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Caltech's Sarah Reisman Wins Arthur C. Cope Scholar Award

Sarah Reisman, assistant professor of chemistry at Caltech, is one of 10 winners of 2013 Arthur C. Cope Scholar Award from the American Chemistry Society. Winning in the "early career scholar" category, Reisman will accept the award at the annual meeting of the American Chemistry Society in Indianapolis in September 2013.

According to the award citation, Reisman was recognized for her Caltech research group's original contributions to the understanding of complex molecule synthesis and reaction development.

"It is a wonderful honor in recognition of our research program," says Reisman. "I am very proud of my students and post-doctoral fellows whose dedication and hard work helped to make this award possible."

The award includes a certificate, a $5,000 cash prize, a $40,000 unrestricted research grant, and up to $2,500 in travel expenses for Reisman to deliver a lecture at the American Chemical Society's meeting in Indianapolis next year.

 

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Caltech Again Named World's Top University in <i>Times Higher Education</i> Global Ranking

PASADENA, Calif.—The California Institute of Technology (Caltech) has been rated the world's number one university in the 2012–2013 Times Higher Education global ranking of the top 200 universities.

Oxford University, Stanford University, Harvard University, and MIT round out the top five.

"We are pleased to be among the best, and we celebrate the achievements of all our peer institutions," says Caltech president Jean-Lou Chameau. "Excellence is achieved over many years and is the result of our focus on extraordinary people. I am proud of our talented faculty, who educate outstanding young people while exploring transformative ideas in an environment that encourages collaboration rather than competition."

Times Higher Education compiled the listing using the same methodology as in last year's survey. Thirteen performance indicators representing research (worth 30 percent of a school's overall ranking score), teaching (30 percent), citations (30 percent), international outlook (which includes the total numbers of international students and faculty and the ratio of scholarly papers with international collaborators, 7.5 percent), and industry income (a measure of innovation, 2.5 percent) make up the data. Included among the measures are a reputation survey of 17,500 academics; institutional, industry, and faculty research income; and an analysis of 50 million scholarly papers to determine the average number of citations per scholarly paper, a measure of research impact.

In addition to placing first overall in this year's survey, Caltech came out on top in the teaching indicator as well as in subject-specific rankings for engineering and technology and for the physical sciences.

"Caltech held on to the world's number one spot with a strong performance across all of our key performance indicators," says Phil Baty, editor of the Times Higher Education World University Rankings. "In a very competitive year, when Caltech's key rivals for the top position reported increased research income, Caltech actually managed to widen the gap with the two universities in second place this year—Stanford University and the University of Oxford. This is an extraordinary performance."

Data for the Times Higher Education's World University Rankings were provided by Thomson Reuters from its Global Institutional Profiles Project, an ongoing, multistage process to collect and validate factual data about academic institutional performance across a variety of aspects and multiple disciplines.

The Times Higher Education site has the full list of the world's top 400 schools and all of the performance indicators.

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John Brady Wins Fluid Dynamics Prize

John Brady, Chevron Professor of Chemical Engineering and professor of mechanical engineering at Caltech, will receive the 2012 Fluid Dynamics Prize from the American Physical Society at the Division of Fluid Dynamics annual meeting in November. Brady was cited for his contributions to the study of the deformation and flow of complex fluids, for developing a computational model known as Stokesian Dynamics, and for his contributions to the field of fluid dynamics through his role as a journal editor.

"I am honored to receive this award from the American Physical Society," Brady says. "The mechanics of complex fluids is a very exciting field right now. While we gained a great deal of understanding of these materials over the past few decades, there is still so much yet to be discovered. That's what keeps me and my research group going."

 

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Showing the Way to Improved Water-Splitting Catalysts

Caltech chemists identify the mechanism by which such catalysts work

PASADENA, Calif.—Scientists and engineers around the world are working to find a way to power the planet using solar-powered fuel cells. Such green systems would split water during daylight hours, generating hydrogen (H2) that could then be stored and used later to produce water and electricity. But robust catalysts are needed to drive the water-splitting reaction. Platinum catalysts are quite good at this, but platinum is too rare and expensive to scale up for use worldwide. Several cobalt and nickel catalysts have been suggested as cheaper alternatives, but there is still plenty of room for improvement. And no one has been able to determine definitively the mechanism by which the cobalt catalysts work, making it difficult to methodically design and construct improved catalysts.

Now chemists at the California Institute of Technology (Caltech) have determined the dominant mechanism for these cobalt catalysts. Their findings illuminate the road to the development of better catalysts—even suggesting a route to the development of catalysts based on iron, an element that is plentiful and cheap and could offer part of the answer to our energy woes.

