Duke Research Blog

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

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Duke Scientists Visit Raleigh to Share Their Work

This post by graduate student Dan Keeley originally appeared on Regeneration NEXT. It is a followup to one of our earlier posts.

As a scientist, it is easy to get caught up in the day-to-day workflow of research and lose sight of the bigger picture. We are often so focused on generating and reporting solid, exciting data that we neglect another major aspect of our job; sharing our work and its impacts with the broader community. On Tuesday May 23rd, a group of graduate students from Duke went to the North Carolina legislative building to do just that.

L-R: Andrew George, Representative Marcia Morey (Durham County), Senator Terry Van Duyn (Buncombe County), Sharlini Sankaran, Dan Keeley, and Will Barclay at the NC legislative building.

Dr. Sharlini Sankaran, Executive Director of Duke’s Regeneration Next Initiative, organized a group of graduate students to attend the North Carolina Hospital Associations (NCHA) “Partnering for a Healthier Tomorrow!” advocacy day at the state legislature in Raleigh. The event gave representatives from various hospital systems an opportunity to interact with state legislators about the work they do and issues affecting healthcare in the state. Andrew George, a graduate student in the McClay Lab, Will Barclay, a graduate student in the Shinohara Lab, and I joined Dr. Sankaran to share some of the great tissue regeneration-related research going on at Duke.

Our morning was busy as elected officials, legislative staff, executive branch agency officials, and staff from other hospital systems stopped by our booth to hear what Regeneration Next is all about. We talked about the focus on harnessing Duke’s strengths in fundamental research on molecular mechanisms underlying regeneration and development, then pairing that with the expertise of our engineers and clinicians. We discussed topics including spine and heart regeneration mechanisms from the Poss Lab, advances in engineering skeletal muscle from the Bursac Lab, and clinical trials of bioengineered blood vessels for patients undergoing dialysis from Duke faculty Dr. Jeffrey Lawson.

It was remarkable to hear how engaged everyone was, we got great questions like ‘what is a zebrafish and why do you use them?’ and ‘why would a bioengineered ligament be better than one from an animal model or cadaver?’.  Every person who stopped by was supportive and many had a personal story to share about a health issue experienced by friends, family, or even themselves. As a graduate student who does basic research, it really underscored how important these personal connections are to our work, even though it may be far removed from the clinic.

Communicating our research to legislators and others at NCHA advocacy day was a great and encouraging experience. Health issues affect all of us. Our visit to the legislature on Tuesday was a reminder that there is support for the work that we do in hopes it will help lead to a healthier tomorrow.

Guest post by Dan Keeley, graduate student in BiologyDan Keeley

Scientists Engineer Disease-Resistant Rice Without Sacrificing Yield

Researchers have developed a way to make rice more resistant to bacterial blight and other diseases without reducing yield. Photo by Max Pixel.

Researchers have successfully developed a novel method that allows for increased disease resistance in rice without decreasing yield. A team at Duke University, working in collaboration with scientists at Huazhong Agricultural University in China, describe the findings in a paper published May 17, 2017 in the journal Nature.

Rice is one of the most important staple crops, responsible for providing over one-fifth of the calories consumed by humans worldwide. Diseases caused by bacterial or fungal pathogens present a significant problem, and can result in the loss of 80 percent or more of a rice crop.

Decades of research into the plant immune response have identified components that can be used to engineer disease-resistant plants. However, their practical application to crops is limited due to the decreased yield associated with a constantly active defense response.

“Immunity is a double-edged sword, ” said study co-author Xinnian Dong, professor of biology at Duke and lead investigator of the study. “There is often a tradeoff between growth and defense because defense proteins are not only toxic to pathogens but also harmful to self when overexpressed,” Dong said. “This is a major challenge in engineering disease resistance for agricultural use because the ultimate goal is to protect the yield.”

Previous studies have focused on altering the coding sequence or upstream DNA sequence elements of a gene. These upstream DNA elements are known as promoters, and they act as switches that turn on or off a gene’s expression. This is the first step of a gene’s synthesis into its protein product, known as transcription.

