ROBERTO CAR receives American Chemistry Society national award

Roberto Car

Roberto Car (Photo by Frank Wojciechowski)

Roberto Car, the Ralph W. *31 Dornte Professor in Chemistry, was recognized for his innovative research by the American Chemical Society (ACS) during a ceremony March 15, 2016. He received the ACS Award in Theoretical Chemistry for the “depth, originality and scientific significance” of his work.

Car’s research explores materials at the level of atoms and electrons. He uses theoretical tools and numerical simulations to gain insight into the chemical and physical processes underlying chemical reactions. While Car’s research is theoretical and fundamental, his discoveries may have technological implications that can aid in the design of new materials and devices with desirable properties. Car, who is a professor of chemistry and the Princeton Institute for the Science and Technology of Materials, is known for the invention of an ab initio moleculardynamics method with Italian physicist Michele Parrinello that is now a standard tool for molecular simulation. The method has been applied to a variety of problems in condensed matter and chemical physics, materials science, geosciences, chemistry and biochemistry.

 

PAUL CHIRIK receives Presidential Green Chemistry Challenge Award

PAUL CHIRIK

Paul Chirik (Photo by C. Todd Reichart)

Paul Chirik, the Edwards S. Sanford Professor of Chemistry, was among five recipients nationwide of the 2016 Presidential Green Chemistry Challenge Awards presented by the U.S. Environmental Protection Agency. Chirik was recognized for discovering a new class of catalysts that produce silicones without using hard-to-obtain platinum, which could dramatically reduce the mining of ore and reduce costs, greenhouse-gas emissions and waste. The winners were recognized during a ceremony June 13, 2016.

Of swords, stars and superconductors

Robert Cava weaves physicists’ dreams into exotic new materials

By Bennett McIntosh

ROBERT CAVA PULLS A LONG CURVED steel blade from its ornate sheath, revealing a rippling pattern of light and dark metal. The sword is a Japanese katana made from steel of such legendary strength and sharpness that it was said to be able to cut a hair as it fell to the ground.

In his office where the shelves are lined with mineral samples and crystal structures, Cava, Princeton’s Russell Wellman Moore Professor of Chemistry, recounts the sword’s role in his destiny. He’d entered the Massachusetts Institute of Technology (MIT) wanting to study applied physics. “Someone at MIT interpreted ‘applied physics’ as being about materials science,” he said. “So, I ended up in a freshman seminar about samurai swords.”

Samurai swords derive their mythic properties from distinctive arrangements of iron and carbon atoms, Cava learned. His fascination with the atomic structure of the ancient metal turned into a career arranging atoms into materials for a more modern age: batteries, superconductors and materials with strange and exotic properties that could become the basis for future electronic devices.

In the 1970s, when Cava was a student, these technologies were far off in the future. Captivated by the science of materials, Cava stayed at MIT to earn his Ph.D. in ceramics. “Now I know how to make toilet bowls,” Cava quipped. In fact, ceramics have a wide range of electrical properties that make them useful in computers, televisions and communications devices. After graduation and a postdoctoral fellowship at the National Bureau of Standards, Cava took a job at Bell Laboratories, the research arm of the then-dominant AT&T telephone company.

Renowned for hiring the best and giving its researchers intellectual freedom, Bell Labs was at the time brimming with new ideas. “Collaborations were built by sitting with random people in the cafeteria,” Cava recalled. One day in 1986, one of these collaborators invited Cava to a seminar on high temperature superconductors, which were newly discovered materials that conducted electricity with no energy loss, but required less of the expensive refrigeration conventional superconductors needed.

Sitting in the seminar, Cava contemplated how the atoms in the new materials could be arranged to improve their performance. “I went back to the lab and four days later I had made a better superconductor,” he said. He would co-author more than 30 papers on superconductors in 1987 alone. One former colleague, Bertram Batlogg, now at the Swiss Federal Institute of Technology in Zurich (ETH Zurich), recalled being so excited about one discovery that they wrote the paper in one night, fueled by “European-strength coffee and fresh home-baked cornbread.”

In 1996, as AT&T broke up and spun off Bell Labs, Cava moved to Princeton, where he established a reputation of being able to weave physicists’ dreams into exotic new materials. When his collaborators in the Department of Physics come to him with theoretical predictions, he can often make a material that exhibits the desired properties. Some of the new materials he has conjured are topological insulators, materials that act like superconductors on their surface but conduct no electricity at all under the surface. “It is dark magic,” said B. Andrei Bernevig, a Princeton professor of physics and a frequent collaborator of Cava’s.

