New Professor Practices the Art of Organic Chemistry

Organic chemistry—the branch that deals with carbon-containing compounds—has intimidated many a student trying to master all of its mechanisms and electron-pushing details. But Gregory C. Fu, the newest member of the Division of Chemistry and Chemical Engineering at Caltech, looks at his discipline in a more creative light. "I think there is an aspect of art to it," Fu says. "It's not a field where you can always use an entirely analytical process to come up with the next experiment. There is some intuition and creativity to it that I have always found attractive." 

Fu, the Altair Professor of Chemistry, uses his intuition and creativity to develop new chemical reactions that make chemical conversions more efficient—enabling organic chemists to convert reactants into their desired products in fewer steps or with higher yields than previously possible, for example. He is most interested in reactions that form carbon-carbon bonds and those that control the chirality, or "handedness," of molecules.

Many organic compounds exist in two distinct versions, each having the same chemical formula and bond structure as the other, but with their 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.

It is often the case that only one of the two possible hands of a compound can "shake hands" with another chemical and fit appropriately. So, as Fu explains, "We're trying to develop methods to generate molecules that all have the same handedness."

In one effort, Fu's team has developed the first catalytic reaction for controlling the handedness of a family of compounds called aza-beta-lactams (ABLs). These chemicals are closely related to beta-lactams, which include such widely used antibiotics as penicillin. Both beta-lactams and ABLs contain rings of four atoms, the difference being that beta-lactams include only one nitrogen atom within those rings, while ABLs contain two. "Our thought in creating these aza-beta-lactams is that, since they have structural similarities to beta-lactams but contain an additional nitrogen, they might serve different and useful biological purposes."

As it turns out, some of them do. Once Fu's team had prepared some of their ABLs, they wanted to make them available to medicinal chemists and biologists for testing. Fu had heard about the National Institutes of Health Common Fund Molecular Libraries Program, which allows scientists to deposit structurally interesting compounds, while permitting other academic researchers to use high-throughput screening methods to search those thousands of compounds for target molecules that might be important for studies of human health.

Benjamin Cravatt III, professor and chair of the department of chemical physiology at the Scripps Research Institute, was one of those researchers. In 2010, his group was hunting in one of the molecular libraries for possible inhibitors of an enzyme called phosphatase methylesterase (PME-1), which belongs to a family of enzymes called serine hydrolases. 

PME-1 modifies another enzyme, called PP2A, in such a way that PP2A becomes unable to perform one of its usual functions—suppressing tumor cells. If you can get PME-1 off PP2A's back, however, PP2A can go back to fighting cancer.

One of Fu's ABLs popped up in Cravatt's search as a potent and highly selective inhibitor of PME-1. Thus far, it has inhibited PME-1 activity in studies in cells and the brains of mice, making it promising as a possible anti-cancer therapy.

Fu's group is continuing this project in new labs in the Warren and Katharine Schlinger Laboratory for Chemistry and Chemical Engineering. They are making related ABLs for Cravatt's group to investigate. "We're looking for inhibitors of other serine hydrolases," Fu says. "It turns out there are many, many serine hydrolases, and many of them don't have known active inhibitors."

Fu has spent his academic career in two cities—Cambridge, Massachusetts, and Pasadena. He earned his BS at the Massachusetts Institute of Technology in 1985 and his PhD at Harvard University in 1991. After that, he spent two years working as a postdoctoral fellow with Bob Grubbs, the Victor and Elizabeth Atkins Professor of Chemistry at Caltech. Then, in 1993, Fu headed back east to join the faculty at MIT. Last year, he came to Caltech as a Moore Distinguished Scholar, and this year he became the Altair Professor of Chemistry. He brought 17 members of his lab with him to Caltech, and has already added several Caltech students to his group.

"I think Caltech has a wonderful intellectual atmosphere—one that is very conducive to research," Fu says "After 18-plus years at MIT, I thought it would be healthy to sort of shake things up and try something different." And it does not hurt, he adds, that he gets to leave those cold Cambridge winters behind.

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Greg Fu: The Art of Organic Chemistry
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New Class of Catalysts Opens Up Green Route to a Range of Chemical Products

Caltech chemists in the lab of Nobel laureate Bob Grubbs have developed a new class of catalysts that will increase the range of chemicals—from pharmaceuticals, insect pheromones, and perfume musks to advanced plastics—that can be synthesized using environmentally friendly methods.

