Winter 2009

end­­eavors WINTER 2009

Research and Creative Activity • The University of North Carolina at Chapel Hill

LET’S GET VISUAL Science looks better than ever. page 4

ANDREY PROKHOROV

The notion that science is boring might have some-

thing to do with the fact that numbers don’t look good naked.

Except for experienced scientists and scholars, people generally have trouble imagining the connection between raw data and the living, breathing world the data describe.

Today, that is changing. In almost every field of science and scholarship, the data are coming alive.

Imagine Charles Darwin exploring the wilds of South America, or venturing ashore into the lava-rock landscape of the Galapagos Islands. Much of the information he gathered was visual. The story of life began to unfold in his mind because he had seen it.

That was the way of science for generations, until advanced mathematics and powerful instruments enabled us to explore the realms we could not see. We had entered a new age of science, but it wasn’t always as sensual or exciting as a sea voyage to unexplored lands, and the data piling up in our labs sometimes overwhelmed

our capacity to grasp them. How could we comprehend the patterns of wind through a city, or predict the extent of a flood from a coastal hurricane, or fathom the structure of a protein from numbers alone?

Over the last decade or so, our tools have gotten better. In the right hands, computers can now convert blizzards of data into organized, visual patterns displayed in bright hues on a screen. At last, we can see our way into the data. Often, we can understand them immediately, intuitively. And we can find in those images very real meaning, just as Darwin found meaning in the beak of a finch.

And so we have entered a new age of science: the age of visualization. It will not be boring. Everywhere we turn, we discover new patterns. The images they form are startling in their complexity, thrilling in their originality. And very often, they are beautiful, because they have tapped into some of the deepest structures of Nature’s grand design. Science has never looked better.

—The Editor

end­­eavors

Winter 2009 • Volume XXV, Number 2 Endeavors engages its readers in the intellectual life of the University of North Carolina at Chapel Hill by conveying the excitement of creativity, discovery, and the rigors and risks of the quest for new knowledge.

Endeavors (ISSN 1933-4338) is published three times a year by the Office of the Vice Chancellor for Research and Economic Development at the University of North Carolina at Chapel Hill.

Send comments, requests for permission to reprint material, and requests for extra copies to: Endeavors Office of Information and Communications CB 4106, 307 Bynum Hall University of North Carolina at Chapel Hill Chapel Hill, NC 27599-4106 phone: (919) 962-6136 e-mail: endeavors@unc.edu

Holden Thorp, Chancellor Bernadette Gray-Little, Provost and Executive Vice Chancellor Tony Waldrop, Vice Chancellor, Research and Economic Development

contents

Winter 2009

2 overview

MSG and obesity, stopping a leak with pig gut, a hot balloon beats cancer, and a 3-D map for

radiation therapy.

More than pretty pictures, the images of science show us patterns that data alone may conceal.

by Mark Derewicz

features 16 How do you get to Carnegie Hall?

Left at West 42nd St; right at 10th Ave; right on West 57th; right on 7th Ave. Or do what Mayron Tsong did.

by Meagen Voss

18 The Symbols on the Stone

Learning to read what the Olmecs wrote.

by Margarite Nathe

22 Let the Water Flow

Archaeologists dig in to help a Peruvian village.

by Susan Hardy

When it comes to pain, PAP is the new FRAP.

by Meagen Voss

Editor: Neil Caudle, Associate Vice Chancellor, Research and Economic Development Associate Editor: Jason Smith Writers: Mark Derewicz, Susan Hardy, Beth Mole, Prashant Nair, Margarite Nathe, Deborah Neffa, and Meagen Voss

James Evans tells it to the judge.

by Prashant Nair

32 Thick and Thin

cover story 4 Let’s Get Visual

24 Digging for Relief

28 Taking DNA to Court

Darryl Stafford uncovers warfarin’s secrets.

by Mark Derewicz

34 Seeds of Invasion

What can turf wars teach us about the spread of disease?

by Beth Mole

38 Sounding Out the White House Every new presidential administration comes in with hundreds of questions. Terry Sullivan helps answer them.

by Mark Derewicz

42 Boning up on Stem Cells How to heal a fracture faster.

by Susan Hardy

44 in print

A suitcase full of Holocaust letters, and one man’s Civil War.

49 endview

An orphanage in Nairobi.

On the cover: This visualization shows the impact of injury intervention techniques and laws on the prevention and control of injuries and violence related to traffic, alcohol, and firearms.

Visualization: Hong Yi, Renaissance Computing Institute. Research: UNC epidemiologist Andres Villaveces

Design: Neil Caudle and Jason Smith Print production and website: Jason Smith

http://research.unc.edu/endeavors/

©2009 by the University of North Carolina at Chapel Hill in the United States. All rights reserved. No part of this publication may be reproduced without the consent of the University of North Carolina at Chapel Hill. Use of trade names implies no endorsement

by UNC-Chapel Hill.

overview Can MSG make us F-A-T?

H

animals, but this study was the first to link MSG use to obesity in humans.

He says that MSG consumption has increased dramatically during the past few decades. “Almost everyone consumes it in foods they make at home, eat at restaurants, or buy in stores,” he says.

He and his colleagues in the United States and China found that participants who used the most MSG were nearly three times more likely than nonusers to be overweight. About 82 percent of participants used MSG; the average intake was 0.33 grams per day. The median intake for participants consuming the most MSG was 0.7 grams per day.

He says that MSG may also affect the brain’s hypothalamus and alter the functioning of leptin, a hormone that regulates food intake and energy balance.

MSG is commonly used in Asian dishes

AMY WALTERS

aving trouble losing weight? Cutting back on monosodium glutamate might help. People who use the common flavor enhancer MSG are more likely than nonconsumers to be overweight—even when they have the same calorie intake and physical activity levels, according to a study by School of Public Health researchers.

The study measured MSG use in 752 people from north and south China who ate most of their meals at home. Ka He, lead author of the study, says measuring MSG consumption by people who eat mainly home-cooked food is easier than measuring consumption by people who eat out frequently. “Restaurants would be hesitant to give us the ingredients they put in their food,” He says.

MSG stimulates taste buds, tempting people to eat more. Previous studies have linked MSG consumption to weight gain in

and other popular foods, including some brands of snacks, salad dressings, soy sauce, packaged lunch meats, and canned soups and vegetables. The Food and Drug Administration uses the term MSG to mean a 99-percent pure combination of glutamic acid and sodium. “Food companies can make it 95 percent or 80 percent purified and call the seasoning anything they want,” He says. “But it still contains substantial amounts of MSG.” He is creating another study to test the link between MSG consumption and weight gain in humans. “Based on only this single study, we cannot say MSG causes obesity,” He says. “Our weight is determined by our lifestyle, not just a single factor like MSG consumption. MSG’s effects can be attenuated by exercise or healthful eating.”

—Deborah Neffa Deborah Neffa is a senior majoring in journalism at Carolina.

Ka He is an assistant professor of nutrition and epidemiology in the Gillings School of Global Public Health. The study appeared in the August 2008 issue of the journal Obesity and was funded by the National Institutes of Health.

2 endeavors

Pig intestine for a new fix ecky Brown had to undergo five surgeries and was about to have a sixth before UNC radiologist Joe Stavas developed a new way to repair Brown’s two recurring fistulae.

A fistula is an abnormal tunnel that connects an internal organ to the surface of the skin. Brown’s fistulae formed when an internal abscess caused by Crohn’s disease burst and leaked fluids. Her body’s response was to create a channel to drain the fluids.

Instead of cutting into Brown’s abdomen to insert a fistula plug, Stavas used a catheter to thread a new kind of plug through the abdominal cavity until it reached the intestine. Doctors use a similar method for heart catheterizations and for removing blood clots in the brain, but Stavas is the first to use a catheter for fistula repair.

The plug he used was derived from pig intestines. It prompts the body’s surrounding tissue to regenerate, closing the hole and allowing the patient to heal. “This is a form of tissue bioengineering,” Stavas says, “and shows promise for future applications of tissue regeneration for wounds and stem cell growth.”

Brown needed six weeks to recover from her traditional surgeries. Each time, at least one fistula reformed. But after Stavas’s procedure, Brown says, “I was back at work the next day.” A year later, no fistulae have returned.

—Mark Derewicz Joseph Stavas is the vice chairman of vascular and interventional radiology and associate professor of radiology in the School of Medicine.

Cook Biotech Inc. made the fistula plug that Stavas uses.

Burning cancer before it begins

3-D maps for radiation therapy

A

E

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hot balloon. That’s what doctors in one clinical trial used to destroy precancerous cells in patients with Barrett’s esophagus, a condition that can lead to throat cancer.

When a patient has acid reflux, stomach acid continually enters the esophagus. The acid sometimes changes esophageal cells into cells similar to those found in the intestines. This is Barrett’s esophagus. In some cases the cells acquire precancerous traits and morph into adenocarcinoma, a cancer that’s difficult to treat.

Nicholas Shaheen led the first randomized clinical trial to see if radiofrequency ablation could destroy the precancerous cells. The ablation system is a set of electromagnetic coils on the surface of a balloon that is inserted into a patient’s esophagus and inflated. The coils generate enough heat to burn away the precancerous cells, but not enough to harm most of the normal cells.

After twelve months of treatment, 85 percent of patients were free of the precancerous cells and 75 percent showed no evidence of Barrett’s esophagus. In the placebo version of the treatment— inserted balloon, no heat—all patients still had Barrett’s. “I thought the results would be good,” Shaheen says, “but I was surprised they would be that good.”