Robert Cava

Chemistry professor Robert Cava can sometimes be spotted walking through Frick Chemistry Laboratory in one of the costumes he dons for his first-year general chemistry course. (Photo by Sameer A. Khan/Fotobuddy)

Cava is more understated in explaining what he calls his “chemical intuition.” The properties of a material depend as much upon the geometrical arrangement of its atoms as on the specific kinds of atoms. Cava approaches designing a new material first by finding the right geometry — how many other atoms of each kind should each atom connect to, and in which orientations — and then finding the right atoms to fit this geometry. All the while, he bounces ideas off his students and collaborators. “In the end, science is very personal,” Cava said.

The move to Princeton from Bell Labs brought more than new collaborators and projects. “At Princeton, I have to be more than a scientist,” Cava said. He had to become a teacher and, often, a performer, to engage the 100-plus students in his first-year general chemistry course.

To share the inspiration he has felt every day since his first materials-science class, Cava peppers his lessons with references to ancient alchemists and demonstrations of the power of their discoveries. Slicing a pumpkin — often adorned with a Harvard cap — with his Samurai sword is perhaps the tamest demonstration. “He’s always blowing something up, or lighting something on fire,” said Marisa Sanders, a Ph.D. student in Cava’s lab.

The antics cross over to his lab, where the lab rules encourage taking experimental risks, and where he can sometimes be spotted walking the lab in a Darth Vader costume, which he wears when he administers final exams, to, as he puts it, “relieve some of the students’ tension.” He is a patient teacher, willing to sit for hours with students to work through a difficult problem or an unexpected result.

But, especially in materials chemistry, such logical teaching only goes so far. The most harebrained ideas will either succeed or teach in their failure, according to Cava. “If he thinks something is not going to work, he won’t tell you not to do it,” said Elizabeth Seibel, a doctoral student in Cava’s lab. “But he might make a bet with you.”

When Cava isn’t conjuring crystals, he pursues his first scientific love, astronomy. Growing up on Long Island during the 1960s Space Race, Cava swapped his model-train set for another student’s home-built telescope just to get a good look at the moon. Now his students laugh at him for having so many telescopes in his garage that there is no room for a car. “I love to sit under the night sky and appreciate how beautiful the universe is,” he said. He shares this love with others, setting up a telescope outside the chemistry building to share eclipses and solar flares with colleagues and students. “It’s something that a bunch of us from the lab really look forward to,” Seibel said.

Beyond his passions for chemistry and astronomy, Cava hopes his mentorship and example help his students find something they love to do. “You have to be passionate about something,” he said. “In the end, you don’t want to look back and think, ‘I didn’t do anything with my life.’” He certainly will not have to worry about that.

Bright future: Princeton researchers unlock the potential of light to perform previously impossible feats

By Bennett McIntosh

One hundred years ago, Italian chemist Giacomo Ciamician predicted a future society that would run on sunlight.

In a paper presented in 1912 to an international meeting of chemists in New York City, he foresaw a future of vibrant desert communities under “a forest of glass tubes and greenhouses of all sizes” where light-driven chemical reactions would produce not just energy but also wondrous medicines and materials.

Ciamician’s vision has not yet arrived, but a handful of Princeton researchers have succeeded with one part of his legacy: they are harnessing light to perform previously impossible feats of chemistry. In Princeton’s Frick Chemistry Laboratory, blue LED lamps cast light on flask after flask of gently stirring chemicals that are reacting in ways they never have before to create tomorrow’s medicines, solvents, dyes and other industrial chemicals.

The leader in this emerging field is David MacMillan, who arrived in Princeton’s chemistry department in 2006. He was intrigued by the potential for using light to coax new chemical reactions. Like most chemists, he’d spent years learning the rules that govern the interactions of elements such as carbon, oxygen and hydrogen, and then using those rules to fashion new molecules. Could light help change these rules and catalyze reactions that have resisted previous attempts at manipulation?

Changing the rules

The idea for using light as a catalyst had been explored since Ciamician’s time with limited success. Light can excite a molecule to kick loose one or more of its electrons, creating free radicals that are extremely reactive and readily form new bonds with one another. However, most chemists did not think this process could be controlled precisely enough to make a wide variety of precision molecules.

But that changed in the summer of 2007.

MacMillan and postdoctoral researcher David Nicewicz were working on a tough problem. The two scientists wanted to create chemical bonds between one group of atoms, called bromocarbonyls, and another group, known as aldehydes. “It was one of those longstanding challenges in the field,” MacMillan said. “It was one of those reactions that was really useful for making new medicines, but nobody knew how to do it.”

Nicewicz had found a recipe that worked, but it involved using ultraviolet (UV) light. This high-energy form of light causes sunburn by damaging the molecules in the skin, and it also damaged the molecules in the reaction mixture, making the recipe Nicewicz had discovered less useful. MacMillan, who is Princeton’s James S. McDonnell Distinguished University Professor of Chemistry, asked Nicewicz to investigate how to do the transformation without UV light.