"We have been trying to develop this particular class of catalysts for about 15 years," says Grubbs, the Victor and Elizabeth Atkins Professor of Chemistry at Caltech.

Like the catalysts that earned Grubbs the 2005 Nobel Prize in Chemistry, the new chemicals include the metal ruthenium and help drive a chemical reaction called olefin metathesis. That reaction has proven useful and efficient for making chemical products that involve pairs of carbon atoms connected by double bonds.

"Our original catalysts have found many applications," Grubbs notes, "but one of the deficiencies was the lack of control of the geometry of the double bond."

And, indeed, what sets the new class of catalysts apart is their ability to selectively form products that have a particular geometry.

To understand that geometry, think first of trans fats. Like other fats, trans fats are essentially chains of fatty acids that contain carbon-carbon double bonds. The "trans" refers to the geometry or configuration of groups of atoms with relation to those double bonds—they can be either trans or cis. If the groups of atoms connected to the carbons of the double bond are located kitty-corner to each other, they exist in the trans configuration; if they are on the same side, the bonds are cis double bonds. Natural fats contain cis double bonds. Trans fats are formed during chemical processing, and the unnatural fats have been found to be unhealthy.

In most circumstances, trans double bonds are much more stable than their cis counterparts. Since metathesis is a double-bond forming reaction that tends to form the more stable product, it primarily forms trans double bonds. But there are many compounds that scientists and manufacturers would like to make that include pure cis, rather than trans double bonds. Some desired compounds that contain cis double bonds are pharmaceutical targets; others make it possible to manufacture polymers with enhanced properties.

"People haven't been able to make these cis double bonds using ruthenium-based olefin metathesis before," says Myles Herbert, a graduate student in Grubbs's lab who has been working with the new catalysts. There are alternative methods for making cis double bonds, but the most popular tend to generate a lot of chemical waste, making them less economical and less environmentally friendly than metathesis, which is considered a green chemical reaction.

Herbert has been focusing on one promising application of the new catalysts—using them to synthesize insect pheromones. Insects such as the gypsy moth and the Douglas-fir tussock moth are responsible for massive deforestation around the world, and others destroy acres of crops. Rather than using poisonous pesticides to control such populations, farmers are beginning to attack the problem by spraying their fields with female insect sex pheromones. Male bugs follow pheromones to locate females; raising the concentration of those chemicals effectively overwhelms their senses, so they are unable to find mates.

"These pheromones are all nontoxic, so it would be great if they could be adapted for use on an industrial scale," Herbert says. "Since many of them involve cis double bonds, I'm trying to use the new catalysts and metathesis to find a shorter synthesis that uses cheaper materials to make these pheromones."

A Serendipitous Discovery

The new class of catalysts was discovered largely by chance. Theoretical work by William Goddard III, Caltech's Charles and Mary Ferkel Professor of Chemistry, Materials Science, and Applied Physics, and his group suggested that one particular catalyst might yield products with cis double bonds. So while visiting Grubbs's lab, Koji Endo, from Mitsui Chemicals in Japan, set about trying to synthesize that catalyst, which was later proven to be ineffective. However, in the process of trying to make that catalyst, Endo happened across a very unusual reaction that produced an entirely unexpected compound, which turned out to be the first in this new class of ruthenium catalysts. 

"We had seen complexes that were reminiscent of this before, but they always decomposed," says Grubbs's graduate student Keith Keitz, a coauthor on several papers published in the past year describing the new class of catalysts. "So it was really surprising to us that, first of all, this was stable, and second, that when Koji threw it in with some of our standard reaction conditions, this catalyst showed an unprecedented selectivity for cis double bonds."

The reaction looked promising, but there was room for improvement. The first-generation catalyst yielded a mix of products containing roughly half cis and half trans double bonds (previously, the best catalysts produced mixtures with 10 times as many compounds with trans double bonds). To convince synthetic chemists to begin regularly using metathesis to create compounds containing cis double bonds, the researchers would need a catalyst that generated cis bonds 80–100% of the time. And the catalyst would need to be reusable, without being used up—that is, have a high turnover number. Endo's first catalyst had a turnover number around 50. It also tended to decompose in solution within about two hours of being exposed to air; an ideal catalyst would be stable in solution or even on the bench top for days at a time.