This outpatient treatment can cause a burning sensation in the chest that can last three or four days. But when Shaheen uses standard laser treatment, he routinely hospitalizes patients because their lower esophagi narrow and they experience much greater pain.

Shaheen says that radiofrequency ablation can’t kill cancer cells that have spread too far or deep. He has also used liquid nitrogen to freeze abnormal cells in the esophagus. He thinks this technique might be as promising as radiofrequency ablation.

“All these treatments are variations on the same theme,” he says. “If you destroy the cancerous cells and give patients rigorous acid-suppression medication, then the normal esophageal cells come back.”

—Mark Derewicz Nicholas Shaheen is the director of the Center for Esophageal Diseases and Swallowing and an associate professor of medicine and epidemiology in the School of Medicine. Patients from nineteen medical centers participated in the clinical trial. BARRX Medical Inc., which manufactures the radiofrequency ablation system, funded the study.

dward Chaney and Stephen Pizer had an idea back in the 1990s to use CT scans and MRIs to create three-dimensional anatomical maps of tumors and surrounding organs. Today that idea is on the verge of helping oncologists plan and deliver radiation therapy.

Normally, an oncologist takes a CT scan of a patient’s prostate, for instance, and uses a computer to manually draw contours around the prostate. Together, the contours form a 3-D rendering of the patient’s prostate and nearby organs. But this process, called segmentation, is costly and time-consuming. So Chaney and Pizer worked with Sarang Joshi, now at the University of Utah, to create a method that automatically segments 3-D renderings of anatomical objects from CTs and MRIs. Chaney’s group wrote algorithms to create mathematical representations of organs in the pelvic area. From these representations they can quickly extract 3-D shapes of organs such as the prostate and bladder. It’s more efficient and less expensive, Chaney says.

The renderings also accurately model the spatial relationships among organs, creating a map of the scanned area. “It’s a critical navigational aid that helps physicians keep a radiation beam focused on the tumor while avoiding body parts that could be harmed by radiation,” Chaney says.

Chaney, Pizer, and Joshi started Morphormics, a UNC spin-off, and worked with UNC’s Office of Technology Development to secure several patents. In fall 2008 the National Cancer Institute awarded Morphormics $2 million, which Chaney says is a big step toward getting his technology into hospitals to help patients. The company also partnered with Accuray, a major manufacturer of radiotherapy equipment.

—Mark Derewicz Edward Chaney is a professor of radiation oncology and biomedical engineering in the School of Medicine. Stephen Pizer is Kenan Professor in the departments of computer science and radiation oncology. The Office of Technology Development (OTD) is the only UNC office authorized to execute license agreements with companies. For information on reporting inventions, contact OTD at 919-966-3929.

For more on medical imaging breakthroughs, see our cover story, “Let’s Get Visual,” on page 4. endeavors 3

By Mark Derewicz

What if we could predict how fast and far winds will carry toxic

fumes after a chemical spill? What if we could forecast exactly how high coastal waters will rise during a hurricane? What if we could see how a new drug affects the microscopic movements inside the lungs of a cystic fibrosis patient, repair a torn knee ligament better, or improve cochlear implants for children?

We’d want to know how, and researchers would show us images and models. We might say these are only visuals; where are the data?

And researchers would say, “You’re looking at them.”

4 endeavors

Visualizing scientific findings has been possible for a long time, especially at UNC, where in the 1970s Fred Brooks pioneered digital protein imaging as founder of Carolina’s computer science department. Before this, scientists hung clumsy copper-plated protein models from their ceilings.

Today researchers use visualization techniques for all kinds of things. To a biologist, visualization might mean creating a 3-D image from a fuzzy two-dimensional photo of lung cells. To a geographer, visualization might mean overlaying colorful field measurements onto satellite images. To other scientists, visualizations are simulations of real events and data that give clues about what happens inside the tiniest of molecules or what might happen to the largest of landmasses.

Sometimes, creating a visualization of scientific data is the only way to understand the data. Sometimes, it makes understanding easier. Sometimes, making a visualization is nearly impossible but also the best way to challenge what scientists think they know.

And almost always, making a visualization requires that people from different fields— people who may never have needed to speak to each other—team up to help patients, inspire peers, and answer tough questions.

•

Radiologist John Clarke was studying his brand-new pictures of a patient’s shoulder joint when he saw Alex Creighton, a UNC surgeon, hurrying down the hall. He showed Creighton the images. Surprised, Creighton admitted he might consider different surgical approaches to certain injuries if he had access to Clarke’s kinds of images.

Creighton continued on his way and Clarke went back to his office, even more convinced that he had found a new and better way to diagnose joint injuries.

Years ago, Clarke was checking out his department’s new CT scanner, which allows doctors to create a virtual colonoscopy—a digital rendering of a patient’s colon as if the viewer is flying through a cavern. Clarke, who had been an orthopaedic surgeon, thought that creating 3-D virtual images of patients’ joints ought to be possible. He checked the literature; others had figured that out. But such visualization, called standard volume rendering, didn’t seem much different from arthroscopic surgery—when doctors insert a pencil-thin camera inside a joint and move it between bone, ligaments,

and cartilage to find and repair injuries.

Standard rendering programs use MRIs and CTs to re-create the joint so that a virtual camera can “fly” between bone and cartilage to let the surgeon look up, down, sideways, and even backwards. What doctors see is real in the sense that real data were used to create the visualization, but Clarke says the technique is still limiting because everything is viewed up close and there’s a lot of bone and ligament in the way.

“It’s kind of like putting the palm of your hand to your face,” Clarke says. “You can look wherever you want and you can see things up close. But you can’t back away and take a look at the entire hand.”

Clarke thought it should be pretty simple to write computer code that “cut away” whatever tissue he didn’t want to see so he could view injuries from better angles. In the case of the shoulder, he wanted to see the entire shoulder socket, which means that the ball of the humerus would have to be rendered invisible.

Stephen Aylward, Clarke’s colleague at the time, told Clarke about Russell Taylor, a computer scientist who needed interesting projects for his visualization course. Taylor liked Clarke’s idea and gave the project to three students who wrote a program to read CT data files of past patients. But because of

time constraints, the students couldn’t create the kinds of visualizations Clarke needed.

Then David Borland, one of Taylor’s graduate students, came into the picture. He wrote his dissertation on what’s now known as flexible occlusion rendering. He used CT scans and MRIs to write an algorithm that assigns numerical values to different shoulder parts, such as bone and cartilage. Then he wrote a program to make the numerical values assigned to certain shoulder parts invisible from certain viewpoints. This allowed Clarke to see whatever he wanted from any angle.

“It’s easy to render all bone and cartilage invisible or visible,” Borland says. “The tricky part is when you have multiple objects of the same material occluding each other.”

“The result is we can pull back and look at whatever we want,” Clark says. “I can turn around and look at the ball of the humerus without having the constraint of being so close or being within the joint.”

Clarke, Borland, and Taylor have two patents pending on their technique, which they licensed nonexclusively to Siemens, a global engineering firm. Clarke says that flexible occlusion rendering will allow doctors to make better and faster judgments and give more information to doctors—if they want it.

Flexible Occlusion Rendering Facing page: a virtual cochlea showing green wireframing that computer scientists use to build visualizations. Image by David Borland and Eric Knisley. Left: the shoulder socket as seen up close and in between shoulder parts. This is standard volume rendering, essentially virtual arthroscopy.

Right: the shoulder socket seen from a distance as if the patient’s humerus has been removed.

This is flexible occlusion rendering, a new visualization technique used to view joints and other body parts. Images by David Borland.

endeavors 5

Essential cilia

SORIN MITRAN

Left: a rendering of one the microscopic cilia that help push mucus out of our lungs. Sorin Mitran created simulations and visualizations showing how cilia move in unison because of hydrodynamics. Cilia do not need electrical or chemical signals to keep them in sync, Mitran says. In this image, the different colors show the magnitude of the normal stress that surrounding fluid exerts on a single cilium.

Right: cilia and mucus from a living human lung cell. The image was captured with a confocal laser scanning microscope and standard volume rendering.

Henry Fuchs, a computer scientist who has been exploring visualization methods for three decades, says he’s spoken to doctors who think traditional images are closer to the truth than virtual visualizations. “But that might not be so,” Fuchs says.

Take x-rays, for instance.

“It’s impossible to tease from that x-ray the three-dimensional nature of what’s happening,” Fuchs says. On the other hand, he says, computer scientists shouldn’t say that their visualizations are perfect. A visualization can sometimes lead researchers to be certain about things that should be left to the imagination.

“Where exactly is that boundary between cartilage and bone?” Fuchs says. “In an eighty-six-year-old patient whose bone density is getting lower and lower, what we say is bone in a visualization might not be bone.”

This gray area is one reason why Taylor thinks of computer scientists as toolsmiths who work with scientists to solve problems.

In the case of flexible occlusion rendering, Clarke can compare his new visualizations to the original shoulder images. The new method adds to knowledge; it doesn’t replace knowledge.

Borland’s technique doesn’t tread too far into the unknown; nor is it very complex, its inventors admit. There are far more intricate systems in the body that are more difficult to visualize. The human lung, for instance, is full of mystery. Visualizing its many microscopic movements takes a whole other level of tool-making.

6 endeavors

Simulating cilia When we last wrote about the Virtual Lung project (See Endeavors, Fall 2004, “Branching Out”), Ric Boucher, Greg Forest, and Rich Superfine had just started working together. Boucher, a medical doctor, was able to explain to Forest, a mathematician, and Superfine, a physicist, how a normal lung clears mucus. Boucher knew what each lung component did but not how they worked together. If Forest and Superfine could help figure that out, then Taylor and others could create virtual models of the lung’s entire system.

