Duke Research Blog

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

Category: Faculty (Page 1 of 12)

How A Zebrafish’s Squiggly Cartilage Transforms into a Strong Spine

A column of green cartilage cells divides into an alternating pattern of green cartilage and red vertebra

Our spines begin as a flexible column called the notochord. Over time, cells on the notochord surface divide into alternating segments that go on to form cartilage and vertebrae.

In the womb, our strong spines start as nothing more than a rope of rubbery tissue. As our bodies develop, this flexible cord, called the notochord, morphs into a column of bone and cartilage sturdy enough to hold up our heavy upper bodies.

Graduate student Susan Wopat and her colleagues in Michel Bagnat’s lab at Duke are studying the notochords of the humble zebrafish to learn how this cartilage-like rope grows into a mature spine.

In a new paper, they detail the cellular messaging that directs this transformation.

It all comes down to Notch receptors on the notochord surface, they found. Notch receptors are a special type of protein that sits astride cell membranes. When two cells touch, these Notch receptors link up, forming channels that allow messages to rapidly travel between large groups of cells.

Notch receptors divide the outer notochord cells into two alternating groups – one group is told to grow into bone, while the other is told to grow into cartilage. Over time, bone starts to form on the surface of the notochord and works its way inward, eventually forming mature vertebrae.

X-ray images of four zebrafish spines

Meddling with cellular signaling on the notochord surface caused zebrafish spines to develop deformities. The first and third image show healthy spines, and the second and fourth image show deformed spines.

When the team tinkered with the Notch signaling on the surface cells, they found that the spinal vertebrae came out deformed – too big, too small, or the wrong shape.

“These results demonstrate that the notochord plays a critical role in guiding spine development,” Wopat said. “Further investigation into these findings may help us better understand the origin of spinal defects in humans.”

Spine patterning is guided by segmentation of the notochord sheath,” Susan Wopat, Jennifer Bagwell, Kaelyn D. Sumigray, Amy L. Dickson, Leonie F. Huitema, Kenneth D. Poss, Stefan Schulte-Merker, Michel Bagnat. Cell, February 20, 2018. DOI: 10.1016/j.celrep.2018.01.084

Post by Kara Manke

Duke Scholars Bridge Disciplines to Tackle Big Questions

A visualization showing faculty as dots that are connected by lines

This visualization, created by James Moody and the team at the Duke Network Analysis Center, links faculty from across schools and departments who serve together on Ph.D. committees. An interactive version is available here.

When the next big breakthrough in cancer treatment is announced, no one will ask whether the researchers are pharmacologists, oncologists or cellular biologists – and chances are, the team will represent all three.

In the second annual Scholars@Duke Visualization Challenge, Duke students explored how scholars across campus are drawing from multiple academic disciplines to tackle big research questions.

“I’m often amazed at how gifted Duke faculty are and how they can have expertise in multiple fields, sometimes even fields that don’t seem to overlap,” said Julia Trimmer, Director of Faculty Data Systems and Analysis at Duke.

In last year’s challenge, students dug into Scholars@Duke publication data to explore how Duke researchers collaborate across campus. This year, they were provided with additional data on Ph.D. dissertation committees and asked to focus on how graduate education and scholarship are reaching across departmental boundaries.

“The idea was to see if certain units or disciplines contributed faculty committee members across disciplines or if there’s a lot of discipline ‘overlap.’” Trimmer said.

The winning visualization, created by graduate student Matthew Epland, examines how Ph.D. committees span different fields. In this interactive plot, each marker represents an academic department. The closer together markers are, the more likely it is that a faculty member from one department will serve on the committee of a student in the other department.

Epland says he was intrigued to see the tight-knit community of neuroscience-focused departments that span different schools, including psychology and neuroscience, neurobiology, neurology and psychiatry and behavioral Sciences. Not surprisingly, many of the faculty in these departments are members of the Duke Institute for Brain Sciences (DIBS).

Duke schools appear as dots and are connected by lines of different thicknesses

Aghil Abed Zadeh and Varda F. Hagh analyzed publication data to visualize the extent to which faculty at different Duke schools collaborate with one another. The size of each dot represents the number of publications from each school, and thickness of each line represents the number of faculty collaborations between the connected schools.

Sociology Professor James Moody and the team at the Duke Network Analysis Center took a similar approach, creating a network of individual faculty members who are linked by shared students. Faculty who sit on committees in only one field are bunched together, highlighting researchers who bridge different disciplines. The size of each marker represents the extent to which each researcher sits “between” two fields.