"We've worked out this mechanism, and now we know what to do to make a really great catalyst out of something that's really cheap as dirt," says Harry Gray, the Arnold O. Beckman Professor of Chemistry at Caltech and senior author of a paper that describes the findings in the current issue of the Proceedings of the National Academy of Sciences (PNAS). "This work has completely changed our thinking about which catalyst designs to pursue."

A major barrier to improving the performance of man-made catalysts has been the lack of understanding of the mechanism—the chemical pathway that such catalysts follow leading to the production of hydrogen. As with any multistep manufacturing project, chemists need to know what is involved in each reaction that takes place—what goes in, what changes take place, and what comes out—in order to maximize efficiency and yield.

Three mechanisms have been suggested for how the cobalt catalysts help make hydrogen—one proposed by a French team, one developed by Caltech researchers, including Nate Lewis and Jonas Peters, and a third suggested more recently by a former graduate student in Gray's group, Jillian Dempsey (PhD '10). Until now, no one has managed to prove definitively which mechanisms actually occur or whether one was dominant, because the reactions proceed so quickly that it is difficult to identify the chemical intermediates that provide evidence of the reactions taking place. 

These cobalt catalysts are complexes that involve the metal bound to many different functional groups, or ligands. In the current study, Caltech postdoctoral scholar Smaranda Marinescu was able to add a set of ligands to cobalt, making the reaction slow down to the point where the researchers could actually observe the key intermediate using nuclear magnetic resonance (NMR) spectroscopy. "Once we could see that key intermediate by NMR and other methods, we were able to look at how it reacted in real time," Gray says. They saw that Dempsey's mechanism is the predominant pathway that these catalysts use to generate hydrogen. It involves a key reactive intermediate gaining an extra electron, forming a compound called cobalt(II)-hydride, which turns out to be the mechanism's active species.

In a previous PNAS paper, work by Gray and lead author Carolyn Valdez suggested that the Dempsey mechanism was the most likely explanation for the detected levels of activity. The new paper confirms that suggestion.

"We now know that you have to put another electron into cobalt catalysts in order to get hydrogen evolution," Gray says. "Now we have to start looking at designs with ligands that can accept that extra electron or those that can make atomic cobalt, which already has the extra electron."

Gray's group is now working on this latter approach. Moreover, these results give his group the information they need to develop an extremely active iron catalyst, and that will be their next big focus.

"We know now how to make a great catalyst," he says. "That's the bottom line."

In addition to Marinescu and Gray, Jay Winkler, a faculty associate and lecturer at Caltech, was also a coauthor on the paper, "Molecular mechanisms of cobalt-catalyzed hydrogen evolution." The work was supported by the National Science Foundation Center for Chemical Innovation in Solar Fuels as well as Chevron Phillips Chemical.

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Chemical Insights About Splitting Water
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Learning One of Cancer's Tricks

Caltech chemists determine one way tumors meet their growing needs

PASADENA, Calif.— Behaving something like ravenous monsters, tumors need plentiful supplies of cellular building blocks such as amino acids and nucleotides in order to keep growing at a rapid pace and survive under harsh conditions. How such tumors meet these burgeoning demands has not been fully understood. Now chemists at the California Institute of Technology (Caltech) have shown for the first time that a specific sugar, known as GlcNAc ("glick-nack"), plays a key role in keeping the cancerous monsters "fed." The finding suggests new potential targets for therapeutic intervention.

The new results appear in this week's issue of the journal Science

The research team—led by Linda Hsieh-Wilson, professor of chemistry at Caltech—found that tumor cells alter glycosylation, the addition of carbohydrates (in this case GlcNAc) to their proteins, in response to their surroundings. This ultimately helps the cancerous cells survive. When the scientists blocked the addition of GlcNAc to a particular protein in mice, tumor-cell growth was impaired.

The researchers used chemical tools and molecular modeling techniques developed in their laboratory to determine that GlcNAc inhibits a step in glycolysis (not to be confused with glycosylation), a metabolic pathway that involves 10 enzyme-driven steps. In normal cells, glycolysis is a central process that produces high-energy compounds that the cell needs to do work. But Hsieh-Wilson's team found that when GlcNAc attaches to the enzyme phosphofructokinase 1 (PFK1), it suppresses glycolysis at an early phase and reroutes the products of previous steps into a different pathway—one that yields the nucleotides a tumor needs to grow, as well as molecules that protect tumor cells. So GlcNAc causes tumor cells to make a trade—they produce fewer high-energy compounds in order to get the products they need to grow and survive.

