Duke Research Blog

Following the people and events that make up the research community at Duke.

Category: Faculty (Page 1 of 19)

Designing Drugs Aimed at a Different Part of Life’s Code

Individual RNA molecules fluoresce green, red and blue inside a breast cancer cell.

Individual RNA molecules fluoresce inside a breast cancer cell. Credit: Sunjong Kwon, Oregon Health & Science University, via Flickr.

Most drugs work by tinkering with the behavior of proteins. Like meddlesome coworkers, these molecules are designed to latch onto their target proteins and keep them from doing what they need to do.

If a protein is responsible for speeding up a reaction, the drug helps slow the reaction down. If a protein serves as a gatekeeper to a cell, regulating what gets in and what stays out, a drug changes how many molecules it lets through.

But proteins aren’t the only doers and shakers in our bodies. Scientists are finding that strings of RNA — known primarily for their role in shuttling genetic information from nucleus-bound DNA to the cell’s protein-manufacturing machinery — can also play a major role in regulating disease.

“There has been what some people are calling an RNA revolution,” said Amanda Hargrove, assistant professor of chemistry at Duke. “In some diseases, non-coding RNAs, or RNAs that don’t turn into protein, seem to be the best predictors of disease, and even to be driving the disease.”

Hargrove and her team at Duke are working to design new types of drugs that target RNA rather than proteins. RNA-targeted drug molecules have the potential help treat diseases like prostate cancer and HIV, but finding them is no easy task. Most drugs have been designed to interfere with proteins, and just don’t have the same effects on RNA.

Part of the problem is that RNA and proteins have many fundamental differences, Hargrove said. While proteins are made of strings of twenty amino acids that can twist into myriad different shapes, RNA is made of strings of only four bases — adenine, guanine, cytosine and uracil.

“People have been screening drugs for different kinds of RNA for quite a while, and historically have not had a lot of success,” Hargrove said. “This begged the question, since RNA has such chemically different properties than proteins, is there something different about the small molecules that we need in order to target RNA?”

To find out, graduate student Brittany Morgan and research associate Jordan Forte combed the scientific literature to identify 104 small molecules that are known interact with specific types of RNA. They then analyzed 20 different properties of these molecules, and compared their properties to those of collections of drug molecules known to interact with proteins.

The team found significant differences in shape, atomic composition, and charge between the RNA-active molecules and the protein-active molecules. They plan to use the results to compile a collection of molecules, called a library, that are chosen to better “speak the language” of the RNA-active molecules. They hope this collection of molecules will be more likely to interact with RNA in therapeutically beneficial ways.

“We found that there are differences between the RNA-targeted molecules and the protein-targeted drugs, and some of them are pretty striking,” Hargrove said. “What that means is that we could start to enrich our screening libraries with these types of molecules, and make these types of molecules, to have better luck at targeting RNA.”

Discovery of Key Physicochemical, Structural, and Spatial Properties of RNA-Targeted Bioactive Ligands.” Brittany S. Morgan, Jordan E. Forte, Rebecca N. Culver, Yuqi Zhang and Amanda Hargrove. Angewandte Chemie, Sept. 18, 2017. DOI: 10.1002/anie.201707641

Lab-Made Protein Chomps Co-Factor Like a Big Ol’ Gator

A protein is illustrated to look like an alligator mouth

The synthetic protein clamps down on the porphyrin like the jaws of an alligator. Credit: Nicholas Polizzi.

Proteins have the power to turbo-charge biochemical reactions inside the body.

Without the help of types of proteins called enzymes, the reaction that builds DNA could take over 130,000 years to complete. Enzymes cut that time down to just a few milliseconds.

To rev up chemical reactions, many proteins team up with smaller molecules or metals called cofactors. Chemists would like to design proteins that bind to non-biological cofactors in order to speed up chemical reactions not found in nature. But first, they have to figure out how to create man-made proteins that attach to new cofactors in exactly the right way, and that is no easy feat.

A team of chemists at Duke and UC San Francisco is the first to solve this protein design puzzle. The team created a synthetic protein that tightly binds a non-biological catalyst, a type of molecule called porphyrin that is capable of stealing electrons from other molecules when it absorbs light.