The map shows a set of strong ties within the natural sciences and within the humanities, but few links between the two groups. Moody points out that philosophy is a surprising exception to this rule, lying closer to the natural sciences cluster than to the humanities cluster.

“At Duke, the strong emphasis on philosophy of science creates a natural link between philosophy and the natural sciences,” Moody said.

Duke graduate student Aghil Abed Zadeh teamed up with Varda F. Hagh, a student at Arizona State University, to create elegant maps linking schools and departments by shared authorship. The size of each marker represents the number of publications in that school or department, and the thickness of the connecting lines indicate the number of shared authorships.

“It is interesting to see how connected law school and public policy school are. They collaborate with many of the sciences as well, which is a surprising fact,” Zadeh said. “On the other hand, we see Divinity school, one the oldest at Duke, which is isolated and not connected to others at all.”

The teams presented their visualizations Jan. 20 at the Duke Research Computing Symposium.

Post by Kara Manke

 

Glitter and Jell-O Reveal the Science of Oobleck

A black and white image showing a circular disk dropping into a container of oobleck

Mixing black glitter with oobleck allowed researchers to track the movement of individual cornstarch particles after a sudden impact. A computer program locked onto pieces of glitter and illustrated their motion. Credit: Melody Lim.

What do gelatin and glitter have to do with serious science? For some experiments, a lot! Duke alumna Melody Lim used jiggly Jell-O and a just a pinch of glitter to solve a scientific mystery about the curious goo many like to call oobleck.

To the uninitiated, oobleck is almost magic. The simple mixture of cornstarch and water feels solid if you squeeze it, but moments later runs through your fingers like water. You can dance across a bathtub full of oobleck, but stand still for too long and you will be sucked into a goopy mess. Not surprisingly, the stuff is a Youtube favorite.

Oobleck is an example of what scientists call a non-Newtonian fluid, a liquid whose viscosity – how easily it changes shape and flows – depends upon the force that is applied. But exactly how it is that this material switches from solid to liquid and back again has remained a mystery to scientists.

A piece of gelatin being squeezed viewed through a circular polarizer

This blogger mixed up a batch of jello to see the photoelastic effect for herself. When viewed with polarized light – from an iPhone screen and a circular polarizer – the jello changes color when squeezed.

“Water is simple to understand, and so is cornstarch,” said Lim, ’16, who is currently a graduate student at the University of Chicago. “However, a combination of the two produces this ‘liquid’ that ripples and flows, solidifies beneath your feet if you run on it, then turns back into a liquid if you stop running and stand still. I wanted to know why.”

The question beguiling scientists was whether sudden impact causes the cornstarch particles to “jam” into a solid like cement, or whether the suspension remains liquid but simply moves too slowly for its liquid-like properties to be apparent — similar to what happens if you skip a rock off the surface of a lake.

“There are these two opposing pictures,” said Robert Behringer, James B. Duke Professor of Physics at Duke. “Either you squish the material and turn it into cement temporarily, or you simply transmit the stress from the impactor straight to the boundary.”

Lim did two sets of experiments to find out which way oobleck works. In one experiment, she mixed black glitter into a transparent channel filled with oobleck, and then used a high-speed camera to watch how the material responded to the impact. The glitter let her track the motion of individual particles after the disc hit.

A piece of gelatin changes color when you squeeze it.

The photoelastic effect in gelatin.

Her video shows that the particles near the impact site jam and become solid, forming what the researchers call a “mass shock” wave that travels slowly through the suspension.

In a second set of experiments, Lim placed the oobleck in a container lined with gelatin, the main ingredient in Jell-O – besides sugar and food dye, of course. Gelatin is what is called a photoelastic material, which means that applying pressure bends light that travels through it, like a prism.

“Next time you eat Jell-O, get out your sunglasses and get somebody else’s sunglasses and look between them,” Behringer said. “Because if you give it a shake you should see all these stress patterns bouncing around.”

After the metal disc hit the oobleck, the gelatin let Lim see how fast the resulting pressure wave traveled through the material and reached the boundary.

A black and white image showing pressure waves traveling through a transparent material after impact

The researchers poured oobleck into a clear container lined with gelatin, a material that bends light when a pressure is applied to it. They saw that the force of a sudden impact is rapidly transmitted through the oobleck and to the boundary with the gelatin. Credit: Melody Lim.

They found that when the impact is sudden, the pressure wave traveled to the gelatin boundary faster than the “mass shock” wave. This means that the reason oobleck appears solid after a sudden impact is because the force of the collision is quickly transmitted to a solid boundary.