Nicewicz recalled some experiments that he’d seen as a graduate student at the University of North Carolina-Chapel Hill. Researchers led by chemistry professor Malcom Forbes had split water into oxygen and hydrogen fuel using visible light and a special molecule, a catalyst containing a metal called ruthenium. The approach was known as “photoredox catalysis” because particles of light, or photons, propel the exchange of electrons in a process called oxidation-reduction, or “redox” for short.

David MacMillan

David MacMillan is a leader in developing the use of light to catalyze chemical reactions — a technique called photoredox catalysis. (Photo by Sameer A. Khan/Fotobuddy)

Visible light is lower in energy than ultraviolet light, so Nicewicz and MacMillan reasoned that the approach might work without damaging the molecules. Indeed, when the researchers added a ruthenium catalyst to the reaction mixture and placed the flask under an ordinary household fluorescent lightbulb, the two scientists were astounded to see the reaction work almost perfectly the first time. “More times than not, the reaction you draw on the board never works,” Nicewicz said. Instead, the reaction produced astonishing amounts of linked molecules with high purity. “I knew right away it was a fantastic result,” he said.

With support from the National Institutes of Health, MacMillan and Nicewicz spent the next year showing that the reaction was useful for many different types of bromocarbonyls and aldehydes, results that the team published in Science in October 2008. Research in the lab quickly expanded beyond this single reaction, and each new reaction hinted at a powerful shift in the rules of organic chemistry. “It just took off like gangbusters,” MacMillan said. “As time goes on you start to realize that there are nine or 10 different things that it can do that you didn’t think of.”

Old catalysts, new tricks

At the time that Nicewicz and MacMillan were making their discovery, chemistry professor Tehshik Yoon and his team at the University of Wisconsin-Madison found that combining the ruthenium catalyst with light produced a different chemical reaction. They published their work in 2008 in the Journal of the American Chemical Society the same day MacMillan’s paper appeared in Science. Within a year of MacMillan publishing his paper, Corey Stephenson, a University of Michigan chemistry professor, and his team found yet another photoredox-based reaction.

With these demonstrations of the versatility of photoredox catalysts, other chemists quickly joined the search for new reactions. About 20 photoredox catalysts were already available for purchase from chemical catalogs due to previous research on watersplitting and energy storage, so researchers could skip the months-long process of building catalysts. However, by designing and tailoring new catalysts, the chemists unlocked the potential to use light to drive numerous new reactions, and today there are more than 400 photoredox catalysts available.

The secret to these catalysts’ ability to drive specific reactions lies in their design. The catalysts consist of a central atom, often a metal atom such as ruthenium or iridium, surrounded by a halo of other atoms. Light frees an electron from the central atom, and the atoms surrounding the center act as a sort of channel that ushers the freed electrons toward the specific atoms that the chemists want to join.

One scientist who became intrigued with the power of photoredox catalysts was Abigail Doyle, a Princeton associate professor of chemistry. Doyle, whose work is funded by the National Institutes of Health, uses nickel to help join two molecules. In 2014, she was searching for a way to conduct a reaction that had long eluded other scientists. She wanted to find a catalyst that could make perhaps the most common bond in organic chemistry — between carbon and hydrogen — reactive enough to couple to another molecule. Perhaps a photocatalyst could make a reactive free radical, allowing her to then bring in a nickel catalyst to attach the carbon-carbon bond.

Abigail Doyle

Abigail Doyle is one of a handful of Princeton professors to quickly adapt the use of blue LED light and photoredox catalysis to rewrite the rules of organic chemistry. Drug companies have taken notice. (Photo by Sameer A. Khan/Fotobuddy)

Unbeknownst to Doyle, the MacMillan lab had recently turned their attention to combining photoredox and nickel catalysts on a similar reaction, coupling molecules at the site of a carboxylate group, a common arrangement of atoms found in biological molecules from vinegar to proteins.

Given the similarities in their findings, the MacMillan and Doyle labs decided to combine their respective expertise in nickel and photoredox chemistry. Together, the teams found a photocatalyst based on the metal iridium that worked with nickel to carry out both coupling reactions — at the carbon-hydrogen bond and at the carboxylate group. Their collaborative paper, published in Science July 25, 2014, showed the extent of photoredox catalysis’ power to couple molecules with these common features.

The ability to combine molecules using natural features such as the carbon-hydrogen bond or the carboxylate group makes photoredox chemistry extremely useful. Often, chemists have to significantly modify a natural molecule to make it reactive enough to easily link to another molecule. One popular reaction — which earned a Nobel Prize in 2010 — requires several steps before two molecules can be linked. Skipping all these steps means a far easier and cheaper reaction — and one that is rapidly being applied.

“It’s one of the fastest-adopted chemistries I’ve seen,” Doyle said. “A couple of months after we published, we were visiting pharmaceutical companies and many of them were using this chemistry.”