"We have identified a novel molecular mechanism that cancer cells have co-opted in order to produce intermediates that allow them to grow more rapidly and to help them combat oxidative stress," says Hsieh-Wilson, who is also an investigator with the Howard Hughes Medical Institute.

This is not the first time scientists have identified a mechanism by which tumor cells might produce the intermediates they need to survive. But most other mechanisms have involved genetic alterations, or mutations—permanent changes that lead to less active forms of enzymes, for example. "What's unique here is that the addition of GlcNAc is dynamic and reversible," says Hsieh-Wilson. "This allows a cancer cell to more rapidly alter its metabolism depending on the environment that it encounters."

In their studies, Hsieh-Wilson's team found that this glycosylation—the addition of GlcNAc to PFK1—is enhanced under conditions associated with tumors, such as low oxygen levels.  They also found that glycosylation of PFK1 was sensitive to the availability of nutrients. If certain nutrients were absent, glycosylation was increased, and the tumor was able to compensate for the dearth of nutrients by changing the cell's metabolism.

When the researchers analyzed human breast and lung tumor tissues, they found GlcNAc-related glycosylation was elevated two- to fourfold in the majority of tumors relative to normal tissue from the same patients. Then, working with mice injected with human lung-cancer cells, the researchers replaced the existing PFK1 enzymes with either the normal PFK1 enzyme or a mutant form that could no longer be glycosylated. The mice with the mutant form of PFK1 showed decreased tumor growth, demonstrating that blocking glycosylation impairs cancerous growth.

The work suggests at least two possible avenues for future investigations into fighting cancer. One would be to develop compounds that prevent PFK1 from becoming glycosylated, similar to the mutant PFK1 enzymes in the present study. The other would be to activate PFK1 enzymes in order to keep glycolysis operating normally and help prevent cancer cells from altering their cellular metabolism in favor of cancerous growth.

Hsieh-Wilson's group has previously studied GlcNAc-related glycosylation in the brain. They have demonstrated, for example, that the addition of GlcNAc to a protein called CREB inhibits the protein's ability to turn on genes needed for long-term memory storage. On the other hand, they have also shown that having significantly lower levels of GlcNAc in the forebrain leads to neurodegeneration. "The current thinking is that there's a balance between too little and too much glycosylation," says Hsieh-Wilson. "Being at either extreme make things go awry, whether it's in the brain or in the case of cancer cells."

Additional Caltech coauthors on the paper, "Phosphofructokinase 1 Glycosylation Regulates Cell Growth and Metabolism," were lead author Wen Yi, a postdoctoral scholar in Hsieh-Wilson's group; Peter Clark, a former graduate student in Hsieh-Wilson's group; and William Goddard III, the Charles and Mary Ferkel Professor of Chemistry, Materials Science, and Applied Physics. Daniel Mason and Eric Peters of the Genomics Institute of the Novartis Research Foundation and Marie Keenan, Collin Hill, and Edward Driggers of Agios Pharmaceuticals were also coauthors.

The work was supported by the National Institutes of Health, the Department of Defense Breast Cancer Research Program, and a Tobacco-Related Disease Research Program postdoctoral fellowship.

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Caltech Chemist Wins ASBMB Young Investigator Award

The American Society of Biochemistry and Molecular Biology (ASBMB) named Caltech chemistry professor Shu-ou Shan a recipient of the 2013 Young Investigator Award. The award will be presented at the ASBMB annual meeting in Boston next April.

Shan was recognized for her research that addresses how "a novel class of nucleotide hydrolases drives the efficient and accurate delivery of newly synthesized proteins to their correct destinations."

"This award would not have been possible without the support from my subgroup and division and all the wonderful Caltech students and postdocs who work so hard," says Shan.

"We are extremely happy that ASBMB has selected Shu-ou Shan for the Young Investigators Award," said Jacqueline Barton, Arthur and Marian Hanisch Memorial Professor, professor of chemistry, and chair of the Division of Chemistry and Chemical Engineering at Caltech. "It is a testament to the hard work and dedication of Shan and her team here at Caltech."

Shan's research interfaces between chemistry and biology to understand fundamental cellular processes at the level of chemical and physical principles. More information about Shan's research group at Caltech can be found at http://shangroup.caltech.edu.

The ASBMB Young Investigator Award recognizes outstanding research contributions to biochemistry and molecular biology. The recipient must have no more than 15 years postdoctoral experience. Nominations for these awards are made by ASBMB members, but nominees need not be members. The award consists of a plaque, $5,000, transportation, and expenses to present a lecture at the 2013 ASBMB annual meeting.

 

 

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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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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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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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