By attaching a promoter that gives an “on” signal to a defense gene, a plant can be engineered to be highly resistant to pathogens, though at a cost to growth and yield. These costs can be partially alleviated by attaching the defense gene to a “pathogen specific” promoter that turns on in the presence of pathogen attack.

To further alleviate the negative effects of active defense, the Dong group sought to add an additional layer of control. They turned newly discovered sequence elements, called upstream open reading frames (uORFs), to help address this problem. These sequence elements act on the intermediate of a gene, or messenger (RNA, a molecule similar to DNA) to govern its “translation” into the final protein product. A recent study by the Dong lab in an accompanying paper in Nature has identified many of these elements that respond in a pathogen-inducible manner.

The Dong group hypothesized that adding this pathogen-inducible translational regulation would result in a tighter control of defense protein expression and minimize the lost yield associated with enhanced disease resistance.

To test this hypothesis, the researchers started with Arabidopsis, a flowering plant commonly used in laboratory research. They created a DNA sequence that contains both the transcriptional and translational elements (uORFs) and fused them upstream of the potent “immune activator” gene called snc1. This hybrid sequence was called a “transcriptional/translational cassette” and was inserted into Arabidopsis plants.

When plants have snc1 constitutively active, they are highly resistant to pathogens, but have severely stunted growth. Strikingly, plants with the transcriptional/translational cassette not only have increased resistance, but they also lacked growth defects and resembled healthy wild-type plants. These results show the benefits of adding translational control in engineering plants that have increased resistance without significant costs.

The Dong group then sought to apply these findings to engineer disease-resistant rice, as it is one of the world’s most important crops. They created transgenic rice lines containing the transcriptional/translational cassette driving expression of another potent “immune activator” gene called AtNPR1. This gene was chosen as it has been found to confer broad spectrum pathogen resistance in a wide variety of crop species, including rice, citrus, apple and wheat.

The dry yellowish leaves on these rice plants are a classic symptom of bacterial blight, a devastating disease that affects rice fields worldwide. Photo by Meng Yuan.

The transgenic rice lines containing the transcriptional/translational cassette were infected with bacterial/fungal pathogens that cause three major rice diseases — rice  blight, leaf streak, and fungal blast. These showed high resistance to all three pathogens, indicating broad spectrum resistance could be achieved. Importantly, when grown in the field, their yield — both in terms of grain quantity and quality per plant — was almost unaffected. These results indicate a great potential for agricultural applications.

This strategy is the first known use of adding translational control for the engineering of disease-resistant crops with minimal yield costs. It has many advantages, as it is broadly applicable to a variety of crop species against many pathogens. Since this strategy involves activating the plants’ endogenous defenses, it may also reduce the use of pesticides on crops and hence protect the environment.

Additionally, these findings may be broadly applicable to other systems as well. These upstream elements (uORFs) are widely present in organisms from yeast to humans, with nearly half of all human transcripts containing them. “The great potential in using these elements in controlling protein translation during specific biological processes has yet to be realized,” Dong said.

Corresponding author Xinnian Dong can be reached at xdong@duke.edu or (919) 613-8176.

CITATION:  “uORF-Mediated Translation Allows Engineered Plant Disease Resistance Without Fitness Costs,” Guoyong Xu, Meng Yuan,   Chaoren Ai, Lijing Liu, Edward Zhuang, Sargis Karapetyan, Shiping Wang and Xinnian Dong. Nature, May 17, 2017. DOI: 10.1038/nature22372

 

Guest post by Jonathan Motley

If the Cancer Doesn’t Kill You, the Drug Prices Might

The medical community is growing alarmed about a creeping malady that can diminish the quality of life for patients in treatment and even shorten their lives.

It’s found everywhere in the United States, but not to the same degree in other developed countries. They’re calling it “Financial Toxicity.”

Yousuf Zafar is an oncologist and health policy researcher.

A cancer diagnosis more than doubles an American’s chance of declaring bankruptcy, Duke medical oncologist  Yousuf Zafar, MD, MHS,  told an audience of nursing faculty and students at a May 10 luncheon lecture sponsored by the Duke Center for Community and Population Health Improvement. And that bankruptcy, in turn, has been shown to decrease survival rates.