The search for new drugs often involves testing vast libraries of molecules for ones that interact with a biological target, like trying thousands of keys to see which ones open a door. Pharmaceutical companies leapt at the chance to quickly and cheaply make many more kinds of molecules for their libraries.

Merck & Co., Inc., a pharmaceutical company with research labs in the Princeton area, was one of the first companies to become interested in using the new approach — and in funding MacMillan’s research.The company donated $5 million to start Princeton’s Merck Center for Catalysis in 2006, and recently announced another $5 million in continued research funding.

In addition to aiding drug discovery, photoredoxcatalyzed reactions can produce new or less expensive fine chemicals for flavorings, perfumes and pesticides, as well as plastic-like polymer materials. And the techniques keep getting cheaper. MacMillan published a paper June 23, 2016, in Science showing that with the aid of a photoredox catalyst, a widely used reaction to make carbon-nitrogen bonds can be carried out with nickel instead of palladium. Because nickel is thousands of times cheaper than palladium, companies hoping to use the reaction were contacting MacMillan before the paper was even published.

Spreading the light

Doyle has continued to explore photoredox chemistry, as have other Princeton faculty members, including two new assistant professors, Robert Knowles and Todd Hyster.

Hyster combines photoredox catalysis with reactions inspired by biology. Drugs often function by fitting in a protein like a hand fits in a glove. But just as placing a left hand in a right glove results in a poor fit, inserting a left-handed molecule into a protein designed for a right-handed molecule will give poor results. Many catalysts produce both the intended product and its mirror image, but by combining photoredox catalysts with artificial proteins, Hyster is finding reactions that can make that distinction.

Hyster, who arrived at Princeton in summer 2015, was drawn to Princeton’s chemistry department in part because of the opportunities to share knowledge and experience with other groups researching photoredox catalysis. “The department is quite collegial, so there’s no barrier when talking to colleagues about projects that are broadly similar,” he said.

Students from different labs chat about their work over lunch, teaching and learning informally — and  formally, as the labs encourage collaboration and sharing expertise, said Emily Corcoran, a postdoctoral researcher who works with MacMillan. When Corcoran was trying to determine exactly how one of her reactions  worked, she was able to consult with students in Knowles’ lab who had experience using sensitive magnetic measurements to find free radicals in the reaction mixture.

“If you have a question, you can just walk down the hall and ask,” Corcoran said. “That really pushes all the labs forward at a faster pace.”

A bright future

After the graduate students go home at night, the blue LEDs continue to drive new chemical reactions and new discoveries. “This is really just the beginning,” Doyle said.

Hyster thinks that within a few years, manufacturers may take advantage of photoredox chemistry to produce biological chemicals — such as insulin and the malaria drug artemisinin — to meet human needs. For his part, MacMillan envisions zero-waste chemical plants in the Nevada desert, driven not by fossil fuels but by the sun.

MacMillan’s vision echoes that of the original photochemist, Ciamician. The Italian’s optimistic vision of a sunlit future is brighter than ever.

Computer chip for point-of-care diagnosis

Lab on a chip is smaller than a penny.

Kaushik Sengupta and his team are developing a computer chip-based diagnostic system, which is smaller than a penny but contains hundreds of different sensors for simultaneous detection of disease-causing agents.

Assistant Professor of Electrical Engineering Kaushik Sengupta and his team are developing a computer chip-based diagnostic system, which rests comfortably on a fingertip but contains hundreds of different sensors for simultaneous detection of disease-causing agents. The eventual goal is to use the chip in a handheld, portable diagnostic device that could be deployed in health clinics around the globe, especially in resource-limited settings.

The chip detects and measures the presence of DNA or proteins to help diagnose health conditions. Most existing methods for detecting these agents involve shining light on fluorescent labels attached to the DNA or protein and reading a resulting signal. However, in many types of tests, the signal is so weak that complex optical equipment is necessary to read the signal.

To perform this analysis using a simple handheld device, Sengupta is co-opting silicon chip technology similar to that found in personal computers and mobile phones. “This is a great technology for handheld medical diagnostic devices because it allows us integrate extremely complex systems in a single chip at very low cost. The vision is to unleash Moore’s law in diagnostics,” said Sengupta, referring to Intel co-founder Gordon Moore’s observation that processing power in computer chips has increased rapidly over the years.

The team starts with highly sensitive light-detecting components, or photodetectors, that are already ubiquitous in smartphone cameras, then adds new optical processor capabilities to the chip. The researchers found a way to re-wire the architecture of the chip so that in addition to carrying electrical information necessary for image processing, the chip also interacts with the incoming photons from the fluorescent light, and can block them out, allowing the signal that carries information about the test sample to be detected and processed.