“If you are running across the water, that actually puts you into an impact velocity range where the pressure wave is significantly faster than the mass shock,” Behringer said. “Whereas if you try to walk across it, the impact speeds are slow, and the system actually doesn’t have the ability to transport the momentum quickly through the material and so you just sink in.”

“If you’d told me when I started that I would line a narrow container with Jell-o, add cornstarch, water, and black glitter, drop a piece of metal on it, then publish a paper on the results, I would have laughed at you,” Lim said.

CITATION: “Force and Mass Dynamics in Non-Newtonian Suspensions,” Melody X. Lim, Jonathan Barés, Hu Zheng and Robert P. Behringer. Physical Review Letters, Nov. 3, 2017. DOI: 10.1103/PhysRevLett.119.184501

Post by Kara Manke

Duke’s Researchers Are 1 Percent of the Top 1 Percent

This year’s listing of the world’s most-cited researchers is out from Clarivate Analytics, and Duke has 34 names on the list of 3,400 researchers from 21 fields of science and social science.

Having your publication cited in a paper written by other scientists is a sign that your work is significant and advances the field. The highly-cited list includes the top 1 percent of scientists cited by others in the years 2005 to 2015.

“Citations by other scientists are an acknowledgement that the work our faculty has published is significant to their fields,” said Vice Provost for Research Lawrence Carin. “In research, we often talk about ‘standing on the shoulders of giants,’ as a way to explain how one person’s work builds on another’s. For Duke to have so many of our people in the top 1 percent indicates that they are leading their fields and their work is indeed something upon which others can build.”

In addition to the Durham researchers, Duke-NUS, our medical school in Singapore,  claims another 13 highly cited scientists.

The highly-cited scientists on the Durham campus are:

Barton Haynes

CLINICAL MEDICINE
Robert Califf
Christopher Granger
Kristin Newby
Christopher O’Connor
Erik Magnus Ohman
Manesh Patel
Michael Pencina
Eric Peterson

ECONOMICS AND BUSINESS
Dan Ariely
John Graham
Campbell Harvey

Drew Shindell

ENVIRONMENT/ECOLOGY
John Terborgh
Mark Wiesner

GEOSCIENCES
Drew Shindell

IMMUNOLOGY
Barton Haynes

MATHEMATICS
James Berger

Georgia Tomaras

Georgia Tomaras

MICROBIOLOGY
Bryan Cullen
Barton Haynes
David Montefiori
Georgia Tomaras

PHARMACOLOGY & TOXICOLOGY
Robert Lefkowitz

PHYSICS
David R. Smith

PLANT AND ANIMAL SCIENCE
Philip Benfey

Terrie Moffitt

Terrie Moffitt

PSYCHIATRY & PSYCHOLOGY
Angold, Adrian
Caspi, Avshalom
Copeland, William E
Costello, E J
Dawson, Geraldine
Keefe, Richard SE
McEvoy, Joseph P
Moffitt, Terrie E

SOCIAL SCIENCES (GENERAL)
Deverick Anderson
Kelly Brownell
Michael Pencina

Oral Histories of the Gulag

Gulag Voices: Oral Histories of Soviet Detention and Exile (2011), edited by Jehanne M. Gheith and Katherine R. Jolluck, brings interviews with Gulag survivors to English-speaking audiences. In an interview with Gheith, she reflected on how she began her research on the Soviet forced labor camps called Gulags, ethical complications and different kinds of research opportunities for students.

Dr. Jehanne M. Gheith, Associate Professor of Russian Culture at Duke University and Licensed Clinical Social Worker for Duke Hospice

In the early 1990s, Gheith taught a Gulag memoir to Duke students and realized that while students are aware of the Holocaust, their knowledge on Gulags is limited. After the dissolution of the Soviet Union in the 1990’s, it was possible for Gheith to interview Gulag survivors. She and her co-editor, Katherine Jolluck, connected ten years later when Jolluck was a professor at Stanford. Jolluck had published Exile and Identity: Polish Women in the Soviet Union During World War II, a book about Polish women in the Gulag, the two embarked on a collaborative partnership. Taking the interviews  Gheith had conducted, she and  Jolluck added archival sections and reviewed the interviews.

Memoirs and scholarly works differ from collections of interviews. Gheith felt it was important to conduct a project where she and others could hear the stories of survivors. An influential source that she consulted was the The Gulag Archipelago 1981-1956 (1973) by Nobel Literature Prize winner Aleksandr Solzhenitsyn. The Gulag Archipelago covers three volumes of Solzhenitsyn’s personal experience in the Russian Gulags and his critiques on the Stalin regime.

