Monthly Archives: March 2013

Serendipity Pays Off (Science)

By Catherine Zandonella, Office of the Dean for Research

Serendipity –­­ the act of finding something good or useful while not specifically searching for it – can sometimes pay off. Now Princeton University chemistry researchers report that this non-specific type of searching has yielded a new method of building molecules for use in new drugs, new agricultural chemicals and even new perfumes.

In a paper published today in the journal Science, Princeton’s David MacMillan and his team describe the discovery of a new chemical reaction – not noted before in nature or in any lab – that could assist pharmaceutical chemists and others who routinely create new chemicals for a variety of industries.

Until now, no one realized this chemical reaction – which involves adding atoms to a specific carbon atom on a molecule – could occur, according to MacMillan, the James S. McDonnell Distinguished University Professor of Chemistry at Princeton. “If you show this chemical reaction to most chemists, they immediately say ‘that’s impossible,'” MacMillan said.

In this case, the team discovered this “impossible” reaction using an approach MacMillan pioneered that he calls “accelerated serendipity.” The researchers use robotic arms to conduct thousands of reactions per day by combining in test tubes different combinations of chemicals along with catalysts that spur the reactions. When the investigators find a reaction that makes an interesting product, they study it to understand how the reaction occurs.

“We didn’t invent this new reaction – nature did that,” MacMillan said, “but we figured out how to get the reaction to happen in the lab.” said MacMillan. His team, which included graduate student Michael Pirnot, postdoctoral researcher David Martin and former postdoctoral researcher Danica Rankic, uses ordinary light bulbs as catalysts, a technique developed in MacMillan’s lab and published in Science in 2008, to spur the reactions.

Going forward, chemists can add this new reaction to their tool box of methods for building up molecules, which they do in a way analogous to joining together pieces of Kinex or Tinker Toys, by swapping in new parts to increase the function of the molecule. In the new reaction published today, the team discovered a way to join so-called “functional groups” to a specific carbon atom (see diagram) in larger structures known as ketones and aldehydes. The ability to add functional groups to that carbon atom was thought impossible until now.

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Caption: Upper and lower left: Green spots indicate carbon atoms known to undergo reactions. Right panel: Purple spot indicates a carbon atom thought not to undergo reactions. The team discovered, using accelerated serendipity, a way to cause this carbon to react, resulting in addition of functional groups, and potentially leading to new drugs or other important industrial chemicals. (Source: Science)

This new chemical reaction has wide applications, MacMillan said. “This is a fundamental reaction which any chemist can start using.”

For example, a chemist who is building a drug to treat Alzheimer’s disease might desire to add a chemical group to the reluctant carbon atom. Normally that would require the chemist to conduct several different chemical reactions over several weeks, but with the new reaction the chemist could build the drug in two days and be testing drug candidates much more quickly.

Similarly a chemist at a fragrance company could use the new reaction to experiment with the creation of new perfume formulations.

MacMillan’s original paper on accelerated serendipity, published in 2011 in Science, successfully discovered a reaction now used in the drug industry. Yet it was controversial because other scientists interpreted the robotic searches as random searches, when in fact they were not random. “We chose chemicals that had never been shown to react with each other – those are the ones we believe might lead to as-yet undiscovered reactions.” MacMillan said that these reactions may have been created in the past by chemists who didn’t recognize what they were.

Read the abstract.

Michael T. Pirnot, Danica A. Rankic, David B. C. Martin, David W. C. MacMillan. Photoredox Activation for the Direct β-Arylation of Ketones and Aldehydes. Science 29 March 2013. Vol. 339 no. 6127 pp. 1593-1596.

This research was supported by the National Institute of General Medical Sciences grant R01 GM103558-01 and gifts from Merck, Amgen, Abbott, and Bristol-Myers Squibb.