The Grubbs team has now made several versions of the catalyst and found one that can be used at least 1,000 times and is much more stable than the original. "We can expose a solution of this to oxygen, and it will stay alive for more than 12 hours," Keitz says. "If you just take a vial of this powder and leave it on the bench, it will be good for over 10 days."

Going forward, the researchers hope to use the new catalysts to synthesize large chemical rings, or macrocycles. Macrocycles are common in chemical fragrances (particularly musks) and are found in pharmaceuticals used to treat cancer and other diseases. Previous metathesis catalysts have been used to create trans macrocycles for these purposes, but the catalysts could not make rings that had a high cis double bond content. "We're hoping that our new catalysts will make it possible to synthesize these compounds using metathesis—a proven green reaction," says Grubbs.

Over the past year and a half, the Grubbs group has published several papers in the Journal of the American Chemical Society about these new catalysts. The work is financially supported by the National Science Foundation, the National Institutes of Health, Mitsui Chemicals, Inc., the Department of Defense, and the Swiss National Science Foundation.

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Notes from the Back Row: "Making Molecules"

"I grew up cooking, waiting tables, and doing dishes in the family diner in Chicago," says Jonas Peters. These days, as Caltech's Bren Professor of Chemistry, Peters is more an executive chef than a spatula jockey: he coordinates the menu and helps dream up the recipes for new molecules, but his students whip them up and wash the glassware. In his Watson Lecture on March 14, 2012, Peters leads a cook's tour of the art and science of chemistry. In his words, "What holds molecules together? How do we design one, plan the recipe, and know how well it came out?"

"The craft of making molecules hasn't changed that much" since the days of the alchemists, says Peters. "Take of cranium humanum as much as you please," he says, quoting a recipe from John French's The Art of Distillation, written in 1651. "Break it into small pieces, which put into a glass retort well luted [sealed airtight], with a large receiver well luted. Put a strong fire to it by degrees, continuing of it until you see no more fumes come forth, and you shall have a yellowish spirit, a red oil, and a volatile salt. Take this salt and the yellow spirit, and digest them by circulation two or three months in balneum [in a hot bath], and you shall have a most excellent spirit." While this extract is no longer the remedy of choice for dropsy—whatever that is—its method of preparation will be familiar to anyone who spent some time in the chem lab in high school. 

On the other hand, the theory behind making molecules has advanced considerably, allowing modern chemists to create very complex arrangements of atoms by design. Peters's own lab, for example, contributes to Caltech's Joint Center for Artificial Photosynthesis, an initiative to develop the technologies needed to run our civilization entirely on sunlight. We are still a long way from that happy dawn, but we are well beyond another piece of advice from alchemist John French, who counseled the uninitiated to "try not at first experiments of great cost or great difficulty, for it will be a great discouragement to you, and you will be very apt to mistake." At Caltech, notes Peters, "we have fantastic grad students and postdocs, so we can dive right in and do experiments of great difficulty knowing they can pull it off."

"Making Molecules" is available for download in HD from Caltech on iTunesU. (Episode 10)

 

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Doug Smith
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Zooming in on Single Cells

A Caltech chemist improves imaging technology with the help of an NIH award

Last fall, assistant professor of chemistry Long Cai received a New Innovator Award from the National Institutes of Health (NIH)—funding meant to both stimulate highly innovative research and support promising new investigators. Now, just nine months later, Cai has published the first results of his supported research.   

The New Innovator Award is one of the NIH Director's Awards, administered through the organization's Common Fund. The fund provides support for biomedical research deemed to be both innovative and risky.

Cai and his colleagues are working to use high-powered microscopy to help them better understand the genetic programs in individual cells. "We developed a new technique to show that super-resolution microscopy (SRM)—which is a cool, single-molecule-based technology that has been used to zoom in on structures and organelles in cells—can also be used to look at genetic information within a cell, like RNA and proteins," says Cai, who joined the Caltech faculty in 2010.

His paper, "Single-cell systems biology by super-resolution imaging and combinatorial labeling," is available as an advance online publication of the journal Nature Methods.

With the help of coauthor Eric Lubeck, a graduate student in biochemistry and molecular biophysics, Cai labeled individual mRNA molecules within a cell with distinct molecular barcodes. When the cell is imaged using SRM, the barcodes can be resolved and used to read the gene expression levels.   

"If you want to look at a genetic network, then you want to look at many of the individual genes at the same time—this is a way to allow you to do that in single cells," says Cai. "This technique may provide valuable information about rogue cells that are involved in cancer and other diseases, and look at gene expression in single cells within their native environments."