To find interview subjects for the oral project, Gheith contacted the Russian civil rights organization Memorial. She also interviewed people outside of Memorial using what she described as a “snowball sample.” To piece together the fragmented memories of survivors, Gheith listened and transcribed the stories in the order they were remembered with connecting passages of text. Though time can lead to the misrepresentation of facts, Gheith said, “the facts may be wrong, but you can get to emotional truths.” People may incorrectly recall small details due to numerous factors – nevertheless, through Memorial,  Gheith and Jolluck were able to verify key records of camp survivors, showing the years they were in the camps and the kinds of work they did there.

There were ethical complications Gheith had to surmount – participants could be reluctant to speak about their experiences and expressed surprise that audiences were interested in their memories. Some interviewees were fearful of the Gulag re-occurring and needed to be connected to support resources upon being asked about their encounters.

Gheith also needed to be vigilant about the context and history surrounding Gulags. Because Gulag survivors may have been forced to sign false confessions in the labor camps, Gheith had approval from the Institutional Review Board  to secure verbal agreements on tape in lieu of consent forms.

For students conducting interviews, Gheith suggested reading an oral history, communicating with experts and beginning with a smaller project. Additionally, she had two key points: 1) it is crucial to gain approval from the Institutional Review Board to work with human subjects and 2) if conducting research in a foreign language, the choice between a translator or transcriber should be carefully made, as a translator may shift the relationship dynamic.

In the future, Gheith will be connecting her clinical work to Russian literature and culture. She believes that for students interested in medicine, the arts and humanities have a significant connection to scientific research. Storytelling is also a key part of law and policy, and as students begin to conduct studies in these fields, they are likely to find that the ability to weave a narrative is an indispensable skill. Gheith said she would be happy to talk about the connections between story and medicine with any interested students.

By Ameya Sanyal

Who Gets Sick and Why?

During his presentation as part of the Chautauqua lecture series, Duke sociologist Dr. Tyson Brown explained his research exploring the ways racial inequalities affect a person’s health later in life. His project mainly looks at the Baby Boomer generation, Americans born between 1946 and 1964.

With incredible increases in life expectancy, from 47 years in 1900 to 79 today, elderly people are beginning to form a larger percentage of the population. However among black people, the average life expectancy is three and a half years shorter.

“Many of you probably do not think that three and half years is a lot,” Brown said. “But imagine how much less time that is with your family and loved ones. In the end, I think all of us agree we want those extra three and a half years.”

Not only does the black population in America have shorter lives on average but they also tend to have sicker lives with higher blood pressures, greater chances of stroke, and higher probability of diabetes. In total, the number of deaths that would be prevented if African-American people had the same life expectancy as white people is 880,000 over a nine-year span. Now, the question Brown has challenged himself with is “Why does this discrepancy occur?”

Brown said he first concluded that health habits and behaviors do not create this life expectancy gap because white and black people have similar rates of smoking, drinking, and illegal drug use. He then decided to explore socioeconomic status. He discovered that as education increases, mortality decreases. And as income increases, self-rated health increases. He said that for every dollar a white person makes, a black person makes 59 cents.

This inequality in income points to the possible cause for the racial inequality in health, he said.  Additionally, in terms of wealth instead of income, a black person has 6 cents compared to the white person’s dollar. Possibly even more concerning than this inconsistency is the fact that it has gotten worse, not better, over time. Before the 2006 recession, blacks had 10-12 cents of wealth for every white person’s dollar.

Brown believes that this financial stress forms one of many stressors in black lives including chronic stressors, everyday discrimination, traumatic events, and neighborhood disorder which affect their health.

Over time, these stressors create something called physiological dysregulation, otherwise known as wear and tear, through repeated activation of  the stress response, he said. Recognition of the prevalence of these stressors in black lives has lead to Brown’s next focus on the extent of the effect of stressors on health. For his data, he uses the Health and Retirement Study and self-rated health (proven to predict mortality better than physician evaluations). For his methods, he employs structural equation modeling. Racial inequalities in socioeconomic resources, stressors and biomarkers of physiological dysregulation collectively explain 87% of the health gap with any number of causes capable of filling the remaining percentage.

Brown said his next steps include using longitudinal and macro-level data on structural inequality to understand how social inequalities “get under the skin” over a person’s lifetime. He suggests that the next steps for society, organizations, and the government to decrease this racial discrepancy rest in changing economic policy, increasing wages, guaranteeing work, and reducing residential segregation.