Lingyu Hong and Kaushik Sengupta

Lingyu Hong, a graduate student in electrical engineering, and Kaushik Sengupta, an assistant professor of electrical engineering at Princeton University are developing technology for use in a handheld diagnostic system for healthcare in resource-limited settings.

This ability to integrate optical elements with electronics inside a single silicon chip is enabling the team to build detection systems for both genetic material and proteins. Millions of photodetectors can already be crammed into smartphone cameras and Sengupta plans to put hundreds or even thousands of such sensors on the new chip to create a platform capable of testing many agents at once. In addition to being cheap and robust, this “lab-on-a-chip” will be user-friendly. Sengupta and his colleagues envision that the chips will be used in a portable device similar to a smartphone that can use an app to analyze the fluorescence data and display diagnosis results in a clear, simple format.

To make the device truly portable, it will be necessary to develop a small and lightweight apparatus to isolate proteins and genetic material from blood or other fluids, and Sengupta and his collaborators are working on this challenge. “The entire end-to-end system may take another couple of years to reach, but we’ve demonstrated the feasibility of the approach,” said Sengupta, who collaborates with Professor of Chemistry Haw Yang. “Princeton provides the kind of environment that makes it easy to reach out to faculty members across the campus and to work on creative endeavors that cut across traditional disciplines.”

The initial work on the chip was supported by Project X, a fund established through a donation from G. Lynn Shostack S’69 for the support of exploratory research. The project involvesgraduate students Lingyu Hong in the Department of Electrical Engineering and Hao Li in the Department of Chemistry, Postdoctoral Research Associate Simon McManus and undergraduate Victor Ying. Lingyu and Hao were awarded a Qualcomm Innovation Fellowship for 2015-16 for this work.

-By Takim Williams

New chemistry aids drug development

Tova Bergsten

Tova Bergsten PHOTO CREDIT: C. TODD REICHART

DRUG DEVELOPMENT OFTEN INVOLVES modifying the chemical structure to get the right combination of properties, such as stability and activity. Working in the laboratory of John Groves, the Hugh Stott Taylor Chair of Chemistry, undergraduate Tova Bergsten and graduate student Xiongyi Huang developed a practical and versatile method for altering molecules that could have wide application in drug synthesis and basic research. The method involves using a manganese catalyst to convert carbon-hydrogen bonds into chemical structures known as azides, which are useful for modifying the properties of drugs.

“Since this was my first long-term lab experience, I learned quite a bit,” Bergsten said. “It was eye-opening to be involved in the experimenting, writing and publishing side of a paper. I plan to continue with scientific research, and what I’ve learned through this experience will definitely be useful for my future work.”

The research, which was supported by the National Science Foundation, was published in the Journal of the American Chemical Society on April 14, 2015.

–By Tien Nguyen

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Listening in on bacterial communications

Leah Bushin and Mohammad Syedsayamdost

While an undergraduate, Leah Bushin (left) co-authored an article on the structure of a signaling molecule involved in bacterial communication with co-first author Kelsey Schramma and adviser Mohammad Seyedsayamdost (right), assistant professor of chemistry, PHOTO BY C. TODD REICHART

BACTERIA SPEAK TO ONE ANOTHER using a soundless language known as quorum sensing. In a step toward translating bacterial communications, researchers have revealed the structure and biosynthesis of streptide, a signaling molecule involved in the quorum sensing system common to many diseasecausing streptococci bacteria.

The research team included undergraduate Leah Bushin, who was the co-first author on an article published on April 20, 2015, in Nature Chemistry. Bushin helped determine the structure of streptide as part of her undergraduate senior thesis project.

To explore how bacteria communicate, first she had to grow them, a challenging process in which oxygen had to be rigorously excluded. Next, she isolated the streptide and analyzed it using two-dimensional nuclear magnetic resonance (NMR) spectroscopy, a technique that allows scientists to deduce the connections between atoms.

The experiments revealed that streptide contains an unprecedented crosslink between two unactivated carbons on the amino acids lysine and tryptophan. To figure out how this novel bond was being formed, the researchers took a closer look at the gene cluster that produces streptide. Within the gene cluster, they suspected that a radical S-adenosyl methionine (SAM) enzyme, which they dubbed StrB, could be responsible for this unusual modification.

“Radical SAM enzymes catalyze absolutely amazing chemistries,” said Kelsey Schramma, a graduate student and the other co-first author on the article. The team showed that one of the iron-sulfur clusters reductively activated one molecule of SAM, kicking off a chain of one-electron (radical) reactions that gave rise to the novel carbon-carbon bond.

Kelsey Schramma is a graduate student in chemistry working on a project to study bacterial communication. Disrupting communication could lead to novel strategies to fight infections. PHOTO CREDIT: C. TODD REICHART

Kelsey Schramma is a graduate student in chemistry working on a project to study bacterial communication. Disrupting communication could lead to novel strategies to fight infections. PHOTO CREDIT: C. TODD REICHART

“The synergy between Leah and Kelsey was great,” said Mohammad Seyedsayamdost, an assistant professor of chemistry who led the research, which was supported by the National Institutes of Health. “They expressed interest in complementary aspects of the project, and the whole ended up being greater than the sum of its parts,” he said.