He says that the idea was sparked after a discussion with Barbara Wold, Bren Professor of Biology, about transcription regulation and new advances in single- molecule techniques. "It's really great to have ideas stimulated from an afternoon discussion over coffee," says Cai, "and this is part of what makes Caltech special." The project was started nearly three years ago, when Cai was a Beckman Fellow in the laboratory of Michael Elowitz, professor of biology and a Howard Hughes Medical Institute investigator. "Michael was very generous in letting me use his microscopes and lab to start the experiment," he says. "The NIH award helped us to finish the work when I set up my own lab."

Cai explains that their new method combines two existing technologies. In their proof-of-principle study, the duo was able to measure mRNA molecules in 32 genes simultaneously and within the same cell.   

"Now we're trying to show that it is possible to look at 100 genes at the same time," says Cai, who thinks it will be possible to measure thousands of genes concurrently. "It's just a matter of time."  

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Caltech Chemical Engineers Devise New Way to Split Water

Nontoxic, noncorrosive, "low-temperature" method makes use of wasted heat

PASADENA, Calif.—Providing a possible new route to hydrogen-gas production, researchers at the California Institute of Technology (Caltech) have devised a series of chemical reactions that allows them, for the first time, to split water in a nontoxic, noncorrosive way, at relatively low temperatures.

A research group led by Mark Davis, the Warren and Katharine Schlinger Professor of Chemical Engineering at Caltech, describes the new, four-reaction process in the early edition of the Proceedings of the National Academy of Sciences (PNAS).

Hydrogen is a coveted gas: industry uses it for everything from removing sulfur from crude oil to manufacturing vitamins. Since its combustion does not emit carbon dioxide into the atmosphere, there is some belief that it could even fuel a potential "hydrogen economy"—an energy-delivery system based entirely on this one gas. But since there is no abundant supply of hydrogen gas that can be simply tapped into, this lighter-than-air gas has to be mass-produced.

One way to make hydrogen is by using heat to split water, yielding pure hydrogen and oxygen. Known as thermochemical water splitting, this method is appealing because it can take advantage of excess heat given off by other processes. Thus far, it has been attempted in two ways: using two steps and taking advantage of high temperatures (above 1000°C) associated with solar collectors; or through multiple steps at "lower temperatures"—those below 1000°C—where, for example, the excess heat from nuclear reactors could drive the chemistry.

Davis is interested in this latter approach, which actually takes him back to his academic roots: his first paper as a graduate student dealt with a low-temperature water-splitting cycle, called the sulfur-iodine system, which has since been piloted for use around the world. Although that cycle operates at a maximum temperature of 850°C, it also produces a number of toxic and corrosive liquid intermediates that have to be dealt with. The cycle's high-temperature counterparts typically involve simpler reactions and solid intermediates—but there are very few processes that produce excess heat at such high temperatures.

"We wanted to combine the best of both worlds," Davis says. "We wanted to use solids, as they do in the high-temperature cycles, so we could avoid these toxicity and corrosion issues. But we also wanted to learn how to lower the temperature."

The first thing postdoctoral scholar and lead author Bingjun Xu and graduate student Yashodhan Bhawe did was to prove via thermodynamic arguments that a two-step, low-temperature cycle for water splitting will not be practical. "Nature's telling you 'No way,'" Davis says. "It was really a key point that told us we had to go away from looking for a two-step process, and that guidance directed us down another pathway that turned out to be quite fruitful."

The four-reaction cycle the team came up with begins with a manganese oxide and sodium carbonate, and is a completely closed system: the water that enters the system in the second step comes out completely converted into hydrogen and oxygen during each cycle. That's important because it means that none of the hydrogen or oxygen is lost, and the cycle can run over and over, splitting water into the two gases. In the current paper, the researchers ran their newly created cycle five times to show reproducibility. It will be needed to show that the cycle can run thousands of times in order to be practical. Experiments of this type are beyond the capabilities currently in the Davis lab.

"We're excited about this new cycle because the chemistry works, and it allows you to do real thermochemical water splitting with temperatures of 850°C without producing any of the halides or other types of corrosive acids that have been problems in the past," Davis says. Still, he is careful to point out that the implementation of the cycle as a functioning water-splitting system will require clever engineering. For example, for practical purposes, engineers will want some of the reactions to go faster, and they would also need to build processing reactors that have efficient-energy flows and recycling amongst the different stages of the cycle.

