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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In Our Community

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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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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Kimm Fesenmaier
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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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Katie Neith
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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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Kimm Fesenmaier
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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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Kimm Fesenmaier
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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."

Writer: 
Kimm Fesenmaier
Writer: 

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