Several computer programs would be dedicated to each component of the lung, says the computer scientist Taylor, who’s also involved in the project. Researchers could enter information into the programs and run simulations on how, for example, a new asthma drug might work. Then researchers could watch everything unfold in three dimensions on a huge computer screen.

This would inspire new experiments and treatments.

But while the researchers were trying to figure out how the lung’s components speak to each other, they realized that they themselves weren’t speaking the same language.

“During those early meetings,” Forest says, “one of the great words we were using with very different meanings was ‘stress.’

Someone actually had to say, ‘Stress for us actually has physical units that can be measured.’”

Superfine laughs and adds, “Here’s another great word—model. For Greg, a model is a system of equations. For medical scientists, a model is a rat or a mouse.”

MICHAEL CHUA

Forest says, “So you say a word and it triggers understanding, right? But a lot of times we’d talk and talk, and we wouldn’t understand each other.”

But they kept meeting weekly, without grant money. After about a year they all got on the same page. They got grants, attracted people to their cause, and started visualizing various parts of the lung.

Sorin Mitran, an applied mathematician who works with Forest, created a simulation that shows how cilia beat.

Cilia stick out of lung cells and move in coordination to push mucus over a thin layer of water. When the cilia don’t work properly, mucus lingers in the lung and becomes a breeding ground for bacteria and infection.

This is what happens in patients with cystic fibrosis.

Scientists have three theories for why cilia beat in unison to push fluid. Maybe a chemical signal tells them to “beat now.” Maybe cilia are part of some electrical network. Or, the simplest explanation: maybe individual cilia feel which way the fluid is moving, and try to beat with the prevailing flow conditions rather than oppose them. Mitran tested that last one.

“My goal was to build a computational model that captures as much as possible the true physics involved in cilia beating and thereby propelling fluid,” he says.

A single cilium is made up of flexible cables that are linked together by evenmore-flexible springs.

“This is essentially a beam and truss structure,” Mitran says. “We can use specific models of structural mechanics to create a mathematical description of a cilium.”

Mitran wrote his equations, plugged them into three dozen CPUs, and let them evolve.

About a week later, the computers kicked out a boatload of data in the form of numerical simulations. Mitran then used different computer programs to create visualizations so that colleagues could see what his equations revealed about the nature of cilia.

He found that each cilium can beat randomly but can then adjust its beating so that it doesn’t expend too much effort in pushing mucus, and when all cilia behave this way, they coordinate and push mucus more efficiently. The natural interaction between cilia and mucus helps cilia push mucus out of the lung.

Researchers had thought a signal might be responsible for cilia coordination because there was no other explanation. “My work shows that there’s no need for a signal,” Mitran says. “The point here is that, well, no, you don’t really need to think about it that way.”

Biologist Bill Davis, a cystic fibrosis researcher, says that Mitran’s simulations have helped him understand mucus clearance, even though a simulation doesn’t show exactly what happens inside a lung.

“Sorin starts his simulation with thousands of cilia beating randomly,” Davis says, “and then you can see them starting to beat together. It’s amazing to actually see it.”

Taylor says that Mitran’s model will eventually be coupled with others to test therapies, though this is some way off.

The lung is “incredibly complicated,” Davis says. “There are thousands of proteins involved, and how they all work together is a bigger problem than any mind can understand. So ultimately, the hope is that through these models we’ll come to understand the right questions we need to answer so we can write the next iteration of models and progressively get them better and better.

And our understanding of how the whole system works will then be elevated.”

“Right now,” Taylor adds, “we have bits and pieces of the entire system.”

For Mitran, his data sets are more important than the visualizations they help create.

“It’s the physical theory we’re interested in verifying,” he says, “because it’s the theory that provides insight and understanding.

Where visualization is important is in stimulating a researcher’s imagination to build a new theory and also in popularizing results to a wider audience.”

IMAGESURFER, ALAIN BURETTE

The naked neuron Above: Neurobiologist Alain Burette worked with computer scientists to create 3-D images that trimmed away all the parts of the neuron that he didn’t want to see. Below: The images allowed him to pinpoint calcium pumps, which are key components of brain function.

endeavors 7

Also, Davis points out that simulations and models contain what Forest calls sins of approximation—assumptions that researchers have to make when writing code for models because no one really knows the exact physics of cilia and mucus or how thousands of proteins interact.

Biologists, then, typically make a distinction between simulation and visualization.

“To me, visualization is creating an image from something that exists,” Davis says. And for biologists, that’s microscopy.

Davis and many others work with Michael Chua, director of the Michael Hooker Microscopy Facility, to create 3-D images from 2-D confocal microscope scans. The technology works like a digital camera.

The electronic shutter in a microscope’s camera lets in shades of light that are given numerical values. From those numbers a color image is created. Chua extracts those numbers from the camera to make 3-D color visualizations, including images of cilia.

Neurobiologist Alain Burette worked with Chua to create 3-D images of neurons to find out where calcium pumps are positioned on a dendrite—an extension of a nerve cell by which cells communicate. Calcium is a key part of how neurons communicate with each other and how memories are stored.

“It was extremely difficult to get a sense

of where things are in a two-dimensional image,” Burette says. Even in a three-dimensional image, he couldn’t find the pumps.

Chua introduced Burette to Taylor, whose grad student Dennis Jen wrote computer code that, like Clarke and Borland’s program, assigned numerical values to different parts of the neuron. This allowed Burette to remove whatever he didn’t need to see from the 3-D images so he could pinpoint the pumps.

Burette says that molecular biologists now have an extensive list of protein parts. “But now we’re entering something of a new era where we’re asking how things are actually built. It’s like a car; we need the blueprints to understand where everything is and how the parts work together.”

Burette created a website to let scientists download the visualization program ImageSurfer. His team is now upgrading the software package to allow plug-ins. “This would turn our software into a platform so that people could write a little bit of code to solve their own problems and then port their code to our software so everyone could use it.”

Thousands of researchers have downloaded ImageSurfer, and Burette hopes it will one day rival ImageJ, a popular online software package for 2-D image analysis.

STEVE WALSH

Before oil companies were invited to explore Ecuador, few people ventured too far into the Amazon Forest. New roads changed that. They changed the landscape too, as Steve Walsh’s visualization shows.

On the left side of the river, the dark brown represents unsullied forest. On the right, the bright green represents new farms where the forest used to be.

8 endeavors

Davis says, “Alain’s project is one of the best quantitative microscopy projects I’ve ever seen because it was developed to answer actual biology questions.”

Many researchers would like their fields to be as exact as microscopy, but they often have to deal with a lot of unknowns. Taylor and others say visualizations such as Mitran’s models help make sense of those unknowns.

And so do models that use known data to predict how future events will unfold.

Mapping the future Geographer Steve Walsh uses satellite images, aerial photography, and field imagery to show how landscapes have changed and might change in the years to come, even in faraway places we think of as pristine.

In the Galapagos Islands, guava trees are swallowing up native grasslands and endangering endemic flora and fauna. Walsh says that eradication techniques work best when the guava trees are small and not clumped together. So Walsh created maps and models of the islands to show where the guava is and where it might spread. He used a handheld spectral radiometer, a plant canopy analyzer, and GPS technology to measure the amount of energy reflecting off of guava plants of different sizes, shapes, and ages. He also analyzed plant type, condition, and the density of the forest canopy. Then he superimposed this data onto satellite images to show the huge swaths of guava as red splotches on the landscape. Using data from several trips, Walsh’s team created models to show how guava will spread if left alone and how guava will react to specific eradication methods.

And he gave his findings to conservationists on the islands.

Walsh used similar techniques in the Amazon. After oil companies built roads to explore the forest, Ecuadorians used the roads to penetrate the Amazon and start farming. Walsh modeled this evolution; the change from forest to farms and barren fields is stunning.

“There is almost no forest left in this one area,” Walsh says. “And it didn’t really take that long for this to happen.”

Sometimes it takes Walsh’s team weeks or months to make models—not a big concern for geographers. But other researchers don’t have that kind of time.

Marine scientist Rick Luettich has been making models of hurricane storm surges for a decade, and his simulations used to

JASON COPOSKY

Storms and floods Above: Before Hurricane Gustav hit the Gulf Coast last summer, Rich Luettich worked with other marine scientists to accurately predict storm surge levels. On this map of Louisiana, the colors represent the height of storm surge in feet. New Orleans, which was spared the kind of damage it saw during Hurricane Katrina, sits on the gray strip between Lake Pontchartrain and the large yellow mass at the center of the image.

Right: Scientists can now transpose data on top of Google Earth maps. RENCI produced forty-nine weather maps for each hour on December 25 and 26, 2006. The maps include temperature, precipitation, wind direction, and barometric pressure. This kind of visualization will help North Carolina prepare for weather-related disasters.

endeavors 9

Above: an area of downtown Manhattan. The streamlines are colored blue, white, or red depending on the strength of the wind at each point along a given streamline. This visualization shows the complex wind pattern caused by the geometry of the buildings.

Blowing in the wind Wind patterns in cities affect the spread of odors or toxins from accidents or terrorist attacks. Using computer-based models and visuals such as these, Alan Huber can predict the patterns. Imaging by David Borland.

Right: a view down a Manhattan street. The translucent imaginary cylinder that extends down the length of the street uses red and yellow to represent the strength of the wind at each point in the cylinder. The colored streamlines show where pollutants would be carried if released into the wind.

Left: a Manhattan street from ground level.