Going forward, the team plans to study further the chemistry of the cycle at the molecular level. They have already learned that shuttling sodium in and out of the manganese oxide is critical in lowering the operating temperature, but they want to know more about what exactly is happening during those steps. They hope that the enhanced understanding will allow them to devise cycles that could operate at even lower maximum temperatures.

Figuring out ways to decrease the operating temperatures is at the heart of Davis's interest in this project. "What we're trying to ask is, 'Where are the places around the world where people are just throwing away energy in the form of heat?'" he says. He speculates that there could be a day when water-splitting plants are able to run on the heat given off by a variety of manufacturing industries such as the steel- and aluminum-making industries and the petrochemicals industries, and by the more traditional power-generation industries. "The lower the temperature that we can use for driving these types of water-splitting processes," he says, "the more we can make use of energy that people are currently just wasting."

The PNAS paper, "Low-temperature, manganese oxide-based thermochemical water splitting cycle" is now online. The work was funded by a donation from Mr. and Mrs. Lewis W. van Amerongen.  

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Kimm Fesenmaier
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From the Ground Up

What's it like to build an entire research program from scratch? It's all about becoming part of a community, according to three brand-new professors: 

"It's very important to generate an environment where people help each other." —André Hoelz 

"I have two challenges getting started here. One is bringing in students and postdocs, and the other is fostering a connection between economics and computer science." —Katrina Ligett

"It is not traditionally a field Caltech has done. . . . So when I was looking at coming to Caltech, the idea of being 'the oceanographer' was an exciting prospect.' —Andrew Thompson

Read "From the Ground Up" in the Spring 2012 issue of Caltech's Engineering & Science magazine. 

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Doug Smith
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Building a Research Program from the Ground Up
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American Chemical Society Names Caltech Chemist Sarah Reisman a Rising Star

Sarah E. Reisman, an assistant professor of chemistry at Caltech, will receive the WCC Rising Star Award today, making her one of 10 midcareer women chemists to be honored with the award in its inaugural year. The distinction, bestowed by the Women Chemists Committee (WCC) of the American Chemical Society (ACS), will be presented at the society's 243rd national meeting in San Diego and is intended to help promote the retention of women in science.

"We have done a better job in encouraging women into the STEM (science, technology, engineering, and mathematics) fields with higher numbers achieving both Bachelors and Doctoral degrees," said Nancy Jackson, immediate past president of the ACS, in a statement. "However, the actual number of women in mid-career positions continues to decline. I am pleased to see the WCC address this important issue, and the WCC Rising Star Award is a perfect opportunity to highlight successful women chemists to promote retention in the chemical enterprise."

Reisman was cited by the WCC "for excellence in the development of catalytic asymmetric methodologies for natural product synthesis." Her group at Caltech works to develop new ways to synthesize in the laboratory chemical compounds that are produced naturally by plants, bacteria, or fungi.

Reisman explains that her group chooses to work on natural products for two reasons: From a biology standpoint, organisms often make these compounds as mechanisms of chemical warfare—bacteria produce antibiotics to kill other bacteria, for instance. This can make the chemicals desirable for pharmaceutical development. From a chemistry standpoint, she says, "we usually select really complicated, challenging molecules because they require us to develop new chemistry if we want to prepare them in any sort of straightforward fashion."

The Reisman group has recently focused on synthesizing a class of compounds called ETPs, short for the chemical functional group epidithiodiketopiperazine that these compounds contain. ETPs are extremely reactive and participate in a lot of interesting biology, but this reactivity also makes them difficult to work with. Reisman and her colleagues recently published a paper in the Journal of the American Chemical Society describing the synthesis of an ETP called acetylaranotin, which was isolated in the 1960s but had never been prepared synthetically. "It's exciting because it provides the first synthetic access to a particular class of ETP compounds," Reisman says. "We know that they have some promising properties in terms of cancer therapeutics, but they haven't been studied in any detail."

Reisman was born and raised in Bar Harbor, Maine. She earned her BA at Connecticut College in 2001 and her PhD at Yale University in 2006. She was a postdoctoral fellow at Harvard University and joined the faculty at Caltech in 2008.

When she thinks back on her education, she says she fell in love with synthetic organic chemistry when she took her first organic chemistry class as a premed requirement. She quickly realized that she no longer wanted to go to medical school, but instead she wanted to do organic chemistry research.