Younger cancer patients experience greater increase in religiosity (Social Science Research)

By Michael Hotchkiss, Office of Communications

People diagnosed with cancer at younger ages are more likely to become more religious than their counterparts diagnosed at older ages, researchers including a Princeton research scholar have found.

Overall, the researchers found that people diagnosed with cancer experienced a one-time increase in religiosity, with the greater increase among those who experienced a diagnosis at a younger age, what’s known as an “off-time diagnosis.”

“Off-time diagnoses may also be related to increased religiosity because the meaning of having cancer may be different for those in middle adulthood compared to older adulthood,” the researchers said. The results come from a review of surveys of more than 3,400 people conducted in 1994-95 and 2004-06.

The research, detailed in an article in the March issue of Social Science Research, was conducted by Michael McFarland, a postdoctoral researcher at Princeton’s Office of Population Research, Tetyana Pudrovska, an assistant professor at Pennsylvania State University; Scott Schieman, a professor at the University of Toronto; Christopher Ellison, a professor at the the University of Texas at San Antonio; and Alex Bierman, an assistant professor at the University of Calgary.

Read the abstract.

McFarland, Michael J., Tetyana Pudrovska, Scott Schieman, Christopher G. Ellison, and Alex Bierman. March 2013. Does a cancer diagnosis influence religiosity? Integrating a life course perspective. Social Science Research. Vol. 42, Issue 2, pp. 311–20.

Drug-resistant MRSA bacteria – here to stay in both hospital and community (PLoS Pathogens)

By Catherine Zandonella, Office of the Dean for Research

A colorized scanning electron micrograph of a white blood cell eating an antibiotic resistant strain of Staphylococcus aureus bacteria, commonly known as MRSA. (Source: National Institute of Allergy and Infectious Diseases (NIAID))

A colorized scanning electron micrograph of a white blood cell eating an antibiotic resistant strain of Staphylococcus aureus bacteria, commonly known as MRSA. (Source: National Institute of Allergy and Infectious Diseases (NIAID))

The drug-resistant bacteria known as MRSA, once confined to hospitals but now widespread in communities, will likely continue to exist in both settings as separate strains, according to a new study.

The prediction that both strains will coexist is reassuring because previous projections indicated that the more invasive and fast-growing community strains would overtake and eliminate hospital strains, possibly posing a threat to public health.

Researchers at Princeton University used mathematical models to explore what will happen to community and hospital MRSA strains, which differ genetically.  Originally MRSA, which is short for methicillin-resistant Staphylococcus aureus, was confined to hospitals. However, community-associated strains emerged in the past decade and can spread widely from person to person in schools, athletic facilities and homes.

Both community and hospital strains cause diseases ranging from skin and soft-tissue infections to pneumonia and septicemia. Hospital MRSA is resistant to numerous antibiotics and is very difficult to treat, while community MRSA is resistant to fewer antibiotics.

The new study found that these differences in antibiotic resistance, combined with more aggressive antibiotic usage patterns in hospitals versus the community setting, over time will permit hospital strains to survive despite the competition from community strains. Hospital-based antibiotic usage is likely to successfully treat patients infected with community strains, preventing the newcomer strains from spreading to new patients and gaining the foothold they need to out-compete the hospital strains.

The researchers made their predictions by using mathematical models of MRSA transmission that take into account data on drug-usage, resistance profiles, person-to-person contact, and patient age.

Published February 28 in the journal PLOS Pathogens, the study was conducted by postdoctoral researcher Roger Kouyos, now a scholar at the University of Zurich, and Eili Klein, a graduate student who is now an assistant professor in the Johns Hopkins School of Medicine. They conducted the work under the advisement of Bryan Grenfell, Princeton’s Kathryn Briger and Sarah Fenton Professor of Ecology and Evolutionary Biology and Public Affairs at Princeton’s Woodrow Wilson School of International and Public Affairs.

Read the article (open access).