“To be able to combine man-made catalysts with proteins would be really big in the chemistry field because then you could combine the power of an enzyme with that of a reaction that isn’t found in nature,” said former Duke graduate student Nicholas Polizzi, who is now a postdoctoral researcher in William DeGrado’s lab at UCSF.

“We were able to figure out the design criteria necessary to place that porphyrin in a protein to within a very high accuracy,” Polizzi said. “That was a really big stepping stone to be able to design new protein-cofactor combinations not seen in nature.”

Proteins are made of chains of hundreds or thousands of smaller amino acids that twist and loop into complex 3-D shapes that can interlock with other molecules like pieces of a jigsaw puzzle. To catalyze chemical reactions, protein-cofactor combinations hold two or more molecules in precisely-shaped pockets that keep the molecules in just the right positions, and provide the right environment, for a chemical reaction to occur.

An illustration of a protein jigsaw puzzle

Chemists at Duke and UCSF designed a synthetic protein that tightly binds a non-biological molecule. Credit: Nicholas Polizzi.

Millions of years of evolution have created proteins that fold into the shapes that tightly grip specific cofactors and provide the perfect environments to catalyze chemical reactions.

For over 25 years, chemists have used what they know about protein folding to design synthetic amino acid sequences that twist up into useful shapes. But so far, they have been unable to design a protein that binds a non-biological cofactor with the precision necessary to power complex new chemical reactions.

Polizzi said this may be because these designs focused primarily on the “binding site” where cofactors and reacting molecules fit into the protein, while ignoring the rest of the structure. “What I did differently is that I considered essentially the entire interior of protein as the binding site for the porphyrin, as opposed to just a few amino acids that touch the porphyrin,” Polizzi said.

To understand how this works, you can think of the protein as the mouth of an alligator, said Michael Therien, William R. Kenan Jr. Professor of Chemistry at Duke. The protein latches onto a cofactor in the same way that an alligator uses its front teeth to chomp down on dinner. But for the front teeth to get a strong grip, the jaw and back teeth also have to be designed correctly.

“The new concept here is that the non-binding region of the protein is held in a shape that allows the binding region to work,” Therien said.

“We called the protein ‘gator’ in the lab,” Polizzi said.

The jaws of the gator protein actually clamp down so hard on the porphyrin cofactor that the whole structure is too rigid to catalyze a reaction, Polizzi said. But with a few tweaks to loosen up the structure, he thinks he can get it to work.

“In this reaction, often times you need a little bit of wiggle room in the protein for it to move. And there was no wiggle room in our protein, everything fit too perfectly,” Polizzi said.

CITATION: “De novo design of a hyperstable non-natural protein-ligand complex with sub-A accuracy.” Nicholas F. Polizzi, Yibing Wu, Thomas Lemmin, Alison M. Maxwell, Shao-Qing Zhang, Jeff Rawson, David N. Beratan, Michael J. Therien and William F. DeGrado. Nature Chemistry, Aug. 21, 2017. DOI: 10.1038/nchem.2846

Kara J. Manke, PhDPost by Kara Manke

Energy Program on Chopping Block, But New Data Suggest It Works

Duke research yields new data about energy efficiency program slated for elimination

Do energy efficiency “audits” really benefit companies over time? An interdisciplinary team of Duke researchers (economist Gale Boyd, statistician Jerome “Jerry” Reiter, and doctoral student Nicole Dalzell) have been tackling this question as it applies to a long-running Department of Energy (DOE) effort that is slated for elimination under President Trump’s proposed budget.

Evaluating a long-running energy efficiency effort

Since 1976, the DOE’s Industrial Assessments Centers (IAC) program has aimed to help small- and medium-sized manufacturers to become more energy-efficient by providing free energy “audits” from universities across the country. (Currently, 28 universities take part, including North Carolina State University.)

Gale Boyd

Gale Boyd is a Duke Economist

The Duke researchers’ project, supported by an Energy Research Seed Fund grant, has yielded a statistically sound new technique for matching publicly available IAC data with confidential plant information collected in the U.S. Census of Manufacturing (CMF).

The team has created a groundbreaking linked database that will be available in the Federal Statistical Research Data Center network for use by other researchers. Currently the database links IAC data from 2007 and confidential plant data from the 2012 CMF, but it can be expanded to include additional years.

