been elected to all three branches of the National Academies.

"Both Mark and Dave have made important interdisciplinary contributions that span the fields of chemical and biomolecular engineering," says Jacqueline Barton, the Arthur and Marian Hanisch Memorial Professor of Chemistry and chair of the Division of Chemistry and Chemical Engineering at Caltech. "It is fitting that they be honored by all three academies."

Although election to all three branches of the academies is a rare distinction, Davis and Tirrell are not the first from Caltech to earn the honor—the Institute now has three faculty members and two alumni on the list of 13. Frances Arnold, the Dick and Barbara Dickinson Professor of Chemical Engineering, Bioengineering, and Biochemistry joined the ranks in 2008, and alumni Leroy Hood and Yuan-Cheng Fung are also on the list.

Mark Davis, the Warren and Katharine Schlinger Professor of Chemical Engineering, is a member of the experimental therapeutics program at the City of Hope Comprehensive Cancer Center. His research focuses on the design and synthesis of nanoscale materials that are designed to be combined with therapeutic molecules. These "nanomedicines" have the potential to change the way cancer is treated—by providing more targeted therapies with fewer side effects—and are currently being tested in clinical trials.

"I am honored to receive this recognition," Davis says, "as it gives us validation that the medical community appreciates our work on creating new cancer therapeutics."

Davis earned his BS, MS, and PhD at the University of Kentucky in 1977, 1978, and 1981, respectively. He joined the Caltech faculty as a professor in 1991, was named Schlinger Professor in 1993, and served as executive officer for chemical engineering from 1999 to 2004.

David Tirrell, the Ross McCollum-William H. Corcoran Professor and professor of chemistry and chemical engineering, is known for work that bridges chemistry, biology, and materials science. Tirrell has developed a method for getting bacterial cells to "read" artificial genes and then produce protein-like structures with unusual or desired properties. The new materials could be useful in biomedical applications.

"It's always nice when a group of colleagues indicates that they think the research going on in your laboratory is worthwhile," Tirrell says. "My students and postdocs work on fundamental problems in protein chemistry, usually without specific clinical objectives. But we hope that what we do might someday find its way into medical practice and into other areas of science and technology."

Tirrell received his BS from MIT in 1974 and his PhD from the University of Massachusetts in 1978. He joined Caltech's faculty in 1998 and served as chair of the Division of Chemistry and Chemical Engineering from 1999 until 2009.

The IOM was established in 1970 by the National Academy of Sciences and is recognized as "a national resource for independent, scientifically informed analysis and recommendations on human health issues."

The election of Davis and Tirrell brings Caltech's total representation in the IOM to six faculty members and two trustees. This year, 65 new members and five foreign associates were elected to the IOM, bringing the total active membership to 1,688 members and the total number of foreign associates to 102.

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Watch Jackie Barton Receive the National Medal of Science

Today, President Obama will present Jacqueline K. Barton, chair of the Division of Chemistry and Chemical Engineering at Caltech, and six other recipients with the National Medal of Science. The medal is the highest honor bestowed by the United States government on scientists.

The ceremony is scheduled to be webcast live at 11 a.m. (PT) on the White House website. The president will also present the National Medal of Technology and Innovation to five recipients and will announce additional steps to speed the process of moving new ideas from the laboratory to the marketplace.

Barton's selection was announced last month. She was cited by the White House for her "discovery of a new property of the DNA helix, long-range electron transfer, and for showing that electron transfer depends upon stacking of the base pairs and DNA dynamics. Her experiments reveal a strategy for how DNA repair proteins locate DNA lesions and demonstrate a biological role for DNA-mediated charge transfer."

There have been 56 recipients of the National Medal of Science, including Barton, who are alumni or faculty at Caltech. Barton is the first woman at Caltech to receive the medal.

For a full list of this year's medal recipients, click here.

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$10 Million Gift Creates Partnership to Fuel Fundamental Research

Dow establishes long-term vision for innovation as founding member of Caltech's Corporate Partners Program

PASADENA, Calif.—In a strategic move to strengthen fundamental science and technology and foster transformational advances in renewable energies, the Dow Chemical Company (NYSE: DOW) and the California Institute of Technology (Caltech) have established a $10 million partnership.

Through the gift—bolstered with funds from the Gordon and Betty Moore Matching Program—Dow, one of the world's leading chemical companies, becomes a founding member of Caltech's Corporate Partners Program. The program is designed to strengthen the connection between the Institute's pioneering research and industry's needs, resulting in science and technology breakthroughs that can more easily and directly reach the community and the world.