It shows streamlines at a fixed distance from the viewer. The streamlines—colored blue, white, or red depending on the strength of the wind—give an idea of the wind direction in front of and above the view.

10 endeavors

take two weeks to process because he lacked proper computer power. Now he has it.

In March 2006, UNC finished building the Topsail computing cluster, one of the twenty largest computer clusters in the world, to help people such as Luettich. Last summer his team created accurate models of the storm surges that came with hurricanes Gustav on the Gulf Coast and Hanna in North Carolina, thereby helping state and federal agencies warn people in harm’s way what to expect. A few days after Gustav, the New Orleans Times-Picayune used Luettich’s model results to create a front-page visual that showed readers why the storm surge did not cause too much damage, which is what Luettich forecast.

To make the model, Luettich’s team created a digital grid of many triangles and placed it on a map of the coastline. Within each triangle, computer code adds information such as wind, ocean depth, ocean current, and storm statistics to calculate what a hurricane will do to the water level.

Within each triangle, all the information is the same. So the smaller the triangles, the more accurate the model.

This same sort of technique can be used in other large-scale situations, but modeling some landscapes—such as cities—and predicting something that changes every second—such as wind—can get a little complicated.

The Manhattan project In January 2007 environmental scientist Alan Huber jumped to his feet while watching news reports of a foul stench that Manhattan police and firefighters could not identify. The city shut down its rail line to Hoboken, New Jersey. Police evacuated buildings. New Yorkers immediately assumed terrorism. But Manhattan’s health department, the Coast Guard, and Con Ed Energy determined that the odor was natural gas. And it dissipated later that day.

Had Huber been there, he would’ve offered his services; he had been creating models of what might happen if a toxin were released in Manhattan.

For ten years Huber had been making more and more detailed simulations as a scientist at the Environmental Protection Agency (EPA). But over time his simulations demanded more computing power than the agency could provide. As an adjunct professor at UNC, Huber was able to produce

simulations of wind flow in Manhattan that were impossible to make at the EPA. He now uses more than 256 of Topsail’s 4,016 computer processors, and he’s working with the Renaissance Computing Institute (RENCI) in Chapel Hill to create visualizations.

First, Huber’s team created a digital model of midtown Manhattan’s seven thousand buildings. The team used commercially available geometry that had been created after telecommunications companies took aerial photos of New York to figure out where to put cell phone towers.

Next, Huber applied fluid dynamics numerical methods to the model to solve for the winds, pollutants, and particles that flow through midtown. The entire model is divided into fifty-four million cells; think of a mosquito net tossed over Manhattan.

Dividing the model into geometric cells— as Leuttich did with his triangles—allows Huber to calculate detailed wind flows on city streets and up the sides of buildings.

When Huber adds a change of wind direction into an experiment, he can produce different visualizations of what the city would look like if a pollutant were released and carried by wind.

Without the visualization, Huber says, the most he could do with his data would be to pull out a few numbers and plot them on a graph. Maybe those numbers would say something about the air quality of a few isolated places in Manhattan. His visualization, though, actually presents all of the data at one time.

“There are some people who would say, ‘That’s a picture,’” Huber says. “I have to be careful to assure them that I have the physics set up and without the picture, I’d have nothing. I couldn’t even understand what’s going on without the visualization. The danger, though, is that someone could use inaccurate information to make a visualization that looks realistic.”

Last year Huber started working with David Borland at RENCI to create more detailed visualizations that Huber wants to view in RENCI’s special viewing rooms. Ideally, Huber would start the simulation and then change some of the model parameters so he could interact with his data as the simulation evolves.

“But I haven’t even told the guys at RENCI about this yet,” Huber said.

So I did. Borland told me that Huber’s idea is entirely possible.

Borland has created several visualizations that, if viewed in RENCI’s dome room, make you feel as if you’re standing on Broadway’s yellow line and seeing the wind, symbolized by streamlines of different colors, whirl past you.

“If you’ve spent some time in a city, you know the wind will be in your face and then a half a block down it’ll be at your back due to the influence of buildings,” says Huber.

“We want to create that real experience as much as possible.”

Retuning the ear The dome room is like a small, closeup planetarium. It lets visitors become immersed in whatever’s being displayed.

Researchers like this room because it takes their abstruse data and makes them real. For some, this process inspires more questions and pushes their work forward.

This is what Charles Finley hoped would happen when he began working with RENCI. During a 2008 seminar, Finley used the dome room to present visualizations of cochlear implants—devices that help the deaf to hear. He worked with Borland and Eric Knisley to create several visualizations, including one that shows what it would be like to fly through a cochlea. It’s an incredible teaching tool but not as important to patients as RENCI’s other visualizations, one of which shows how electrical currents communicate sound from the cochlea to the implanted device behind the ear. The way electrical pulses travel along these pathways could affect how much a cochlear implant helps a patient hear.

A cochlear implant works by using electrodes placed deep inside the ear to stimulate nerves inside the cochlea. These electrical signals then flow to another electrode implanted under the scalp behind the external ear and, with help from a speech processor, allow a deaf person to hear.

“For some patients, the implant works really well,” Finley says. “But a lot of patients say they would be able to hear what I’m saying if I could make the noise go away.”

The noise sounds like an echo, or like the patient is standing at the end of a long hallway. Some patients say the noise sounds like a detuned radio.

Finley couldn’t figure out what might be causing the problem until he had graduate student Punita Christopher measure electrical field patterns around patients’ heads. endeavors 11

“Her data were unexpected,” he says.

“When we stimulated a particular part of the cochlea, all the current flowed along the same pathway as it left the inner ear.

We couldn’t tell which electrode inside the cochlea was being stimulated.”

Finley’s hypothesis is that the electrical currents may be stimulating two different areas along a course of nerves, causing interference or noise. He worked with Mark Reed, a research scientist at RENCI, to model a cochlear implant inside a patient.

Then they gave their data to Borland, who created visualizations that show exactly where the currents are flowing.

“Because of these visualizations we’re getting a good appreciation for the actual pathway where the current flows,” Finley says. “We think it flows out through some little channels in the cochlea where the nerves are and it’s forced that way because of the bony structure of the ear.

“We’re now developing new experiments with patients to see if we can manipulate this type of stimulation. And we’ll see if the echoes or noises go away.”

Finley had his eye on RENCI ever since it formed in 2004. RENCI’s first director,

Dan Reed, was still working out of boxes when Finley knocked on his door to talk about collaborating. Reed left RENCI in December of 2007, but interim director Alan Blatecky says visualization is a key tool now more than ever. “You’ve heard the term ‘data tsunami,’ right?” Blatecky says.

“We’re getting this incredible growth of data in science and business. And we need to figure out how to get useful information out of all those data. The only way to do that well is through some sort of visualization.

If you give people a stack of 150 pages of numbers, nothing happens. But if you have a good visualization of those numbers, then people say, ‘Hey, look at this trend,’ or, ‘I hadn’t noticed this,’ or, ‘What if you tweak the data this way?’”

In autumn 2006, RENCI started a fellowship program to attract UNC faculty who were interested in working with its computer scientists on visualization projects. Finley jumped at the chance, won a fellowship along with three others, and started working with Borland, Knisley, and Mark Reed.

Carolina researchers, though, don’t have to win a fellowship to work with RENCI. And they don’t have to be scientists, either.

DAVID BORLAND

This visualization shows the pathways of electrical current from a cochlear implant (red) to another device (blue) implanted just beneath the scalp behind the ear. It shows how many currents find their way around bone and other structures and helps explain why some patients have better success than others with cochlear implants. A likely result: better devices.

12 endeavors

A bigger picture When Julia Cardona Mack in Romance Languages saw Finley’s presentation at RENCI and “flew” through a virtual cochlea, she thought, “Wow, wouldn’t it be great to use this technology to explore a really big space?”

Cardona Mack knew just the right building: the Cathedral of Seville.

“Imagining what this structure looks like is really hard because the naked eye can’t capture all of it,” she says. “It’s dark inside, and it’s just so huge. It takes up a whole city block.”

The cathedral is the largest Gothic cathedral on the planet, a United Nations World Heritage Site, and a classic example of what happens to very old buildings when one culture subsumes another. For three hundred years, the building was a mosque. Then Christians reclaimed Spain, and in 1401 the locals decided to transform the building into a Roman Catholic cathedral, and built on top of the original structure.

Cardona Mack, who has been to the cathedral several times, can point out where the mosque ends and the cathedral begins.

Muslim builders used mostly brick and tile; Christians added marble, gold, and alabaster.

In pictures, Cardona Mack can see some of the many different construction styles used over the course of eight centuries. From the floor of the cathedral, she can see paintings and stained glass windows sixty feet above, but not the wood carvings on their frames.

She can’t see the intricate details on sculptures, paintings, or the dome ceiling; nor can she fully appreciate the gold and ironwork on the choir grill. And some of the decorative structures, such as windows and engravings, are in disrepair. Visualizations could show us what these artful pieces look like now and what they once looked like.

All this, she says, would be especially valuable to students in UNC’s Year in Seville study abroad program. “When students see a building during a study abroad trip, it’s going to be one of ten buildings they see that day,” she says. “If students had already flown through the building, so to speak, then they’d be primed for it when they see it in person. And because this building has seen so much history, it’s a good place to start a discussion about tolerance, coexistence, and the hybrid nature of societies at any point in time.”