"What I love about organic chemistry is that it takes the best aspects of scientific research and adds a kind of creative discipline," Reisman says. "When you go in the lab and when you're designing experiments, that's grounded in our scientific method, but before you get into the lab, when you're thinking about how you want to make a given molecule, that's a very creative endeavor, and I really like that aspect. In some ways, it's very much like solving a logic puzzle."

For a complete list of the winners of the inaugural Rising Star Award, click here

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Kimm Fesenmaier
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American Chemical Society Honors Shu-ou Shan

The American Chemical Society (ACS) has honored Shu-ou Shan, professor of chemistry at Caltech, with this year's Nobel Laureate Signature Award for Graduate Education in Chemistry.

According to the ACS website, the purpose of the award is "to recognize an outstanding graduate student and her or his preceptor(s), in the field of chemistry, as broadly defined."

Shan was honored as preceptor along with Xin Zhang, a student at the Scripps Research Institute.

They were selected "for pioneering mechanistic studies on the fidelity of protein targeting mediated by the signal recognition particle system," and they will be honored at an awards ceremony on March 27 in conjunction with the 243rd ACS national meeting in San Diego.

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Allison Benter
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Caltech Study Supports Model for Locating Genetic Damage Through DNA Charge Transport

PASADENA, Calif.—Our genetic information is under constant attack—not only from outside sources such as UV radiation and environmental toxins, but also from oxidative stress, the production of highly reactive forms of oxygen, within our bodies. Luckily, repair proteins are typically hard at work, locating and fixing damaged DNA. Over the past decade, Caltech chemist Jacqueline Barton has been exploring a model that describes how repair proteins might work together in this scouting mission to efficiently home in on lesions or mismatches within the DNA.

Essentially, the model suggests that two DNA-bound repair proteins can use DNA like a wire to shuttle electrons between themselves—a process called charge transport. When one protein receives an electron from the other, its affinity for the DNA to which it clings decreases, causing the protein to fall off that strand. If instead, a lesion—a structural defect in the DNA—prevents that electron from being transferred between the proteins, both members of the pair remain bound to the DNA and begin inching toward the problem area. Since this signaling can be achieved over long molecular distances, the model could explain how it is that the relatively few repair proteins in our cells are able to scour so much genetic information to efficiently locate problems. 

Providing support for that model, Barton's team has recently shown that two different repair proteins that are part of two different genome-maintenance pathways preferentially reposition themselves onto damaged strands of DNA. Publishing in the journal Proceedings of the National Academy of Sciences (PNAS), the group recently reported that repair proteins relocate in this way only if they have the capability to participate in charge transport. In the study, proteins with mutations that destroy their charge-transport capabilities could not zero in on DNA lesions. Versions of those mutated proteins found in humans are associated with diseases such as colorectal cancer, Cockayne syndrome, and xeroderma pigmentosum, suggesting that charge transport may indeed be a necessary part of genome maintenance.

"These findings are consistent with and provide data to support the model of facilitated search for lesions through DNA-mediated signaling between proteins," says Barton, the Arthur and Marian Hanisch Memorial Professor of Chemistry and chair of the Division of Chemistry and Chemical Engineering at Caltech. "This provides another piece of the puzzle."

In their study, the researchers investigated XPD, a protein involved in both DNA repair and replication. First, the scientists attached very short strands of DNA to a gold electrode, added the XPD, and used the electrode to measure the protein's electrical potential, or its ability to send or receive electrons. Separately, the chemists made a solution of the protein along with both regularly matched strands of DNA and longer strands that included a mismatched pair of nucleotides, which are the individual chemical units that make up DNA. Then they used microscopy to visualize and count the number of proteins that bound themselves to the different types of DNA. They found that only the proteins that were able to send and receive electrons through the DNA repositioned themselves in the vicinity of the mismatched nucleotides.

"We believe that the redistribution comes from two proteins using charge transport to communicate with one another, and falling off of the strands that don't have a lesion and attaching to the strands that do," says Pam Sontz, lead author on the study and a graduate student at Caltech.

In a previous study, the Barton lab had conducted similar experiments with Endonuclease III (EndoIII), a repair protein that removes damaged bases. They found that like XPD, EndoIII redistributes itself so that it can home in on mismatches in DNA, and that mutant forms of EndoIII that cannot participate in charge transfer do not relocalize.