Post by Lydia Goff

Cheating Time to Watch Liquids do the Slow Dance

Colorful spheres simulating liquid molecules shift around inside a cube shape

The team’s new algorithm is able to simulate molecular configurations of supercooled liquids below the glass transition. The properties of these configurations are helping to solve a 70-year paradox about the entropy of glasses. Credit: Misaki Ozawa and Andrea Ninarello, Université de Montpellier.

If you could put on a pair of swimming goggles, shrink yourself down like a character from The Magic School Bus and take a deep dive inside a liquid, you would see a crowd of molecules all partying like it’s 1999.

All this frenetic wiggling makes it easy for molecules to rearrange themselves and for the liquid as a whole to change shape. But for supercooled liquids — liquids like honey that are cooled below their freezing point without crystallizing – the lower temperature slows down the dancing like Etta James’ “At Last.” Lower the temperature enough, and the slow-down can be so dramatic that it takes centuries or even millennia for the molecules to rearrange and the liquid to move.

Scientists can’t study processes that last longer than their careers. But Duke chemists and their Simons Foundation collaborators have found a way to cheat time, simulating the slow dance of deeply supercooled liquids. Along the way, they have found new physical properties of “aged” supercooled liquids and glasses.

A droplet rises above a surface of water

Credit: Ruben Alexander via Flickr.

To understand just how slow deeply supercooled liquids move, consider the world’s longest-running experiment, the University of Queensland’s Pitch Drop Experiment. A single drop of pitch forms every eight to thirteen years — and this pitch is moving faster than deeply supercooled liquids.

“Experimentally there is a limit to what you can observe, because even if you managed to do it over your entire career, that is still a maximum of 50 years,” said Patrick Charbonneau, an associate professor of chemistry and physics at Duke. “For many people that was considered a hard glass ceiling, beyond which you couldn’t study the behavior of supercooled liquids.”

Charbonneau, who is an expert on numerical simulations, said that using computers to simulate the behavior of supercooled liquids has even steeper time limitations. He estimates that, given the current rate of computer advancement, it would take 50 to 100 years before computers would be powerful enough for simulations to exceed experimental capabilities – and even then the simulations would take months.

To break this glass ceiling, the Charbonneau group collaborated with Ludovic Berthier and his team, who were developing an algorithm to bypass these time constraints. Rather than taking months or years to simulate how each molecule in a supercooled liquids jiggles around until the molecules rearrange, the algorithm picks individual molecules to swap places with each other, creating new molecular configurations.

This allows the team to explore new configurations that could take millennia to form naturally. These “deeply supercooled liquids and ultra-aged glasses” liquids are at a lower energy, and more stable, than any observed before.

“We were cheating time in the sense that we didn’t have to follow the dynamics of the system,” Charbonneau said. “We were able to simulate deeply supercooled liquids well beyond is possible in experiments, and it opened up a lot of possibilities.”

Two columns of blue and red spheres represent simulations of vapor-deposited glasses.

Glasses that are grown one layer at a time have a much different structure than bulk glasses. The team used their new algorithm to study how molecules in these glasses rearrange, and found that at low temperatures (right), only the molecules at the surface are mobile. The results may be used to design better types of glass for drug delivery or protective coatings. Credit: Elijah Flenner.

Last summer, the team used this technique to discover a new phase transition in low-temperature glasses. They recently published two additional studies, one of which sheds light on the “Kauzmann paradox,” a 70-year question about the entropy of supercooled liquids below the glass transition. The second explores the formation of vapor-deposited glasses, which have applications in drug delivery and protective coatings.

“Nature has only one way to equilibrate, by just following the molecular dynamics,” said Sho Yaida, a postdoctoral fellow in Charbonneau’s lab. “But the great thing about numerical simulations is you can tweak the algorithm to accelerate your experiment.”

Configurational entropy measurements in extremely supercooled liquids that break the glass ceiling.” Ludovic Berthier, Patrick Charbonneau, Daniele Coslovich, Andrea Ninarello, Misaki Ozawa and Sho Yaida. PNAS, Oct. 24, 2017. DOI: 10.1073/pnas.1706860114

The origin of ultrastability in vapor-deposited glasses.” Ludovic Berthier, Patrick Charbonneau, Elijah Flenner and Francesco Zamponi. PRL, Nov. 1, 2017. DOI: 10.1103/PhysRevLett.119.188002

Post by Kara Manke

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

Individual RNA molecules fluoresce 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.

A portrait of Amanda Hargrove

Amanda Hargrove is an assistant professor of chemistry at Duke University.

“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 proteins and RNA 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

Kara J. Manke, PhDPost by Kara Manke

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

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