Future work will target streptide’s biological function — its meaning in the bacterial language — as well as confirming its production by other streptococcal bacteria strains.

–By Tien Nguyen

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FOUR PROFESSORS Receive Presidential Science Awards

PECASE award winners

Clockwise from top left: Abigail Doyle, Yael Niv, Ramon von Handel and Rodney Priestley

Four professors received the 2013 Presidential Early Career Award for Scientists and Engineers, the highest honor bestowed by the U.S. government on science and engineering professionals in the early stages of their research careers.

Associate Professor of Chemistry Abigail Doyle, Assistant Professor of Psychology and the Princeton Neuroscience Institute Yael Niv, Assistant Professor of Chemical and Biological Engineering Rodney Priestley, and Assistant Professor of Operations Research and Financial Engineering Ramon van Handel were among the 102 researchers at American institutions selected by the Office of Science and Technology Policy within the Executive Office of the President. The winners received their awards at a White House ceremony on April 14, 2014.

“The impressive achievements of these early-stage scientists and engineers are promising indicators of even greater successes ahead,” President Barack Obama said in a release announcing the award. “We are grateful for their commitment to generating the scientific and technical advancements that will ensure America’s global leadership for many years to come.”

The annual award, established in 1996, recognizes researchers’ “pursuit of innovative research at the frontiers of science and technology and their commitment to community service as demonstrated through scientific leadership, public education or community outreach.”

–By Emily Aronson

No more mirrors: a new way of making molecules for tracking disease

Abigail Doyle

Abigail Doyle, associate professor of chemistry (Photo by C. Todd Reichart)

RADIOACTIVITY IS USUALLY ASSOCIATED with nuclear fallout or comic-book spider bites, but in very small amounts it can be a useful tool for diagnosing diseases.

Small molecules containing a radioactive isotope of fluorine, called 18F, allow doctors to track tumors using a scanning procedure known as positron emission tomography (PET). But existing methods of making 18F radiotracers tend to produce molecules that are identical in every way but one — the molecules are oppositely oriented, like a person’s right and left hand, or like mirror images. Due to their distinct 3-D structures, only one of the mirror images — known as enantiomers — is useful for tracking tumors.

Now, researchers at Princeton University led by Abigail Doyle, an associate professor of chemistry, report a route that can selectively produce just one type of enantiomer — either right-handed or left-handed — which could aid researchers in making more potent radiotracers. The work was published online in March 2014 in the Journal of the American Chemical Society.

“We know that in biology, small-molecule interactions with enzymes often depend on the 3-D properties of the molecule,” Doyle said. “Being able to prepare the enantiomers of a given tracer, in order to optimize which tracer has the best binding and imaging properties, could be really useful.”

Molecules

Molecules such as the one pictured can occur as two varieties that are identical in every way but one — they are mirror images of each other. Due to their distinct 3-D structures, these mirror images, known as enantiomers, interact with the body differently. Abigail Doyle’s group report a route that can selectively produce just one type of enantiomer, a result that could help researchers make more potent radiotracers for use in disease diagnosis.

Doyle’s research team developed a cobalt fluoride catalyst that causes radioactive fluoride to react with epoxides — triangleshaped molecules that contain an oxygen atom. The researchers’ method demonstrated excellent ability to select single enantiomers for 11 substrates, five of which are known pre-clinical PET tracers.

With this new method, researchers can test single enantiomers of existing or new PET radiotracers and evaluate if these compounds offer any advantage over the enantiomeric mixtures. Ultimately, the goal is to use this chemistry to identify a completely novel PET radiotracer for imaging.

Currently, there are only four FDA-approved 18F radiotracers. One of the major limitations to discovering PET tracers is the source of 18F. Existing 18F sources are strongly basic and, during the process of making the 18F radiotracer, can cause the elimination of alcohol and amine groups and rearrange the groups into mixtures of enantiomers in a process called racemization.

Under Doyle’s less basic reaction conditions, however, even alcohols and secondary amines are tolerated and no racemization is observed. The research was supported by the National Institutes of Health, the National Science Foundation and the Pennsylvania Department of Health.

First author Thomas Graham, who earned his Ph.D. in spring 2014, and graduate student Frederick Lambert commuted to the University of Pennsylvania, where they conducted the radiolabeling experiments in the laboratory of collaborator Hank Kung, an emeritus professor of radiology.

“We demonstrated that the radioactivity is high enough that we could actually use it for imaging. That’s an exciting next step,” Doyle said.