"These long-term partnerships—inaugurated so aptly by this continued collaboration with Dow—will seed the sorts of high-risk, high-return innovations in science and engineering for which Caltech is renowned," says Caltech president Jean-Lou Chameau. "It will not only fund great fundamental science, but will also help us translate our findings into a commercial arena more quickly and seamlessly than ever before."

Under the partnership, Dow will provide ongoing support for graduate student research through five endowed fellowships in chemistry and chemical engineering, as well as five endowed fellowships in energy science. It will also provide Caltech's Resnick Sustainability Institute with funding over the next five years, helping to advance cutting-edge, proof-of-concept ideas with the potential to rapidly produce commercial technologies.

In return for its investment—which includes a rare, long-term corporate commitment that will be realized through endowments—Dow will have the opportunity to collaborate with an array of world-class faculty and student researchers.

"It is vital that we support academic research to ensure universities can continue the tradition of excellence in chemical engineering, chemistry, and materials science to address the needs of our industry and the world," says William Banholzer, chief technology officer at Dow. "Excellence in scientific education and the development of innovative solutions go hand in hand."

"Dow appreciates that you have to invest in something if you want to make change happen," says Hanisch Memorial Professor and Professor of Chemistry Jacqueline Barton, chair of the Division of Chemistry and Chemical Engineering at Caltech. "Outstanding research is under way at Caltech, and the best way for Dow to be involved with that work is to invest. The dividends from its investment will be realized over generations."

Dow's gift builds upon a history of collaborative efforts with Caltech. Both Dow and Caltech have demonstrated a strong commitment to developing sustainable solutions for the creation, storage, and distribution of energy, and both understand the crucial role that fundamental science plays in informing game-changing applications.

"Caltech is a model partner," says Theresa Kotanchek, vice president for sustainable technologies and innovation sourcing at Dow. "Together our research teams are uniting to advance fundamental science and simultaneously building and validating scalable prototypes. The pace of our progress is truly record setting."

In 2009, Dow chose Caltech as a partner in a four-year solar-research initiative that was one of the company's largest externally funded research agreements. This agreement has furthered exploration of earth-abundant materials for solar-energy applications, and also established Dow's first endowed graduate research fellowship for students in Caltech's Division of Chemistry and Chemical Engineering.

Through this newest partnership, Caltech researchers—and, by extension, Dow—will tackle a "broader portfolio of renewable energies and technologies," says the Resnick Sustainability Institute's director, Harry Atwater, who is Howard Hughes Professor and professor of applied physics and materials science at Caltech. The Resnick Institute's faculty currently pursues research focused on a vast spectrum of topics, including fuel cells, alternative wind power, solar photovoltaics, energy-storage materials, and energy sequestration.

The Resnick Sustainability Institute receives a significant portion of the funding in the agreement. Through the new Dow Chemical Company Bridge/CI2 Innovation Program, financial support will be used to further promising graduate and postdoc research that has the possibility of creating licensable technologies and start-ups. The graduate research fellowships in energy—renewable for up to two years—will help advance clean-energy goals.

"I am excited to see Caltech's efforts materialize in a broad-based manner," Atwater says. "We hope to see this partnership grow to include others as we continue to magnify and amplify our efforts so that we can have a greater impact."

More information about Dow's industry-leading partnership with key academic institutions in the United States can be found at http://www.dow.com/innovation/partnership.

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Shayna Chabner McKinney
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Senior Caltech Nobelist Reflects on His Prize-Winning Work

It's a good thing Rudy Marcus loves libraries. Otherwise, the Noyes Professor of Chemistry at Caltech might never have stumbled across the problem that he solved to win the 1992 Nobel Prize in Chemistry.

These days, researchers can read all the leading journals online, but when Marcus was a young associate professor at the Polytechnic Institute of Brooklyn, he spent hours in the library, leafing through the chemical literature. One day in 1955, he happened across a symposium issue of the Journal of Physical Chemistry in which chemist Bill Libby laid out a theory to explain some of the puzzling observations chemists had made in the lab—namely, why some chemical reactions that involve a simple transfer of an electron happen quickly, while others take much longer to transpire.

Marcus was intrigued by Libby's explanation, which was that electrons are so light compared to the nuclei of reactants that they should be able to jump from one reactant to another before the nuclei have a chance to change. "I thought, 'That's fantastic!'" Marcus recalled recently. "Libby was taking the Franck-Condon principle—something that was devised in the 1920s for a totally different application, for interpreting the spectra of molecules—and applying it to the rate of chemical reactions." But after thinking about Libby's theory for a while, he says, "Something didn't seem quite right." That uneasy feeling launched a month-long flurry of work that yielded a different explanation—an equation and the beginnings of the Marcus theory of electron transfer that many years later won Marcus his trip to Stockholm.