Kouyos R., Klein E. & Grenfell B. (2013). Hospital-Community Interactions Foster Coexistence between Methicillin-Resistant Strains of Staphylococcus aureus. PLoS Pathogens, 9 (2) e1003134. PMID:

RK was supported by the Swiss National Science Foundation (Grants PA00P3_131498 and PZ00P3_142411). EK was supported by Princeton University (Harold W. Dodds Fellowship), as well as the Models of Infectious Disease Agent Study (MIDAS), under Award Number U01GM070708 from the National Institute of General Medical Sciences. BG was supported by the Bill and Melinda Gates Foundation; the Research and Policy for Infectious Disease Dynamics (RAPIDD) program of the Science and Technology Directorate, Department of Homeland Security; and the Fogarty International Center, National Institutes of Health.

Quantum computing moves forward (Science)

By Catherine Zandonella, Office of the Dean for Research

New technologies that exploit quantum behavior for computing and other applications are closer than ever to being realized due to recent advances, according to a review article published this week in the journal Science.

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A silicon chip levitates individual atoms used in quantum information processing. Photo: Curt Suplee and Emily Edwards, Joint Quantum Institute and University of Maryland. Credit: Science.

These advances could enable the creation of immensely powerful computers as well as other applications, such as highly sensitive detectors capable of probing biological systems. “We are really excited about the possibilities of new semiconductor materials and new experimental systems that have become available in the last decade,” said Jason Petta, one of the authors of the report and an associate professor of physics at Princeton University.

Petta co-authored the article with David Awschalom of the University of Chicago, Lee Basset of the University of California-Santa Barbara, Andrew Dzurak of the University of New South Wales and Evelyn Hu of Harvard University.

Two significant breakthroughs are enabling this forward progress, Petta said in an interview. The first is the ability to control quantum units of information, known as quantum bits, at room temperature. Until recently, temperatures near absolute zero were required, but new diamond-based materials allow spin qubits to be operated on a table top, at room temperature. Diamond-based sensors could be used to image single molecules, as demonstrated earlier this year by Awschalom and researchers at Stanford University and IBM Research (Science, 2013).

The second big development is the ability to control these quantum bits, or qubits, for several seconds before they lapse into classical behavior, a feat achieved by Dzurak’s team (Nature, 2010) as well as Princeton researchers led by Stephen Lyon, professor of electrical engineering (Nature Materials, 2012). The development of highly pure forms of silicon, the same material used in today’s classical computers, has enabled researchers to control a quantum mechanical property known as “spin”. At Princeton, Lyon and his team demonstrated the control of spin in billions of electrons, a state known as coherence, for several seconds by using highly pure silicon-28.

Quantum-based technologies exploit the physical rules that govern very small particles — such as atoms and electrons — rather than the classical physics evident in everyday life. New technologies based on “spintronics” rather than electron charge, as is currently used, would be much more powerful than current technologies.

In quantum-based systems, the direction of the spin (either up or down) serves as the basic unit of information, which is analogous to the 0 or 1 bit in a classical computing system. Unlike our classical world, an electron spin can assume both a 0 and 1 at the same time, a feat called entanglement, which greatly enhances the ability to do computations.

A remaining challenge is to find ways to transmit quantum information over long distances. Petta is exploring how to do this with collaborator Andrew Houck, associate professor of electrical engineering at Princeton. Last fall in the journal Nature, the team published a study demonstrating the coupling of a spin qubit to a particle of light, known as a photon, which acts as a shuttle for the quantum information.

Yet another remaining hurdle is to scale up the number of qubits from a handful to hundreds, according to the researchers. Single quantum bits have been made using a variety of materials, including electronic and nuclear spins, as well as superconductors.

Some of the most exciting applications are in new sensing and imaging technologies rather than in computing, said Petta. “Most people agree that building a real quantum computer that can factor large numbers is still a long ways out,” he said. “However, there has been a change in the way we think about quantum mechanics – now we are thinking about quantum-enabled technologies, such as using a spin qubit as a sensitive magnetic field detector to probe biological systems.”