RENCI’s Jeff Heard created this visualization to allow UNC pathologist William Kaufmann

to examine his data on how gene ontology terms are assigned to proteins. Kaufmann hypothesized that the ontology was “dirty” and old assumptions and classifications had to be cleaned up to be made useful again. The visualization allows Kaufmann to look at fifty-eight thousand proteins in the human genome at once, based on their similarity and function instead of on their past ontological assignment.

endeavors 13

Paul Jones, director of the internet repository ibiblio, gave RENCI his data on ibiblio’s web traffic and said, “Be creative.” RENCI’s Jeff Heard made this visualization to show search engine indexing hits and where sites hosted by ibiblio connect to each other.

Each circle represents a site that ibiblio hosts. The larger the circle, the more hits the site gets. Inside each circle, colors represent how often four search engines crawled the websites. If a color slice extends beyond the border of the circle, then that site received more indexer crawls than human visits.

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Cardona Mack has been consulting with Knisley about creating a virtual cathedral.

“There are a number of different techniques we could use,” he says, “but it wouldn’t be a trivial task.”

Scanning devices—some that UNC has—can capture raw visual data of the cathedral to make 3-D renderings. Think of a virtual-reality video game. The cathedral is so enormous, though, that Knisley says it would be best to scan one section of the cathedral to see if they can develop a proof of concept.

Cardona Mack has already procured a document that could help Knisley: an atlas that the Spanish National Research Council published in 2007 that contains intricate architectural details and measurements of every square inch of the cathedral.

“There are no pictures or images of what the cathedral looked like when it was a mosque,” Cardona Mack says. “With this material, we could re-create the mosque.

I think that’s fascinating, and I’d think art historians and architects would be really interested in this, too.

“Of course, I also value the sheer joy of the game—traveling up the walls and up the sides of the dome, over the colored paintings, through a window to see the cathedral rooftops and the horizon,” she says. “It’s not an experience any human being is likely to have in real life. Just for that reason I think it’s valuable.”

She also points out that Seville is built on swampy land, a fact that halted construction of skyscrapers as well as a subway in the 1970s. The cathedral’s highest tower is still the tallest building in town. Cardona Mack wonders how long the cathedral will stand.

Right now her vision is only an idea. She has to put together a grant proposal and then find the time to meet with the cathedral’s gatekeepers. She also has to find other faculty who are as interested in this project as she is. Otherwise, she fears she may never get it off the ground.

“Someone once told me that things get done if someone is passionate about it,” she says. “True, but I think more things get done when people work together.” e John Clarke is an associate professor of radiology in the School of Medicine. Russell Taylor is a research professor of computer science, physics and astronomy, and applied sciences and engineering in the College of Arts and Sciences. David Borland and Eric Knisley are senior visualiza-

JULIA CARDONA MACK

Julia Cardona Mack wants to “fly” up the choir grill in Spain’s Cathedral of Seville and see up close architecture and art from several centuries and two distinct cultures.

tion researchers at RENCI. Clarke, Taylor, and Borland worked with the Office of Technology Development to patent and license flexible occlusion rendering. Henry Fuchs is the Federico Gil Professor of Computer Science. Greg Forest is the Grant Dahlstrom Distinguished Professor of Mathematics, and Sorin Mitran is an associate professor of mathematics in the College of Arts and Sciences. Rich Superfine is a professor of physics in the College of Arts and Sciences. Bill Davis is a research professor, Alain Burette is a research associate professor, and Michael Chua is an assistant professor, all in the department of cell and molecular physiology in the School of Medicine. Steve Walsh is a professor of geography in the College of Arts and Sciences, a research fellow at the Carolina Population Center, and

director of UNC’s new Center for Galapagos Studies. Rick Luettich is a professor of marine sciences and director of the Institute of Marine Sciences. Alan Huber is an adjunct assistant professor with the Institute for the Environment.

Charles Finley is a research associate professor of otolaryngology and biomedical engineering in the School of Medicine; he advised Punita Christopher, who received her doctorate in December 2007. Julia Cardona Mack is a senior lecturer in the Romance languages department in the College of Arts and Sciences.

The Office of Technology Development (OTD) is the only UNC office authorized to execute license agreements with companies. For information on reporting inventions, contact OTD at (919) 966-3929. endeavors 15

16 endeavors

COKE WHITWORTH

How do you get to Carnegie Hall?

COKE WHITWORTH

Determination. Sacrifice.

A lot of love for what you do.

And a lot of practice.

by Meagen Voss

W

hen Mayron Tsong was a little girl, her home was filled with pianos. In her father’s workshop there were as many as forty-five at any one time. Everyone in her family played, even the cats.

“The cats really liked to play along with us,” laughs Tsong, who recalls how they would jump on the keys during her practice sessions. All that practice paid off. This year Tsong released her first solo album and played at Carnegie Hall in New York City.

Her album features the works of Russian composers Rachmaninoff, Prokofiev, and Scriabin. “The harmonies are just to die for!” Tsong says. The intricate textures of Russian music make it difficult to play, and Tsong enjoyed the challenge. Russian music has also been a lasting source of inspiration for her. Though she didn’t decide to pursue music as a career until she was nineteen, she realized when she was only twelve that she had a true passion for the piano. Tsong recalls that she was playing a concerto by Rachmaninoff when it suddenly hit her that playing the piano made her truly happy.

Her selections for the album included Russian pieces she knew inside and out, but the recording process was more complicated than Tsong had anticipated. First she had to choose the right recording hall, then the perfect piano, and a capable piano technician. Fortunately, the Academy of Arts and Letters in New York had wonderful acoustics and an ideal location—right next to a cemetery. But even with quiet neighbors, it was still a challenge to arrange microphones in the hall for a good recording. She also had to contend with the climate affecting her sound—the hall had no air conditioning or heat.

After finishing her album, Tsong was invited to play a recital at Carnegie Hall, where artists such as Camille Saint-Saens, George Gershwin, and even the Beatles have performed. She was very excited and very nervous.

“When you think about it it’s almost like imagining, as a little girl, your perfect wedding,” Tsong says. She was surrounded by friends, students, and family. They traveled from all over the world; her parents even flew in from Taiwan. Before the concert, when she went through her routine of tweaking the sound and making sure her music was in order, she felt like she was preparing to play any old concert. But when she got up on stage she found that playing at Carnegie was magical. “It’s like a secret kingdom you have just been given access to,” she says.

Tsong isn’t slowing down. She’s planning a second album in which she will focus on Austrian composer Joseph Haydn. There are many sonatas attributed to Haydn, but the authorship of some of the works is contested. Scholars suspect that the real composers used Haydn’s name to get their pieces published. Tsong plans to include many of the contested sonatas on her album, and will write about the history behind these pieces in the album booklet. She also hopes to perform in London at the famous Wigmore Hall. Since London was one of Haydn’s favorite retreats, she says it would be the best location to launch her new album.

But all of that is far in the future. In the meantime, Tsong will continue teaching, and she’ll perform every chance she gets.

She says she can’t imagine a life without piano music. “I just really love to play.” e Meagen Voss is a doctoral student in neuroscience in the School of Medicine.

Mayron Tsong is a Steinway Artist and an assistant professor of piano in the Department of Music. Her self-titled solo album was produced by Centaur Records. endeavors 17

I

the symbols on the stone A new slant on the Western world’s oldest piece of writing.

by Margarite Nathe

David Mora-Marin was too excited to sleep.

It was late, and he was still in his office exchanging frenzied emails with other linguistic anthropologists. In front of him were a dozen sheets of paper, each covered with strange symbols and his own neon highlighter marks. For days, he’d been tracing out sequences, recurring symbols, and odd patterns. Ever since the latest issue of Science had hit newsstands, he could think of little else but the article—“A block with a hitherto unknown system of writing has been found in the Olmec heartland of Veracruz, Mexico…”

18 endeavors

t was a huge archaeological breakthrough, the first of its kind. “I could barely sleep for ten days and ten nights,” Mora-Marin says. “From the moment it was published, I became practically obsessed with figuring out how the text was read.”

In 1999 road builders unearthed the tablet along with some other artifacts as they were digging fill from an ancient mound in Cascajal. (For years the workers had used the site as a gravel quarry, mining building materials from it for roads in Veracruz.) They piled the artifacts off to the side and left them there. The block stayed in the house of the land’s owner for years before archaeologists realized what it was: the oldest known piece of writing in the Western Hemisphere, and the only existing sample of the mysterious script of the Olmec people.

The Olmecs were the first civilization in Mesoamerica, the region of Central America where pre-Columbian civilizations flourished. “They were the Greeks of the Mesoamerican world,” Mora-Marin says; they formed the template of political and cultural ideas that the Maya would later adopt. Olmec civilization was thriving in 900 BC, around the time the tablet was carved.

For decades, archaeologists suspected the Olmecs had a writing system and that they had, in fact, invented writing in Mesoamerica. But until the block was discovered, archaeologists had no solid proof.

The Science article had included photos of the tablet, which is about the size of a stack of legal pads, standing up on its short edge.

The magazine also printed a breakdown of the sixty-two symbols—some shaped like vegetables and insects—that were carved into it. The authors claimed that the text orientation was clear: because the symbols were elongated, and because plant-like glyphs in Olmec imagery are generally shown sprouting from the top, they hypothesized that the tablet should be held upright and the symbols read left to right.

Mora-Marin wasn’t so sure.

These types of rules don’t always apply in Mesoamerican writing, he says. For example, the Epi-Olmec and Teotihuacan writing

systems have signs that are oriented on their side rather than standing up, and many elongated symbols in ancient Mayan writing can be rotated to either position in some cases.

He suspected there was more to the reading order than anyone knew.