–By Tien Nguyen

Inventions Bridge the Gap between lab and marketplace

Road trip

A road trip offered Mark Zondlo and his team the opportunity to test their new air quality sensors. (Photo by Lei Tao)

The college experience often involves at least one road trip, but most students do not bring along their faculty adviser. But last spring, two graduate students crammed into a rented Chevy Impala with Professor Mark Zondlo and a postdoctoral researcher to drive eight hours a day across California’s Central Valley, testing their new air-quality sensors, which were strapped to a rooftop ski rack.

The sensors are an example of technologies being developed at Princeton that have the potential to improve quality of life as commercial products or services. Although teaching and research are Princeton’s core missions, the campus is home to a vibrant entrepreneurial spirit, one that can be found among faculty members who are making discoveries that could lead to better medicines as well as students working to turn a dorm-room dream into the next big startup.

“Princeton has a number of initiatives aimed at supporting innovation and technology transfer,” said John Ritter, director of Princeton’s Office of Technology Licensing, which works with University researchers to file invention disclosures and patent applications, and with businesses and investment capitalists to find partners for commercialization. “Our goal is to accelerate the transfer and development of Princeton’s basic research so that society can benefit from these innovations,” he said.

Crossing the valley

One of the ways that Princeton supports this transfer is with programs that help bridge the gap between research and commercialization, a gap that some call the Valley of Death because many promising technologies never make it to the product stage. One such program is the Intellectual Property Accelerator Fund, which provides financial resources for building a prototype or conducting additional testing with the goal of attracting corporate interest or investor financing.

Zondlo, an assistant professor of civil and environmental engineering, is one of the researchers using the fund to cross the valley — in this case literally as well as figuratively. Earlier this year, Zondlo and his research team, which consisted of graduate students Kang Sun and David Miller and postdoctoral researcher Lei Tao, tested their air-quality sensor in California’s Central Valley, a major agricultural center that is home to some of the worst air pollution in the nation.

Their goal was to compare the new portable sensors to existing stationary sensors as well as to measurements taken by plane and satellite as part of a larger NASA-funded air-quality monitoring project, DISCOVER-AQ.

One of the new sensors measures nitrous oxide, the worst greenhouse gas after carbon dioxide and methane. Nitrous oxide escapes into the air when fertilizers are spread on farm fields. Currently, to measure this gas, workers must collect samples of air in bottles and then take them to a lab for analysis using equipment the size of refrigerators.

Zondlo’s sensor, which is bundled with two others that measure ammonia and carbon monoxide, is portable and can be held in one hand, or strapped to a car roof. “The portability allows measurements to be taken quickly and frequently, which could greatly expand the understanding of how nitrous oxide and other gases are released and how their release can be controlled,” Zondlo said.

The sensors involve firing a type of battery-powered laser, called a quantum cascade laser, through a sample of air, while a detector measures the light absorption to deduce the amount of gas in the air. The researchers replaced bulky calibration equipment, necessary to ensure accurate measurements in the field, with a finger-sized chamber of reference gas against which the sensor’s accuracy can be routinely tested.

The decision to commercialize the sensor arose from the desire to make the device available to air-quality regulators and researchers, Zondlo said. “Our sensor has precision and stability similar to the best sensors on the market today, but at a fraction of the size and power requirements,” said Zondlo, a member of the Mid-Infrared Technologies for Health and the Environment (MIRTHE) center, a multi-institution center funded by the National Science Foundation (NSF) and headquartered at Princeton. “We are already getting phone calls from people who want to buy it.”

Lighting up the brain — with help from a synthetic liver

Far from the dusty farm roads of California, Princeton faculty member John (Jay) Groves sits in his office in the glass-enclosed Frick Chemistry Laboratory, thinking about the potential uses for a new synthetic enzyme. Modeled on an enzyme isolated from the liver, the synthetic version can carry out reactions that human chemists find difficult to pull off.

One of these reactions involves attaching radioactive fluorine tags to drugs to make them visible using a brain-imaging method known as positron emission tomography (PET) scanning.

PET scans of the radiolabeled drugs could help investigators track experimental medicines in the brain, to see if they are reaching their targets, and could aid in the development of drugs to treat disorders such as Alzheimer’s disease and stroke, according to Groves, Princeton’s Hugh Stott Taylor Chair of Chemistry. The synthetic enzyme adds fluorine tags without the toxic and corrosive agents used with radioactive fluorine today.

Groves’ initial work was supported by the NSF, but to develop the technology for use in pharmaceutical research, the Groves team, which includes graduate students Wei Liu and Xiongyi Huang, is receiving funding from a Princeton program aimed at supporting concepts that are risky but have potential for broad impact. The Eric and Wendy Schmidt Transformative Technology Fund was created with a $25 million endowment from Google executive chairman Eric Schmidt, a 1976 alumnus and former trustee, and his wife, Wendy.