The team’s analysis of this linked data indicate that companies participating in the DOE’s IAC program do become more efficient and improve in efficiency ranking over time when compared to peer companies in the same industry. Additional analysis could reveal the characteristics of companies that benefit most and the interventions that are most effective.

Applications for government, industry, utilities, researchers

This data could be used to inform the DOE’s IAC program, if the program is not eliminated.

But the data have other potential applications, too, says Boyd.

Individual companies who took part in the DOE program could discover the relative yields of their own energy efficiency measures: savings over time as well as how their efficiency ranking among peers has shifted.

Researchers, states, and utilities could use the data to identify manufacturing sectors and types of businesses that benefit most from information about energy efficiency measures, the specific measures connected with savings, and non-energy benefits of energy efficiency, e.g. on productivity.

Meanwhile, the probabilistic matching techniques developed as part of the project could help researchers in a range of fields—from public health to education—to build a better understanding of populations by linking data sets in statistically sound ways.

An interdisciplinary team leveraging Duke talent and resources

Boyd—a Duke economist who previously spent two decades doing applied policy evaluation at Argonne National Laboratory—has been using Census data to study energy efficiency and productivity for more than fifteen years. Boyd has co-appointments in Duke’s Social Science Research Institute and Department of Economics. He now directs the Triangle Research Data Center (TRDC), a partnership between the U.S. Census Bureau and Duke University in cooperation with the University of North Carolina and Research Triangle Institute.

The TRDC (located in Gross Hall for Interdisciplinary Innovation) is one of more than 30 locations in the country where researchers can access the confidential micro-data collected by the Federal Statistical System.

Jerry Reiter is a Duke statistician.

Jerry Reiter is a professor in Duke’s Department of Statistical Science, associate director of the Information Initiative at Duke (iiD), and a Duke alumnus (B.S’92). Reiter was dissertation supervisor for Nicole Dalzell, who completed her Ph.D. at Duke this spring and will be an assistant teaching professor in the Department of Mathematics and Statistics at Wake Forest University in the fall.

Boyd reports, “The opportunity to work in an interdisciplinary team with Jerry (one of the nation’s leading researchers on imputation and synthetic data) and Nicole (one of Duke’s bright new minds in this field) has opened my eyes a bit about how cavalier some researchers are with respect to uncertainty when we link datasets. Statisticians’ expertise in these areas can help the rest of us do better research, making it as sound and defensible as possible.”

What’s next for the project

The collaboration was made by possible by the Duke University Energy Initiative’s Energy Research Seed Fund, which supports new interdisciplinary research teams to secure preliminary results that can help secure external funding. The grant was co-funded by the Pratt School of Engineering and Information Initiative at Duke (iiD).

Given the potential uses of the team’s results by the private sector (particularly by electric utilities), other funding possibilities are likely to emerge.

Boyd, Reiter, and Dalzell have submitted an article to the journal Energy Policy and are discussing future research application of this data with colleagues in the field of energy efficiency and policy. Their working paper is available as part of the Environmental and Energy Economics Working Paper Series organized by the Energy Initiative and the Nicholas Institute for Environmental Policy Solutions.

Energy Efficiency Graphic

For more information, contact Gale Boyd: gale.boyd@duke.edu.

Guest Post from Braden Welborn, Duke University Energy Initiative

3D Virus Cam Catches Germs Red-Handed

A 3D plot of a virus wiggling around

The Duke team used their 3D virus cam to spy on this small lentivirus as it danced through a salt water solution.

Before germs like viruses can make you sick, they first have to make a landing on one of your cells — Mars Rover style — and then punch their way inside.

A team of physical chemists at Duke is building a microscope so powerful that it can spot these minuscule germs in the act of infection.

The team has created a new 3D “virus cam” that can spy on tiny viral germs as they wriggle around in real time. In a video caught by the microscope, you can watch as a lentivirus bounces and jitters through an area a little wider that a human hair.

Next, they hope to develop this technique into a multi-functional “magic camera” that will let them see not only the dancing viruses, but also the much larger cell membranes they are trying breech.

“Really what we are trying to investigate is the very first contacts of the virus with the cell surface — how it calls receptors, and how it sheds its envelope,” said group leader Kevin Welsher, assistant professor of chemistry at Duke. “We want to watch that process in real time, and to do that, we need to be able to lock on to the virus right from the first moment.”