In the new study, the researchers were also able to show that mixtures of EndoIII and XPD were able to coordinate in order to relocate onto the mismatched strands of DNA. The team was working with EndoIII from the bacteria Escherichia coli and XPD from a microorganism called Sulfolobus acidocaldarius.

"Our findings suggest that these two proteins are able to signal one another in order to zero in on a lesion," Sontz says. "They're from different DNA-repair pathways and from totally separate organisms, which is really neat. That's what's really opening the door for a lot of future studies. If EndoIII and XPD can do this, there are probably many other proteins from a variety of organisms that are also able to send or receive charge through DNA."

Coauthor and graduate student Tim Mui adds that this kind of cooperation between tested proteins that are normally completely isolated from one another could indicate that the mechanism has been conserved by organisms across evolutionary history. "It's kind of remarkable that these proteins, which should never ever be in contact with one another, can actually coordinate to do this," he says.

The key to this coordination seems to be that the two types of proteins have comparable electrical potentials when bound to DNA, meaning that they are similar in their likelihood to gain or lose electrons. "We're finding that one of the requirements for a protein to potentially participate in this process is that as it binds to DNA, it has to have a similar potential to other proteins, so that it can release an electron that can shuttle through the DNA to another protein," Sontz says. "If the two proteins are not at similar potentials, you're not going to get accurate cooperation."

The proteins have this ability to send and receive electrons because they contain what are called redox-active iron-sulfur clusters. Both XPD and EndoIII contain four-iron, four-sulfur clusters that play no clear structural role in the proteins but contain metals that can easily gain or lose an electron as they bind DNA. "It's really difficult for the cell to build these clusters," Mui says. "So there is a thought that they must play a significant role in something else, which could be this mechanism to locate lesions within the DNA."

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Kimm Fesenmaier
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Caltech Professor David Tirrell Named Director of the Beckman Institute

David Tirrell, the Ross McCollum-William H. Corcoran Professor and professor of chemistry and chemical engineering at Caltech, has been appointed director of the Beckman Institute. He succeeds biologist Barbara Wold, who has returned to full-time professorial duties after a decade at the institute's helm.

"We would like to thank Barbara Wold for her dedication to and leadership of the Beckman Institute over the past 10 years," says Stephen Mayo, chair of the Division of Biology. "Under her guidance, the Beckman Institute has truly advanced its mission, enabling the invention of methods, instrumentation, and materials that will provide new opportunities for research at the interface of chemistry and biology."

Tirrell, who is known for work that bridges chemistry, biology, and materials science, served as chair of the division of Chemistry and Chemical Engineering at Caltech from 1999 until 2009. He was chosen for the new position by a search committee chaired by Doug Rees, Caltech's Roscoe Gilkey Dickinson Professor of Chemistry.

"Dave's research interests will serve him well in overseeing the Beckman Institute as will his administrative talents as a former chair of the Division of Chemistry and Chemical Engineering for ten years," says Jacqueline Barton, current chair of the division. "We thank him for this important service to the Institute and look forward to his outstanding leadership."

The Beckman Institute was opened in 1989 in a 160,000-square-foot building on the west end of campus with Harry Gray, the Arnold O. Beckman Professor of Chemistry, as the founding director. Made possible by an initial $50 million commitment and challenge from the Arnold and Mabel Beckman Foundation in 1986, the institute provides space for interdisciplinary work in endeavors such as advanced imaging, laser spectroscopy and X-ray diffraction, synthesis and characterization of novel organic and inorganic materials, and advanced mass spectroscopic methods for characterization of large biomolecules.

Tirrell joined the faculty at Caltech in 1998. He earned his BS from MIT in 1974 and his PhD from the University of Massachusetts in 1978. He became an assistant professor at Carnegie-Mellon University in 1978 and signed on as director of the Materials Research Laboratory at the University of Massachusetts in 1984.

Tirrell is one of only 13 living members of all three branches of the National Academies (Sciences, Engineering, and Medicine). He has also been awarded the Arthur C. Cope Scholar, Carl Marvel, Harrison Howe, S. C. Lind, and Madison Marshall Awards of the American Chemical Society, as well as the ACS Award in Polymer Chemistry.

Tirrell has developed methods for getting bacterial cells to "read" artificial genes and produce protein-like structures with unusual properties. His methods have led to new strategies for the design of therapeutic proteins and to new approaches to the analysis of protein synthesis in cells, tissues, and organisms.

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Kimm Fesenmaier
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