In addition to treating cancer patients, Zafar studies access to care and the cost of care at the Duke Cancer Institute, the Sanford School of Public Policy, and the Margolis Center for Health Policy.

Zafar told personal stories of two patients who waved off treatments because of the financial hardship they feared.

Gleevec (Imatinib) is an oral chemotherapy made by Novartis.

One of them had a job with health insurance, but no prescription drug coverage, which put him on the hook for $4,000 in medications to treat his rectal cancer for just a few weeks. Had either the patient or Dr. Zafar brought the topic up, the costs might have been avoided, but they never talked about money, he said.

The other patient passed up another round of treatment for his pancreatic cancer, for fear of the bills his family would be saddled with when he died.

Chemotherapy for cancer would typically cost $100/month in the 1970s, Zafar said. But today that figure can be “ten, or tens, of thousands per month.” (Inflation would make that 1970 dollar about $6, not $600.)

“Pricing in the European Union and the rest of the world is a completely different picture,” he said.  In the US, pricing “simply reflects what the market will bear.”

Another source of the steep climb is the advent of biologic drugs, which are expensive to develop, use and store, but offer more targeted therapy for individual patients. One of the most successful of these is Gleevec (Imatinib) an oral chemotherapy that became 158 percent more expensive from 2007 to 2014, Zafar said.

If you do a Google search for Gleevec, the first thing you find is a Novartis page with the headline “Understand Your Out-Of-Pocket Costs For Gleevec” that includes a link to financial assistance resources.

In the face of outrageous costs and questionable benefits, a treatment team in many cases can help patients find other means of support or alternative treatments to achieve the same end with less financial damage. But they have to have the conversation, Zafar said. He’d like to see Duke’s Cancer Center become the first in the country to be totally transparent about costs, but he acknowledged that it may be a difficult quest.

To help enable those conversations, Zafar developed a mobile app called Pathlight to help patients make more informed decisions and plan better for the financial burden of treatment. For some of the technology used in the project, Zafar has partnered with a software company called Vivor, which has found innovative ways to help patients navigate to financial assistance programs. That part of the project is supported by the NIH’s National Cancer Institute.

Even for people not in treatment, drugs have become more costly. Healthcare premiums rose 182 percent from 1999 to 2013, with workers paying an increasing share of the cost of their own employee health plans.

Is this any way to run a health system?

“I don’t have all the answers – I don’t think anybody does,” Zafar said. “But I think we need to move toward a single-payer system.”

Post by Karl Leif Bates

 

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

Students Share Research Journeys at Bass Connections Showcase

From the highlands of north central Peru to high schools in North Carolina, student researchers in Duke’s Bass Connections program are gathering data in all sorts of unique places.

As the school year winds down, they packed into Duke’s Scharf Hall last week to hear one another’s stories.

Students and faculty gathered in Scharf Hall to learn about each other’s research at this year’s Bass Connections showcase. Photo by Jared Lazarus/Duke Photography.

The Bass Connections program brings together interdisciplinary teams of undergraduates, graduate students and professors to tackle big questions in research. This year’s showcase, which featured poster presentations and five “lightning talks,” was the first to include teams spanning all five of the program’s diverse themes: Brain and Society; Information, Society and Culture; Global Health; Education and Human Development; and Energy.

“The students wanted an opportunity to learn from one another about what they had been working on across all the different themes over the course of the year,” said Lori Bennear, associate professor of environmental economics and policy at the Nicholas School, during the opening remarks.

Students seized the chance, eagerly perusing peers’ posters and gathering for standing-room-only viewings of other team’s talks.

The different investigations took students from rural areas of Peru, where teams interviewed local residents to better understand the transmission of deadly diseases like malaria and leishmaniasis, to the North Carolina Museum of Art, where mathematicians and engineers worked side-by-side with artists to restore paintings.

Machine learning algorithms created by the Energy Data Analytics Lab can pick out buildings from a satellite image and estimate their energy consumption. Image courtesy Hoël Wiesner.