Read the abstract.

Awschalom D.D., Bassett L.C., Dzurak A.S., Hu E.L. & Petta J.R. (2013). Quantum spintronics: engineering and manipulating atom-like spins in semiconductors. Science 339 (6124) 1174-1179. PMID:

The research at Princeton University was supported by the Alfred P. Sloan Foundation, the David and Lucile Packard Foundation, US Army Research Office grant W911NF-08-1-0189, DARPA QuEST award HR0011-09-1-0007 and the US National Science Foundation through the Princeton Center for Complex Materials (DMR-0819860) and CAREER award DMR-0846341.

Researchers discover workings of brain’s ‘GPS system’ (Nature)

By Catherine Zandonella, Office of the Dean for Research

Just as a global positioning system (GPS) helps find your location, the brain has an internal system for helping determine the body’s location as it moves through its surroundings.

A new study from researchers at Princeton University provides evidence for how the brain performs this feat. The study, published in the journal Nature, indicates that certain position-tracking neurons — called grid cells — ramp their activity up and down by working together in a collective way to determine location, rather than each cell acting on its own as was proposed by a competing theory.

Grid cells are neurons that become electrically active, or “fire,” as animals travel in an environment. First discovered in the mid-2000s, each cell fires when the body moves to specific locations, for example in a room. Amazingly, these locations are arranged in a hexagonal pattern like spaces on a Chinese checker board.  (See figure.)

Tank_Brain_GPS

As the mouse moves around in a square arena (left), a single grid cell in the mouse’s brain becomes active, or spikes, when the animal arrives at particular locations in the arena (right). These locations are arranged in a hexagonal pattern. The red dots indicate the mouse’s location in the arena when the grid cell fired. (Image credit: Cristina Domnisoru, Princeton University)

“Together, the grid cells form a representation of space,” said David Tank, Princeton’s Henry L. Hillman Professor in Molecular Biology and leader of the study. “Our research focused on the mechanisms at work in the neural system that forms these hexagonal patterns,” he said. The first author on the paper was graduate student Cristina Domnisoru, who conducted the experiments together with postdoctoral researcher Amina Kinkhabwala.

Domnisoru measured the electrical signals inside individual grid cells in mouse brains while the animals traversed a computer-generated virtual environment, developed previously in the Tank lab. The animals moved on a mouse-sized treadmill while watching a video screen in a set-up that is similar to video-game virtual reality systems used by humans.

She found that the cell’s electrical activity, measured as the difference in voltage between the inside and outside of the cell, started low and then ramped up, growing larger as the mouse reached each point on the hexagonal grid and then falling off as the mouse moved away from that point.

This ramping pattern corresponded with a proposed mechanism of neural computation called an attractor network. The brain is made up of vast numbers of neurons connected together into networks, and the attractor network is a theoretical model of how patterns of connected neurons can give rise to brain activity by collectively working together. The attractor network theory was first proposed 30 years ago by John Hopfield, Princeton’s Howard A. Prior Professor in the Life Sciences, Emeritus.

The team found that their measurements of grid cell activity corresponded with the attractor network model but not a competing theory, the oscillatory interference model. This competing theory proposed that grid cells use rhythmic activity patterns, or oscillations, which can be thought of as many fast clocks ticking in synchrony, to calculate where animals are located. Although the Princeton  researchers detected rhythmic activity inside most neurons, the activity patterns did not appear to participate in position calculations.

Read the abstract.

Domnisoru, Cristina, Amina A. Kinkhabwala & David W. Tank. 2013. Membrane potential dynamics of grid cells. Nature. doi:10.1038/nature11973. Published online Feb. 10, 2013.

This work was supported by the National Institute of Neurological Disorders and Stroke under award numbers 5RC1NS068148-02 and 1R37NS081242-01, the National Institute of Mental Health under award number 5R01MH083686-04, a National Institutes of Health Postdoctoral Fellowship grant F32NS070514-01A1 (A.A.K.), and a National Science Foundation Graduate Research Fellowship (C.D.).