Mora-Marin had spent over a decade studying texts, epigraphy, and pieces of ancient Mesoamerican jade before becoming one of the few specialists in his field: ancient Mayan languages from around 400 BC to 200 AD, a time from which relatively few text samples exist. “But it was all just fate, essentially,” he says. “I didn’t set out to do that.”

Throughout much of his childhood in Costa Rica, Mora-Marin sat hunched over school books and encyclopedias, soaking up all he could about science and ancient history. He still remembers reading about the ancient Maya and the hieroglyphic writing system they developed long before the Spanish arrived; the writings were a mystery, his books said, because no one could translate them.

It wasn’t until he’d left Costa Rica and had taken his first anthropology course in the United States that he found out how outof-date his textbooks had been. The Mayan glyphs had long since been translated, he learned, and scholars were still studying them intensely.

Until then, Mora-Marin had planned to study planetary geology. “But when I first learned that that language had been deciphered and that you could in fact read what they said and reconstruct the history of the area, I was completely hooked,” he says.

“That’s when I switched majors.” When the semester was over, he got to work. “I went to the library and checked out as many books as I could and spent the entire winter break memorizing all the glyphs,” he says.

“I sat down and drew them over and over and over again until I memorized all the phonetic signs—the syllabograms, as they’re called. The logograms, or entire words, take longer to memorize.” After he’d memorized the symbols (and eventually entire texts), he moved on to grammar and structure.

David Mora-Marin became obsessed with the symbols on the stone tablet found by road workers in Cascajal, Veracruz, Mexico. Photo and map by Jason Smith

endeavors 19

MICHAEL COE

O

ut of the thirty Mayan languages still spoken today, we have evidence of the ancestors of eight. By the time the Spanish arrived in the fifteenth century, the Maya had dozens of regional languages, and most had writing systems. We wouldn’t know even this much if the Spanish hadn’t so carefully chronicled their efforts to stamp out indigenous religions. To do this, they had to replace the indigenous writing systems with their own Spanish alphabet. Since Mayan priests were the most reliably literate members of the communities, the Spanish targeted them and destroyed every piece of writing they could find. Some Mayan priests, though, hid their texts and secretly practiced their rituals, Mora-Marin says.

Scientists have long thought that ancient Mayan languages may have been influenced by and have significant similarities to MixeZoquean, the Olmec language. So when the article in Science came out, Mora-Marin began asking questions. Ancient Mayan writing is generally constructed in columns, he says, and some of it uses a complicated zigzag reading pattern. Was Mixe-Zoquean meant to be read from top to bottom or bottom to top? Left to right or right to left? Was it in rows or columns?

“Basically, the way you know how people write is by looking at the margins,” he says.

“In Arabic, for example, it’s the right margin that’s vertically aligned, perfectly. The left margin is not, and so you get all these gaps on the left side that tells you they are writing from right to left. In Japanese, you have the opposite orientation.” He looked for these kinds of clues on the Olmec text. But reading a stone tablet isn’t easy. The glyphs themselves were scratched out in sloping, wandering lines, which made it difficult to make sense of the margins. Seemingly random gaps separate some of the symbols, probably where the carver had to work around weak or crumbly spots in the stone.

Left: Scientists can tell that the person who carved the Cascajal block used two blades: a blunt edge to outline the symbols, and a sharper one to fill in the details. Right: Mora-Marin spent years studying ancient Mayan jade ornaments. But the Olmec block, he says, “is exactly the kind of discovery that people in my field dream of.”

20 endeavors

The block itself is important, Mora-Marin says, because it’s made of a pale-green stone called serpentinite. “Green stones— especially jade or jadeite—were the most sacred and valuable materials in all of ancient Mesoamerica,” he says. That, combined with the fact that some of the glyphs on the tablet are the same as those that represent political titles in Olmec art, gives Mora-Marin some theories about what the writing on the Olmec tablet is about.

“Some people would argue that in the very beginning of writing, the writers didn’t know what the difference was between art and script,” he says. Artists painted or carved scenes and portraits that incorporated certain symbols, and the symbols eventually took on meanings of their own. “So just like when you graduate and you go to the big ceremony with your gown and your hat, if you drew somebody on the wall who was wearing that hat, you would know that it was some sort of graduation ceremony,” he says.

For example, one symbol that appears on the Olmec tablet is one that a real-life Olmec ruler wore as an insignia to show his or her office; archaeologists have seen it before JASON SMITH

in Olmec art. Over time, the symbol was isolated and became a Mixe-Zoquean word.

Its presence on the block from Cascajal suggests the writing has to do with some piece of political history, possibly the details of a new ruler coming to power.

“One of the interesting things about the Olmecs is this—” Mora-Marin pulls his office door closed to show a poster on the back, an imposing line-up of gigantic stone heads. The Olmecs are famous for the colossal sculptures, and some archaeologists have proposed they may actually be portraits of Olmec rulers. “It could be about one of these people!” he says.

I

t took some long hours and close scrutiny, but Mora-Marin finally made sense of the gaps in the Olmec tablet. But even when he was confident he’d found the margins, he was still left with the question of whether to read from the tops or bottoms of the columns. It took several more sleep-deprived days for him to figure it out, he says, but the key lay in the sequences.

Sequence is the term Mora-Marin uses for a combination of glyphs that occurs more than once on the Olmec tablet. He points to his computer screen, where this sentence appears: William Shakespeare was the son of John Shakespeare, a successful glover and alderman originally from Snitterfield.

“The important thing here is that the first time it appears, ‘Shakespeare’ is all contained within one line,” he says. “But the second time it appears, it’s broken up in two.” A reader doesn’t have to know English to see that the letters that make up the first ‘Shakespeare’ appear together, and that the same combination of symbols appears again, only separated onto different lines. “You can tell the direction of reading and writing from how it’s broken up,” Mora-Marin says. And it’s the same with the Olmec glyphs.

So the authors of the Science article may be wrong about the orientation of the

Olmec block, he says.

“It seems to be written just like other Mesoamerican writing system, in columns—you just have to orient it ninety degrees to the right.”

The Olmecs glyphs are actually meant to lie on their side. Then, beginning with the ant-shaped glyph in the top left corner, you would read down the column, then start the next column at the top, and so on.

Of course, reading order is just the first step in decoding any script. Right now there is no way to translate the symbols on the tablet, Mora-Marin says. Linguists will need more than just sixty-two glyphs—which is how many are carved into the Cascajal block—to begin piecing together grammatical structures and, eventually, to make a translation. But it would only take a couple more blocks of similar size and length to know more.

The second step is to establish patterns of sign relationships. “Which signs are found with what other signs, how often, in what patterns of variation?” Mora-Marin says.

An evolved form of Mixe-Zoquean is still spoken today, and linguists will use it as a starting point.

A paper about his reading-order theory will be published later this year. Meanwhile, he’ll continue to study the tablet until another one is discovered. Archaeologists are now doing reconnaissance and excavation at Cascajal, but discoveries like the one made in 1999 are rare. “It could happen tomorrow, or it could happen fifty years from now,” Mora-Marin says. “But at least now it is possible to imagine that one day we’ll know what the ancient Olmecs had to say about themselves.” e David Mora-Marin is an assistant professor of linguistics in the College of Arts and Sciences.

His paper on the Olmec tablet will appear in the journal Latin American Antiquity in 2009.

endeavors 21

COURTESY BRIAN BILLMAN

On a typical day, students and sixty to seventy villagers were out digging trenches and installing the water pipe.

Let the Water Flow Near his research site in Peru, Brian Billman and his students pitched in for a mountain village.

By Susan Hardy 22 endeavors

In June 2008 archaeologist Brian Bill-

man led about two dozen UNC and Duke students to a small village in the Moche Valley of northern Peru. Their goal: to build a new water system for the community by the end of the summer.

It wasn’t the first tough job Billman had taken on in Ciudad de Dios. His relationship with the village extends back to 1998, when he had just started a dig at a site nearby. A series of narrow desert ridges above the village hold the remains of a complex once occupied by the pre-Incan Moche people.

On that first trip, Billman’s team uncovered common as well as elite dwellings, and— unexpectedly—a few pieces of gold.

“As we were wrapping up for the summer, we realized the site would be unprotected until we came back,” Billman says. “What most projects will do is hire a guard, but that doesn’t always work very well.”

So he and Peruvian collaborator Jesus Briceño came up with an unusual idea: they’d hire not just one guard, but the whole village of Ciudad de Dios. The villagers would prevent anyone from looting the site or building on top of the ruins, and in exchange, Billman’s team would contribute twelve hundred dollars each year toward amenities for the community. The arrangement worked well, and over the past decade the stipend has paid for a schoolhouse, a road leading into the village, and other projects.

villagers to dig more trenches and lay two miles of pipe.

Alyson Zandt and other Nourish students blogged about their work as it progressed.

“The original plan was to dig a trench through the loose soil of the farmland in the valley, and reimburse the farmers whose land we disrupted,” Zandt writes. “Unfortunately, most of the farmers objected to our digging through their land.” Instead, the team and the villagers had to run the pipe along the side of a mountain, cutting trenches twenty inches deep into the rocky ground using only pickaxes and shovels.

The project also turned out to be more expensive than expected. In the final weeks of the summer, the team ran out of money for PVC pipe to finish the line, and students came to the rescue by raising five thousand dollars mostly from family and friends in the States.

Despite the last-minute snags, at the end of eleven weeks the team had laid the final pipes and water began to flow through the system. By September the pipeline was bringing more than enough water to meet the needs of the village’s three hundred residents.