Students in the Energy Data Analytics Lab didn’t have to look much farther than their smart phones for the data they needed to better understand energy use.

“Here you can see a satellite image, very similar to one you can find on Google maps,” said Eric Peshkin, a junior mathematics major, as he showed an aerial photo of an urban area featuring buildings and a highway. “The question is how can this be useful to us as researchers?”

With the help of new machine-learning algorithms, images like these could soon give researchers oodles of valuable information about energy consumption, Peshkin said.

“For example, what if we could pick out buildings and estimate their energy usage on a per-building level?” said Hoël Wiesner, a second year master’s student at the Nicholas School. “There is not really a good data set for this out there because utilities that do have this information tend to keep it private for commercial reasons.”

The lab has had success developing algorithms that can estimate the size and location of solar panels from aerial photos. Peshkin and Wiesner described how they are now creating new algorithms that can first identify the size and locations of buildings in satellite imagery, and then estimate their energy usage. These tools could provide a quick and easy way to evaluate the total energy needs in any neighborhood, town or city in the U.S. or around the world.

“It’s not just that we can take one city, say Norfolk, Virginia, and estimate the buildings there. If you give us Reno, Tuscaloosa, Las Vegas, Pheonix — my hometown — you can absolutely get the per-building energy estimations,” Peshkin said. “And what that means is that policy makers will be more informed, NGOs will have the ability to best service their community, and more efficient, more accurate energy policy can be implemented.”

Some students’ research took them to the sidelines of local sports fields. Joost Op’t Eynde, a master’s student in biomedical engineering, described how he and his colleagues on a Brain and Society team are working with high school and youth football leagues to sort out what exactly happens to the brain during a high-impact sports game.

While a particularly nasty hit to the head might cause clear symptoms that can be diagnosed as a concussion, the accumulation of lesser impacts over the course of a game or season may also affect the brain. Eynde and his team are developing a set of tools to monitor both these impacts and their effects.

A standing-room only crowd listened to a team present on their work “Tackling Concussions.” Photo by Jared Lazarus/Duke Photography.

“We talk about inputs and outputs — what happens, and what are the results,” Eynde said. “For the inputs, we want to actually see when somebody gets hit, how they get hit, what kinds of things they experience, and what is going on in the head. And the output is we want to look at a way to assess objectively.”

The tools include surveys to estimate how often a player is impacted, an in-ear accelerometer called the DASHR that measures the intensity of jostles to the head, and tests of players’ performance on eye-tracking tasks.

“Right now we are looking on the scale of a season, maybe two seasons,” Eynde said. “What we would like to do in the future is actually follow some of these students throughout their career and get the full data for four years or however long they are involved in the program, and find out more of the long-term effects of what they experience.”

Kara J. Manke, PhD

Post by Kara Manke

Visualizing the Fourth Dimension

Living in a 3-dimensional world, we can easily visualize objects in 2 and 3 dimensions. But as a mathematician, playing with only 3 dimensions is limiting, Dr. Henry Segerman laments.  An Assistant Professor in Mathematics at Oklahoma State University, Segerman spoke to Duke students and faculty on visualizing 4-dimensional space as part of the PLUM lecture series on April 18.

What exactly is the 4th dimension?

Let’s break down spatial dimensions into what we know. We can describe a point in 2-dimensional space with two numbers x and y, visualizing an object in the xy plane, and a point in 3D space with 3 numbers in the xyz coordinate system.

Plotting three dimensions in the xyz coordinate system.

While the green right-angle markers are not actually 90 degrees, we are able to infer the 3-dimensional geometry as shown on a 2-dimensional screen.

Likewise, we can describe a point in 4-dimensional space with four numbers – x, y, z, and w – where the purple w-axis is at a right angle to the other regions; in other words, we can visualize 4 dimensions by squishing it down to three.

Plotting four dimensions in the xyzw coordinate system.

One commonly explored 4D object we can attempt to visualize is known as a hypercube. A hypercube is analogous to a cube in 3 dimensions, just as a cube is to a square.