A 3D plot spells out the name "Duke"

To test out the microscope, the team attached a fluorescent bead to a motion controller and tracked its movements as it spelled out a familiar name.

This isn’t the first microscope that can track real-time, 3D motions of individual particles. In fact, as a postdoctoral researcher at Princeton, Welsher built an earlier model and used it to track a bright fluorescent bead as it gets stuck in the membrane of a cell.

But the new virus cam, built by Duke postdoc Shangguo Hou, can track particles that are faster-moving and dimmer compared to earlier microscopes. “We were trying to overcome a speed limit, and we were trying to do so with the fewest number of photons collected possible,” Welsher said.

The ability to spot dimmer particles is particularly important when tracking viruses, Welsher said. These small bundles of proteins and DNA don’t naturally give off any light, so to see them under a microscope, researchers first have to stick something fluorescent on them. But many bright fluorescent particles, such as quantum dots, are pretty big compared to the size of most viruses. Attaching one is kind of like sticking a baseball onto a basketball – there is a good chance it might affect how the virus moves and interacts with cells.

The new microscope can detect the fainter light given off by much smaller fluorescent proteins – which, if the virus is a basketball, are approximately the size of a pea. Fluorescent proteins can also be inserted to the viral genome, which allows them to be incorporated into the virus as it is being assembled.

“That was the big move for us,” Welsher said, “We didn’t need to use a quantum dot, we didn’t need to use an artificial fluorescent bead. As long as the fluorescent protein was somewhere in the virus, we could spot it.” To create their viral video, Welsher’s team enlisted Duke’s Viral Vector Core to insert a yellow fluorescent protein into their lentivirus.

Now that the virus-tracking microscope is up-and-running, the team is busy building a laser scanning microscope that will also be able to map cell surfaces nearby. “So if we know where the particle is, we can also image around it and reconstruct where the particle is going,” Welsher said. “We hope to adapt this to capturing viral infection in real time.”

Robust real-time 3D single-particle tracking using a dynamically moving laser spot,” Shangguo Hou, Xiaoqi Lang and Kevin Welsher. Optics Letters, June 15, 2017. DOI: 10.1364/OL.42.002390

Kara J. Manke, PhDPost by Kara Manke

Cooking Up “Frustrated” Magnets in Search of Superconductivity

Sara Haravifard

A simplified version of Sara Haravifard’s recipe for new superconductors, by the National High Magnetic Field Laboratory

Duke physics professor Sara Haravifard is mixing, cooking, squishing and freezing “frustrated” magnetic crystals in search of the origins of superconductivity.

Superconductivity refers to the ability of electrons to travel endlessly through certain materials, called superconductors, without adding any energy — think of a car that can drive forever with no gas or electricity. And just the way gas-less, charge-less cars would make travel vastly cheaper, superconductivity has the potential to revolutionize electronics and energy industry.

But superconductors are extremely rare, and are usually only superconductive at extremely cold temperatures — too cold for any but a few highly specialized applications. A few “high-temperature” superconductors have been discovered, but scientists are still flummoxed at why and how these superconductors exist.

Haravifard hopes that her magnet experiments will reveal the origins of high-temperature superconductivity so that researchers can design and build new materials with this amazing property. In the process, her team may also discover materials that are useful in quantum computing, or even entirely new states of matter.

Learn more about their journey on this fascinating infographic by The National High Magnetic Field Laboratory.

Infographic describing magnetic crystal research

Infographic courtesy of the National High Magnetic Field Laboratory

Kara J. Manke, PhD

Post by Kara Manke

Trapping Light to Enhance Material Properties

Professor Mikkelsen is the Nortel Networks Assistant Professor of Electrical and Computer Engineering and Assistant Professor of Physics at Duke University.

A version of this article appeared in Pratt’s 2017 DukEngineer magazine.

Professor Maiken H. Mikkelsen uses optics to tailor the properties of materials, making them stronger and lighter than anything found in nature. This distinguished researcher also teaches my ECE 340: Optics and Photonics course, giving me a wonderful opportunity to ask about her research and experience at the Photonics Asia conference held in China in October 2016.

Below is an edited transcript of our interview.

Q: What sparked your interest in optics and photonics?
I was really excited about doing hands-on research where you could actually probe nanoscale and quantum phenomena from optical experiments. I started out looking into condensed matter and quantum information science and currently observe delicately designed nanostructures. Optics is, to some extent, a tool to modify the properties of materials.