The relationship between Billman’s

team and Ciudad de Dios will continue, and Billman hopes to foster similar partnerships between archaeological teams and villages at other sites throughout the valley. This is one of the goals of MOCHE, a nonprofit organization he cofounded with students and alums of his archaeological field school and that raised the money for the water system.

Esther Namkoong, a junior who plans to work in global health and environmental science, saw the project as a taste of what she might do after graduation. “You might think that after such a challenging project as this one, you would want to start running in the direction of some high-end job that earns a six-figure salary,” Namkoong writes. “But I feel quite the opposite—I’m excited and ready to work with more projects like this.

There’s something new to prepare for every day, and the people you meet and experiences you have are unforgettable.” e Brian Billman is an associate professor of anthropology in the College of Arts and Sciences.

Julie Tajuba is a master’s student in environmental engineering in the School of Public Health.

Alyson Zandt and Esther Namkoong are a senior and junior majoring in international studies.

COURTESY BRIAN BILLMAN

When the villagers decided

they wanted a better water system than the unreliable government-run pipeline, the UNC and Duke chapters of Engineers Without Borders came up with a blueprint.

“It’s basically a big concrete box that taps water from a spring in the desert above the village,” says Julie Tajuba, a UNC environmental engineering student. “We made sure to pick a source at the highest elevation, so the system could be all gravity-fed.”

Tajuba and other Engineers Without Borders students came to Ciudad de Dios at the beginning of the summer to complete the system design, help build the spring box, and dig trenches throughout the village.

Then students from the UNC antipoverty group Nourish International and a Duke service-learning program worked alongside

Almost everyone in Ciudad de Dios participated in some part of the construction. One of the biggest challenges, Billman says, will be helping the community-elected water committee learn to maintain the system and manage the fees collected from each household.

endeavors 23

diggingforrelief

by Meagen Voss

Like a prospector staking a claim in an abandoned mine, neuroscientist Mark Zylka set out to study a protein that had already been researched for fifty years. His gamble was based on sound scientific instinct and experience, but even he was surprised that he struck gold—the protein relieved pain.

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These Dorsal root ganglia are neurons found in the spinal column. The red cells and yellow cells contain prostatic acid phosphatase. The blue cells and green cells contain other molecules related to pain sensing. Confocal microscopy image by Bonnie Taylor-Blake

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nflammatory pain is relatively common and can usually be controlled with anti-inflammatory medications such as ibuprofen. But prolonged use of these drugs can lead to ulcers and intestinal bleeding. Fewer treatments exist for neuropathic pain, a type of pain that results from nerve damage. Even the most sophisticated treatments for neuropathic pain provide only temporary relief and have dangerous side effects.

When he chose to work on the protein fluoride-resistant acid phosphatase (FRAP), Zylka hoped to find more targets for pain treatment. He was interested in the fact that the protein was found in nociceptors, a type of neuron that senses pain.

A long line of investigators before Zylka had studied FRAP. Several attempted to isolate the protein so that they could determine its function. But they made little progress and the gene for FRAP remained unknown.

“The mystery has persisted for decades,” Zylka says. “Basically people dropped it because other pain-sensing neuron markers came along that were easier to use.”

When Zylka came to UNC in 2006 he directed his lab toward identifying the FRAP gene. He knew that FRAP was an acid phosphatase and that it could be found in pain-sensing neurons. So his lab looked for acid phosphatase genes in these neurons. Their search turned up an enzyme called prostatic acid phosphatase (PAP). Typically found in the prostate, the PAP enzyme is used as a diagnostic marker for prostate cancer.

Wondering why a prostate protein was found in neurons, Zylka’s lab conducted new experiments with PAP. Their results revealed that FRAP and PAP were the same protein.

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ince PAP is commonly used in tests for prostate cancer, purified PAP was readily available. This allowed Meg Twomey, a technician in Zylka’s lab, to test the protein in mice relatively quickly. In her first experiment, Twomey injected mice with PAP. A day later, she applied heat or pressure to each mouse’s paw and measured the time it took for the animal to

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Prostatic acid phosphatase —an enzyme produced by the prostate—may become a standard treatment for pain. withdraw its paw. Mice that were not injected with PAP had short reaction times, indicating a normal pain response. The injected mice, on the other hand, tolerated the pain stimulus much longer. And the effect lasted for several days.

“We were blown away,” Zylka says, “but we were also incredibly skeptical.” He thought that maybe the effect was an anomaly. But Twomey repeated the experiments and confirmed that the effect of PAP was real. “This was the eureka moment,” Zylka says.

Further testing revealed that PAP could relieve different types of pain, including heat-induced pain, inflammatory pain, and neuropathic pain. One dose of PAP relieved pain for days.

Morphine, one of the most powerful pain-relieving drugs on the market, lasts for only a few hours. And since PAP is an enzyme naturally found in the body, the mice experienced no side effects even when receiving the highest doses. Equivalent doses of morphine caused paralysis.

While the thought of developing PAP into a pain treatment was exciting, Zylka says, a key piece of information was missing. “No one actually knew what it was doing physiologically,” he says. In order for PAP to be used in pain treatment, Zylka’s group would have to figure out exactly how the protein was relieving pain.

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raduate student Nate Sowa helped uncover PAP’s painrelieving secret. Enzymes, Sowa says, are like the body’s recycling centers. They have the ability to break apart, or degrade, molecules into their basic components so that they can be reused. Some enzymes can degrade more than one molecule, but often there is one molecule the enzyme prefers.

Early on, Sowa suspected that adenosine monophosphate (AMP) was PAP’s favored target. Adenosine, a molecule known to suppress pain, is the main component of AMP. If PAP was degrading AMP, then the extra adenosine from the reaction could be responsible for the pain relief. Sowa tested PAP activity with many different molecules, including other adenosinecontaining molecules such as adenosine triphosphate. He found that PAP favored AMP over other molecules.

Sowa and Zylka suspected PAP was transforming AMP into adenosine, which activates adenosine receptors found at the surface of cells. To confirm their hypothesis, they would

These mouse neurons show PAP protein (in red). Several other proteins related to pain (shown in green) can be found alongside PAP protein, often in the same neuron. Confocal microscopy images by Bonnie Taylor-Blake

have to demonstrate that the pain-relieving effect was lost in mice that lacked adenosine receptors.

At this point, Sowa says, they were faced with putting the brakes on a fast-moving project. Due to strict quarantine regulations, it can take several months, or even years, to acquire transgenic mice. But Stephen Tilley, a professor in the School of Medicine’s pulmonary medicine department, helped them keep up the breakneck pace.

“Steve Tilley was the only person in the world who had the mice that we needed and his lab was at UNC,” Zylka says.

Within a matter of days, Sowa was able to test PAP on mice that lacked adenosine A1 receptors. The pain-relieving effect disappeared, demonstrating that the A1 receptors were required for PAP to relieve pain. “We got the results right before I left for Christmas break,” Sowa says. “It was a great Christmas gift.”

Zylka now has a direction for developing PAP as a medical treatment. It will be several years before PAP is available to patients, but Zylka envisions it will become a standard treatment for pain. Many patients suffering from intractable pain receive spinal cord injections through an automatic pump filled with morphine. One day, Zylka says, the pumps could be filled with PAP instead. But the majority of chronic-pain sufferers do not require treatment as drastic as a morphine pump. Zylka hopes his work will lead to a less invasive treatment, such as a

pill, that will boost PAP’s pain-relieving activity.

Zylka has a provisional patent for PAP and his lab is working to find molecules that interact with the enzyme. There’s still a lot of work to be done before PAP can be developed commercially, but according to Scott Forrest at the Office of Technology Development at UNC, PAP has great potential.

“PAP is a new tool for discovering traditional oral drugs for pain treatment,” Forrest says.

Zylka, who is still a relatively young investigator, never expected to dig up the mother lode with an abandoned protein.

But, he says, “it’s nice to start with a bang.” e Meagen Voss is a doctoral student in neuroscience and a member of Mark Zylka’s lab.

Mark Zylka is an assistant professor in the UNC Neuroscience Center and the department of cell and molecular physiology in the School of Medicine. Nate Sowa, one of the primary authors of the research, is a doctoral student in neuroscience in the School of Medicine. Lab technician Meg Twomey and research analyst Bonnie Taylor-Blake were coauthors of the study. This work was the cover story for the October 9, 2008, issue of Neuron. Funding came from the National Institutes of Health. The Office of Technology Development (OTD) is the only UNC office authorized to execute license agreements with companies. For information on reporting inventions, contact OTD at (919) 966-3929.

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JASON SMITH

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taking DNA to court James Evans uses hands-on genetics lessons to help our nation’s judges weigh DNA evidence.

by Prashant Nair July 2001. In a tense courtroom in Utah, a plaintiff’s attorney is presenting evidence that could seal the case against the defendant, who is charged with child rape. A spot of blood from the defendant’s undershirt yielded DNA that appears to match the victim’s. But the defendant’s attorney argues that the evidence violates the court’s standard for admission of scientific evidence. The method used to analyze the DNA, PCR-STR-DNA testing, works by identifying unique tidbits of DNA that are like fingerprints of a person’s genetic code. The defense claims that the method is new and therefore unreliable. But a geneticist from the University of Utah School of Medicine testifies that the probability that the DNA belongs to someone other than the victim is 1 in 215 billion.

he prosecution presented voluminous literature and expert testimony to steamroller the defense’s claim that the result was unreliable. An uninformed judge might have been overwhelmed by the subject matter, but judge Sheila McCleve had done her homework. She had attended a series of seminars in genetics to understand how DNA analysis works. McCleve ruled that the court had not abused its discretion by allowing the result of the DNA analysis to be presented. McCleve later told the geneticist who conducted the seminars that what she’d learned there had helped her grasp the scientific complexities of the 2001 case. Her opinion was upheld by the Utah Supreme Court and has become the legal precedent for the use of PCR-STR-DNA testing in the state.