How do we make a hypercube?

To create a 1D line, we take a point, make a copy, move the copied point parallely to some distance away, and then connect the two points with a line.

Similarly, a square can be formed by making a copy of a line and connecting them to add the second dimension.

So, to create a hypercube, we move identical 3D cubes parallel to each other, and then connect them with four lines, as depicted in the image below.

To create an n–dimensional cube, we take 2 copies of the (n−1)–dimensional cube and connecting corresponding corners.

Even with a 3D-printed model, trying to visualize the hypercube can get confusing. 

How can we make a better picture of a hypercube? “You sort of cheat,” Dr. Segerman explained. One way to cheat is by casting shadows.

Parallel projection shadows, depicted in the figure below, are caused by rays of light falling at a  right angle to the plane of the table. We can see that some of the edges of the shadow are parallel, which is also true of the physical object. However, some of the edges that collide in the 2D cast don’t actually collide in the 3D object, making the projection more complicated to map back to the 3D object.

Parallel projection of a cube on a transparent sheet of plastic above the table.

One way to cast shadows with no collisions is through stereographic projection as depicted below.

The stereographic projection is a mapping (function) that projects a sphere onto a plane. The projection is defined on the entire sphere, except the point at the top of the sphere.

For the object below, the curves on the sphere cast shadows, mapping them to a straight line grid on the plane. With stereographic projection, each side of the 3D object maps to a different point on the plane so that we can view all sides of the original object.

Stereographic projection of a grid pattern onto the plane. 3D print the model at Duke’s Co-Lab!

Just as shadows of 3D objects are images formed on a 2D surface, our retina has only a 2D surface area to detect light entering the eye, so we actually see a 2D projection of our 3D world. Our minds are computationally able to reconstruct the 3D world around us by using previous experience and information from the 2D images such as light, shade, and parallax.

Projection of a 3D object on a 2D surface.

Projection of a 4D object on a 3D world

How can we visualize the 4-dimensional hypercube?

To use stereographic projection, we radially project the edges of a 3D cube (left of the image below) to the surface of a sphere to form a “beach ball cube” (right).

The faces of the cube radially projected onto the sphere.

Placing a point light source at the north pole of the bloated cube, we can obtain the projection onto a 2D plane as shown below.

Stereographic projection of the “beach ball cube” pattern to the plane. View the 3D model here.

Applied to one dimension higher, we can theoretically blow a 4-dimensional shape up into a ball, and then place a light at the top of the object, and project the image down into 3 dimensions.

Left: 3D print of the stereographic projection of a “beach ball hypercube” to 3-dimensional space. Right: computer render of the same, including the 2-dimensional square faces.

Forming n–dimensional cubes from (n−1)–dimensional renderings.

Thus, the constructed 3D model of the “beach ball cube” shadow is the projection of the hypercube into 3-dimensional space. Here the 4-dimensional edges of the hypercube become distorted cubes instead of strips.

Just as the edges of the top object in the figure can be connected together by folding the squares through the 3rd dimension to form a cube, the edges of the bottom object can be connected through the 4th dimension

Why are we trying to understand things in 4 dimensions?

As far as we know, the space around us consists of only 3 dimensions. Mathematically, however, there is no reason to limit our understanding of higher-dimensional geometry and space to only 3, since there is nothing special about the number 3 that makes it the only possible number of dimensions space can have.

From a physics perspective, Einstein’s theory of Special Relativity suggests a connection between space and time, so the space-time continuum consists of 3 spatial dimensions and 1 temporal dimension. For example, consider a blooming flower. The flower’s position it not changing: it is not moving up or sideways. Yet, we can observe the transformation, which is proof that an additional dimension exists. Equating time with the 4th dimension is one example, but the 4th dimension can also be positional like the first 3. While it is possible to visualize space-time by examining snapshots of the flower with time as a constant, it is also useful to understand how space and time interrelate geometrically.

Explore more in the 4th dimension with Hypernom or Dr. Segerman’s book “Visualizing Mathematics with 3D Printing“!

Post by Anika Radiya-Dixit.

 

 

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