 

 

How do bacteria clog medical devices? Very quickly. (PNAS)

stone-figure-2D_540A new study has examined how bacteria clog medical devices, and the result isn’t pretty. The microbes join to create slimy ribbons that tangle and trap other passing bacteria, creating a full blockage in a startlingly short period of time.

The finding could help shape strategies for preventing clogging of devices such as stents — which are implanted in the body to keep open blood vessels and passages — as well as water filters and other items that are susceptible to contamination. The research was published in Proceedings of the National Academy of Sciences.

stone-figure-2D_540

Click on the image to view movie. Over a period of about 40 hours, bacterial cells (green) flowed through a channel, forming a green biofilm on the walls. Over the next ten hours, researchers sent red bacterial cells through the channel. The red cells became stuck in the sticky biofilm and began to form thin red streamers. Once stuck, these streamers in turn trapped additional cells, leading to rapid clogging. (Image source: Knut Drescher)

Using time-lapse imaging, researchers at Princeton University monitored fluid flow in narrow tubes or pores similar to those used in water filters and medical devices. Unlike previous studies, the Princeton experiment more closely mimicked the natural features of the devices, using rough rather than smooth surfaces and pressure-driven fluid instead of non-moving fluid.

The team of biologists and engineers introduced a small number of bacteria known to be common contaminants of medical devices. Over a period of about 40 hours, the researchers observed that some of the microbes — dyed green for visibility — attached to the inner wall of the tube and began to multiply, eventually forming a slimy coating called a biofilm. These films consist of thousands of individual cells held together by a sort of biological glue.

Over the next several hours, the researchers sent additional microbes, dyed red, into the tube. These red cells became stuck to the biofilm-coated walls, where the force of the flowing liquid shaped the trapped cells into streamers that rippled in the liquid like flags rippling in a breeze. During this time, the fluid flow slowed only slightly.

At about 55 hours into the experiment, the biofilm streamers tangled with each other, forming a net-like barrier that trapped additional bacterial cells, creating a larger barrier which in turn ensnared more cells. Within an hour, the entire tube became blocked and the fluid flow stopped.

The study was conducted by lead author Knut Drescher with assistance from technician Yi Shen. Drescher is a postdoctoral research associate working with Bonnie Bassler, Princeton’s Squibb Professor in Molecular Biology and a Howard Hughes Medical Institute Investigator, and Howard Stone, Princeton’s Donald R. Dixon ’69 and Elizabeth W. Dixon Professor of Mechanical and Aerospace Engineering.

“For me the surprise was how quickly the biofilm streamers caused complete clogging,” said Stone. “There was no warning that something bad was about to happen.”

By constructing their own controlled environment, the researchers demonstrated that rough surfaces and pressure driven flow are characteristics of nature and need to be taken into account experimentally. The researchers used stents, soil-based filters and water filters to prove that the biofilm streams indeed form in real scenarios and likely explain why devices fail.

The work also allowed the researchers to explore which bacterial genes contribute to biofilm streamer formation. Previous studies, conducted under non-realistic conditions, identified several genes involved in formation of the biofilm streamers. The Princeton researchers found that some of those previously identified genes were not needed for biofilm streamer formation in the more realistic habitat.

Read the abstract.

Drescher, Knut, Yi Shen, Bonnie L. Bassler, and Howard A. Stone. 2013. Biofilm streamers cause catastrophic disruption of flow with consequences for environmental and medical systems. Proceedings of the National Academy of Sciences. Published online February 11.

This work was supported by the Howard Hughes Medical
Institute, National Institutes of Health grant 5R01GM065859, National Science Foundation (NSF) grant MCB-0343821, NSF grant MCB-1119232, and the Human Frontier Science Program.