“The Schmidt funding is enabling us to explore ways to optimize the chemical reaction and create a prototype of an automated system,” Groves said. “This will allow us to create a rapid and noninvasive way to evaluate drug candidates and observe important metabolites within the human brain.”

Aiding the search for planets

Tyler Groff

Postdoctoral researcher Tyler Groff is creating an improved system for adjusting the blurry images seen through telescopes due to atmospheric turbulence, heat and vibrations. (Photo by Denise Applewhite)

Inspired by the search for planets outside our solar system, Princeton postdoctoral researcher Tyler Groff conceived of a technology that could enhance the quality of images from telescopes. Groff received Schmidt funding to develop a device for controlling the mirrors that telescopes use to correct blurring and distortion caused by atmospheric turbulence, heat and vibrations.

This technology, known as adaptive optics, involves measuring disturbances in the light coming into the telescope and making small deformations to the surface of a mirror in precise ways to correct the image. These deformations are made using an array of mechanical devices, known as actuators, each capable of moving a small area of the flexible reflective surface up or down. But existing actuators are limited in the amount of correction they can provide, and the spaces between the actuators create dimples in the mirror, producing a visible pattern in the resulting images that astronomers call “quilting.”

Groff envisioned replacing the array of rigidly attached actuators with flexible ones made from packets containing iron particles suspended in a liquid, or ferrofluid. Just as iron filings can be moved by waving a magnet over them, applying varying magnetic fields to the ferrofluid changes the shape of the fluid in ways that deform the mirror.

The ferrofluid mirror enables highquality images while being more resistant to vibrations and potentially more power efficient, which will be important for future satellite-based telescopes, said Groff, who works in the laboratory of Jeremy Kasdin, professor of mechanical and aerospace engineering. A ferrofluid mirror can also achieve something that a rigid actuator mirror cannot: it can assume a concave or bowl-like shape that aids the focusing of the telescope on objects in space. “A telescope that uses ferrofluid mirrors would be able to see dim objects better,” Groff said, “which would greatly enhance our ability to probe other solar systems.”

From drug discovery to space exploration, Princeton’s dedication to supporting technology transfer and potentially disruptive but high-risk research ideas is yielding tremendous benefits for the advancement of science and the improvement of people’s lives.

Box: From student project to startup

Carlee Joe-Wong (Photo by Steve Schultz)

Carlee Joe-Wong (Photo by Steve Schultz)

In 2009 when Princeton undergraduate Carlee Joe-Wong started working on the technology that would become the DataMi company, she didn’t even own a smartphone. Today, the startup company co-founded by Joe-Wong provides mobile traffic management solutions to wireless Internet providers, and also helps consumers manage their data usage through an app, DataWiz, that has been downloaded by more than 200,000 Apple and Android users.

Joe-Wong became involved in the study of mobile data usage in the spring of her junior year when Professor Mung Chiang challenged her to explore ways that wireless providers could reduce congestion by adjusting their prices based on the variations in network supply and demand. “I mostly just worked on the project in my dorm room,” Joe-Wong said. “I thought it would be cool if it was adopted but I didn’t think that I would be the one helping to make that happen.” After graduation, Joe-Wong became a graduate student working with Chiang on mathematical algorithms that predict the most effective methods for balancing network use across “peak” minutes and “valley” minutes.

“With companies charging $10 per gigabyte, mobile consumers today need to intelligently manage their data,” said Chiang, the Arthur LeGrand Doty Professor of Electrical Engineering. “What the DataWiz app does is tell you when, where and what app used how much of your quota.”

In May 2013 the team, under the engineering leadership of associate research scholar Sangtae Ha, opened an office for DataMi one block off campus. Needless to say, Joe-Wong now has a smartphone.

Taking it to the streets with help from Princeton’s eLab

ELab students

From left: Nathan Haley, Christine Odabashian, Luke Amber and Leif Amber. (Photo by Denise Applewhite)

A love of motorcycles brought them together: three Princeton undergraduates decided to explore building and marketing an electric motorcycle to provide a superior riding experience at significantly lower emissions than gasoline powered models.

The team was one of nine groups selected to participate in the 10-week eLab Summer Accelerator Program, an initiative of the Keller Center in the School of Engineering and Applied Science, which teaches entrepreneurship by offering resources, mentoring and working space.

Throughout the summer, the team members worked on ways to market the bike while simultaneously building a prototype. “We geared the product toward people who enjoy taking weekend trips,” said Nathan Haley, Class of 2014, an economics major.

Haley was joined by Luke Amber, Class of 2015, and Christine Odabashian, Class of 2014, both majors in mechanical and aerospace engineering. The team also included Luke’s older brother, Leif Amber, a graduate student in electrical engineering at Clarkson University.

-By Catherine Zandonella