Marcus realized that Libby's explanation didn't feel right because it violated the law of conservation of energy—if an electron were transferred without the nuclei changing, the system would end up with far more energy after the transfer than before. To get away from that violation, the Marcus theory says that the molecular structure of some of the nuclei of the reactant and solvent molecules have to change positions before an electron can transfer, and then adjust again afterward. Therefore, an energy barrier has to be overcome in order for an electron-transfer reaction to proceed. And since that barrier varies depending on the structure of the molecules involved, it makes sense that some reactions take longer than others. Marcus worked out a mathematical model to describe such electron-transfer reactions and to calculate the expected values for their energy barriers.

"It took one month from start to finish to produce that equation," Marcus says. "For the record, it was the fastest thing I've ever done before or since."

In addition to being completely engrossed by the problem, in many ways Marcus was prepared to attack it. Early on, as both a graduate student at McGill University, in Montreal, and as a postdoctoral fellow at the National Research Council, he had worked in the lab, measuring rates of chemical reactions. But equally critical to his success was the fact that by the time he was pondering Libby's article, Marcus had developed the ability to approach problems from a theoretical standpoint.

He hadn't always had that ability. When Marcus was in school, there were no theoretical chemists in Canada. He had taken a course in theoretical chemistry at McGill, but the professor didn't teach where the theories came from or how they were developed. So Marcus says, "It never occurred to some of us to go into theoretical chemistry." But he had always been very interested in mathematics. In fact, Marcus says he probably took more math courses at McGill than any other chemistry student at the time. So after grad school, sometime during his postdoctoral fellowship, he says, "I became very dissatisfied because I wasn't using the kind of math that I enjoyed so much." It occurred to him that theoretical chemistry might provide the blend of chemistry and mathematics he was looking for.

So he and a friend at the Research Council, Walter Trost, formed a two-man seminar. They took turns describing theoretical papers to each other and then tried to apply the findings to their own experimental work. As simple as it may sound, that preparation encouraged Marcus to take a rather bold step—to apply for a postdoctoral position in theoretical chemistry in the United States. Though Marcus had no formal training on the theoretical side, one professor, Oscar Rice from the University of North Carolina, invited the eager young chemist to join his group.

As it turned out, Marcus's decision to head to Chapel Hill was a good one for more than one reason. Within a couple weeks of his arrival, Marcus met the love of his life, Laura Hearne, a graduate student in sociology and cultural anthropology, whom he married six months later and who passed away in 2003. He was also able to nurture and develop his knowledge of theoretical chemistry. After a few months of sitting in on lectures and reading every theoretical paper he could get his hands on, and after some gentle prodding by Rice, Marcus started working on a theoretical problem that dealt with what are called unimolecular reactions. "I gradually put together the bits of a theory," Marcus says. The theory predicts how long a molecule that has acquired a lot of energy will survive in such a state before breaking up or becoming stabilized, by colliding with another molecule, for example. "Before I realized it—after being there for six months—I had developed a theory of unimolecular reactions that is still used today." That theory is referred to in textbooks as the RRKM theory—the "M" stands for Marcus.

So by the time he joined the faculty at the Polytechnic Institute of Brooklyn in 1951, Marcus had proven his theoretical chops. But sensing that there wouldn't be enough experimental results in the area of unimolecular reactions to continue on that path, he needed a new problem to focus on. Eventually, it was a student's question about electrolytes that got Marcus interested in electrostatics. He published two papers in the field before coming across Bill Libby's symposium paper in the library.

"One often hears something along the lines of, 'Discoveries come to those with a prepared mind,'" Marcus says. "Here, my preparation was that I had published something about treating electrostatic interactions. I combined that background with elements of the work I had read about that were going on in physics at the time . . . It was really a matter of putting a bunch of little ideas together."

Marcus may downplay his accomplishment, but in the Nobel award-ceremony speech, Lennart Eberson of the Royal Swedish Academy of Sciences addressed Marcus, saying, "Your theory is a unifying factor in chemistry, promoting understanding of electron-transfer reactions of biochemical, photochemical, inorganic, and organic nature and thereby contributing to science as a whole."

Marcus received his Nobel medal 19 years ago for work he started more than 35 years before that. He says that the honor changed his life in some ways—more invitations and requests came his way—but that his interest in and enthusiasm for solving problems has never waned. Today, Marcus is 88 years old and still actively working on problems in theoretical chemistry while advising postdocs and grad students.

He's also planning a return to his beloved ski slopes this winter after a couple of seasons off. In his speech at the Nobel Banquet in 1992, Marcus drew comparisons between the sport of skiing and doing theoretical work in science, offering insight into the rush he gets from both. He described "the challenge and sense of excitement when the slope is a little more difficult than one feels comfortable with."

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Kimm Fesenmaier
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