Q: What does your lab do and how do students contribute?
During the last few years, my students and I have been structuring materials on the nanoscale to modify the local electromagnetic environment, which makes these materials behave in new ways. Students play a key role in all aspects of the research, from nanofabrication to performing optical experiments and presenting the results to the scientific community at conferences all over the world. The lab uses tiny metal structures to concentrate the incoming electromagnetic field of light to very small volumes — a research area known as plasmonics. Placing other materials in the near field of this modified environment causes the electrons to behave completely differently.

Platform based on metal nanostructures that allows the lab to dramatically enhance the radiative properties of emitters and other materials.

By controlling how these electrons behave and modifying the geometry of the material, we can gain a deeper understanding of the light-matter interactions. Combining these techniques with our optical experiments shows modifications to material properties that are much stronger than has been seen before. It’s been very exciting!

Q: And this research is what you presented at the Photonics Asia conference?
Yes. With this knowledge, we can enhance the properties of materials significantly, which in the future could lead to ultra-fast and much better LEDs, more efficient photodetectors, or more efficient solar cells and sensors. In Beijing, China, I gave an overview of this research at the leading meeting for the photonics and optics industries in Asia, as well as several other conferences and universities. It was very fulfilling to see how the research I do in a dark lab actually gets noticed around the world. It is always deeply inspiring to learn about recent research breakthroughs from other research groups.

Q: What is the main purpose of trying to find these improved materials?
I am motivated by furthering our fundamental understanding, such as how do light and matter interact when we get to really small scales and how this interaction can be leveraged to achieve useful properties. I believe you often achieve the biggest technological breakthroughs when you’re not trying to solve one particular problem, but creating new materials that could lay the groundwork for a wide range of new technologies. For example, semiconductor materials, with a set of properties that are found naturally, are the cornerstone of most modern technologies. But if you imagine that you now have an entirely new set of building blocks with tailored properties instead, we could revolutionize a lot of different technologies down the road.

The Mikkelsen Research Group. Back row, left to right: Qixin Shen, Andrew Traverso, Maiken Mikkelsen, Guoce Yang, Jon Stewart, Andrew Boyce. Front row, left to right: Wade Wilson, Daniela Cruz, Jiani Huang, Tamra Nebabu.

By improving or completely changing the fabrication technique of these light-matter interactions, new properties begin to emerge. Generally, there’s always a big desire to have something that’s lighter, smaller, more efficient and more flexible. One of the applications we’re targeting with this research is ultrafast LEDs. While future devices might not use this exact approach, the underlying physics will be crucial.

About a year ago, Facebook contacted me and was interested in utilizing our research for omnidirectional detectors that could be ultrafast and detect signals from a large range of incidence angles. This has led to a fruitful collaboration and is one example of how fundamental research can have applications in a wide range of areas — some that you may not even have imagined when you started!

 

Q: What would be your advice to young researchers still trying to decide a career path for themselves or those interested in optics and photonics?
What really helped me was starting to do undergraduate research. I listened to talks by different faculty, asked them to do undergraduate research, and worked on a volunteer basis in their labs. I think that’s really a great way to see if you’re interested in research — use the amazing opportunities both at Duke and around the country. Doing research requires a lot of patience, but I think no two days are the same; there’s always a lot of creativity involved while troubleshooting new problems. After all, if it was easy or if we knew how to do it, it would have already been done. But it hasn’t, so we have to figure it out — I think that is a lot of fun. Doing internships in optics and photonics companies is also another option to learn more about research and development in the industry. Get as many experiences as possible and give things a chance!

Professor Mikkelsen is best known for the first demonstration of nondestructive readout of a single electron spin, ultrafast manipulation of a single spin using all-optical techniques, and extreme radiative decay engineering using nanoantennas.

Mikkelsen has received numerous accolades, including the Cottrell Scholar Award, the Maria Goeppert Mayer Award, and a “triple crown” of Young Investigator Awards from the Air Force, Army and Navy. Her work has been published in the journals Science, Nature Photonics, and Nature Physics, to name a few. Professor Mikkelsen enjoys hiking, gardening, playing tennis, and traveling in her free time.

Learn more at mikkelsen.pratt.duke.edu.

Written by Anika Radiya-Dixit

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