The seminars the judge attended are part of a congressionally mandated program to help judges evaluate scientific expert testimony and interpret scientific evidence presented during trials. In 1993 Maryland lawyer Franklin Zweig recruited scientists to teach science to high court judges through his nonprofit organization, the Einstein Institute for Science, Health and the Courts (EINSHAC), which soon grew into a national endeavor funded by the U.S. government.

UNC geneticist James Evans is an instructor in the program, which includes five to seven scientists nationwide. Evans, a fortynine-year-old professor of clinical genetics, sports a tie with a DNA double helix snaking through its length; he has an air of animated enthusiasm while discussing genetics. When the North Carolina Supreme Court sought the help of EINSHAC to teach science to judges in the Southeast, Zweig approached the dean of the medical school at UNC. The dean’s choice for the program was Evans.

Evans, who had always been drawn to nontraditional applications of genetics, accepted the responsibility. His eyes sparkle as he talks about his motivation for joining the program. “I’ve always been interested in the law,” Evans says. “I like teaching, and I love genetics. So it seemed like an interesting proposition.”

Soon he realized he had made a wise decision. “It was absolutely fascinating for several reasons. The judges were a great audience to teach because they’re very intelligent, very motivated, and yet they don’t know a lot about the subject,” he says. endeavors 29

Medical students often come to his classes having already heard inaccurate or confusing presentations about genetics. “That’s why it’s exciting as a teacher to get at a group of people who are very smart but untainted by prior instruction.”

Lynn Jorde, the University of Utah geneticist who testified in the child rape case, has worked with Evans for more than a decade. “When Jim gives a talk before the judges, it’s very clear that he really cares about the subject and that he cares about introducing judges to it and about helping them understand it,” she says. “He’s a marvelous teacher.”

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n the last decade, Evans has taught more than five hundred judges in the United States and abroad, including trial court judges, state supreme court judges, federal district court judges, and appellate court judges. In Denmark, Norway, Canada, Australia, Israel, Chile and the Philippines, Evans and his team have taught supreme court judges. The classes, which take place at universities or conference centers, include interactive lectures and adjudication clinics where judges work in small groups on hypothetical cases to arrive at rulings based on scientific evaluation of facts.

The judges also get practical experience in genetics; they isolate their own DNA from cheek swabs or mouth rinses, amplify the DNA using a polymerase chain reaction, separate the DNA fragments by gel electrophoresis, and analyze their results with the scientists. “These are judges who have been hearing about DNA in the courtroom, but they have never seen it,” Evans says. “It has

a mystical connotation to them. For them to be able to hold their own DNA and see it is a visceral experience. That demystification is the single most valuable aspect of what we do.”

Many of the judges who participate in Evans’ lectures apply their knowledge in courtrooms. During one of the laboratory sessions when the judges isolated DNA, a judge walked up to Evans.

“How much DNA is here in nanograms?” the judge asked Evans, holding up a tube. Evans eyeballed the quantity and replied, “Probably about ten thousand nanograms.”

A look of relief lit up the judge’s face.

“Oh, good,” he said, and started telling Evans about a case he had ruled on. The prosecution had found some DNA that belonged to a victim, but the defense claimed the amount of DNA was so small it could easily have been contaminated. “I eventually bought the defense’s argument, but I was very unsure, and I’ve lost sleep over that,” the judge said.

The amount of DNA from the victim had been about a nanogram, and the judge had correctly thought that it was too little to be substantial evidence.

When prosecutors and defense attorneys use expert witnesses to give scientific testimony, judges have to know how to evaluate what the scientists say. “Most people agree that there’s real potential for mischief when you’ve got a system like ours where you have hired guns from each side,” Evans says. “If a judge doesn’t have some grasp of the science, you have a potential for problems.”

He’s quick to add that the goal of the program is not to make geneticists out of

“Many of the judges say that they fear their lack of scientific knowledge could cause them to make mistakes...they are afraid of being snookered by expert witnesses.”

—James Evans in the New York Times, July 1, 2008

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judges, but to give judges a solid foundation in genetics. That foundation helps them decide when to permit scientific testimony in a trial and teaches them to recognize evidence that smacks of pseudoscience. The imprimatur of science is not a guarantee of legitimacy, Evans says.

Evans spends a substantial portion of his lectures teaching judges about the science of behavior. Genetic perspectives on behavior allow judges to see the notion of culpability in a whole new light. While the use of behavioral genetics in courts may unleash an array of thorny legal and ethical conundrums, judges are grappling more and more often with the genetic underpinnings of unlawful behavior. Evans also says it may not be long before science makes it possible to use functional MRI scans and PET scans as sophisticated truth potions and lie detectors in courtrooms. “If one can get a neuroimaging profile for when somebody is lying and when somebody is telling the truth, that sort of evidence could bring up scary questions in a court of law,” he says.

Courts sometimes mandate the use of psychotropic drugs to treat patients suffering from mental illnesses. When judges understand the genetic proclivities for violent behavior, Evans suggests, similar treatments might also apply to those accused of violent crimes. “I am not advocating genetic determinism. We are far more than our genes. But they matter in our behavior, and it will be important to see how these issues play out in courts,” he says.

Marvin Garbis, senior district judge for the Maryland district, who has known Evans for nearly a decade, says, “Jim is a particularly talented speaker and teacher. He has a great way of teaching that enables intelligent people lacking a science background to understand the basics of genetics.”

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cientific knowledge helps judges do more than evaluate criminal evidence. Evans cites the case of Kitzmiller v. Dover Area School District. A district court judge ruled in 2005 that a Pennsylvania school board had violated the First Amendment by including intelligent design in the school district’s biology curriculum. “The judge wrote a

“These are judges who have been hearing about DNA in the courtroom, but they have never seen it. It has a mystical connotation to them. For them to be able to hold their own DNA and see it is a visceral experience. That demystification is the single most valuable aspect of what we do.”

stunningly insightful opinion when he said, ‘No, this isn’t science,’” Evans says. “He understood what science was, and that turns out to be an important thing for judges.”

John Jones, who wrote the opinion for the court, has attended Evans’ lectures and has been the keynote speaker at a few sessions in which he deconstructed his decision.

Besides the classic example of DNA fingerprinting in forensic cases, Garbis says, genetics enters the courtroom in cases of privacy, access to genetic information, paternity, medical malpractice, genetically modified foods, and the right to engineer genes to produce designer babies. “Legislatures don’t decide on these difficult questions,” he says.

“They simply leave it to the courts. And the courts do their best, but they need to have enough scientific understanding to be able to comprehend what the experts say.”

Evans observes that a challenge in teaching genetics to judges lies in adopting an approach that doesn’t overrely on mathematics. Judges, like most nonscientists, are intimidated by math. “You’re dead if you go too far down the road of statistics while teaching judges genetics,” Evans says. But geneticists routinely deploy mathematical skills in the course of their experiments, even more so than biochemists and molecular biologists. So, Evans says, he tries to teach

judges the concepts of genetics without delving into its mathematical aspects.

Garbis says another problem facing judges trying to understand science is the ephemeral nature of scientific fact. Judges, he explains, are loath to arrive at rulings based on facts that might well turn out to be misconceptions in the future. Science deals in probabilities, forcing judges to rely on their best guesses when deciding cases that hinge on scientific fact. “Sometimes judges have to make a decision at a time in history when the scientific answer isn’t known,” Garbis says. “At the same time, since the ultimate decision will be based on a combination of scientific understanding and balancing of societal interests, we don’t want to delegate that to the scientists.”

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udges now come to Evans’ lectures in droves. “I’ve been stunned by the enthusiasm they show,” Evans says. “We have always ended up turning judges away from these venues.” Though popular, scientific education for judges is not required. Evans hopes the program will train enough thoughtleaders among judges to spread the word about science education for the judiciary.

Evans proposes a system in which courts could tap into a certified pool of judges who have been trained in science and whom

courts would compensate for serving in trials. But administrative hurdles, the difficulty of finding unbiased instructors, and cash-strapped courts make this unlikely to happen, he says.

Garbis suggests that such a program would fail if it were mandatory, mainly because of funding issues and a lack of motivation among some judges to learn science. But a voluntary certification program, he agrees, would serve the judiciary well. Garbis notes that finding scientists of Evans’ caliber to teach judges basic science is no easy feat. “We’ve discovered over the years that the better scientists are better able to teach at a basic level because they don’t have to hide their insecurities in scientific jargon,” he says.

Evans adds that his own gratification comes not only from transmitting information to the judges, but also from giving them some of his enthusiasm for genetics. “It’s one of the true highlights of my career because they’re an endlessly fascinating bunch,” he says. “It’s enriching to get to hang around people who’re doing something completely different and very important.” e Prashant Nair is a master’s student in medical journalism at Carolina.

James Evans is a clinical professor of genetics in the School of Medicine.

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Thick and Thin Darrel Stafford discovers how to predict a safe dose of blood thinner, patient by patient.

MARK DEREWICZ

By Mark Derewicz

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y father-in-law woke up one morning with his right calf muscle twice as big as the left. He called his doctor, who said, “Go to the emergency room right now.”

It was a deep-vein thrombosis, a blood clot that could have broken into chunks, traveled to his lungs, and killed him on the spot.

Doctors immediately put him on warfarin, a common blood thinner. For three days, they slowly increased the dosage, trying to find the correct level to make his blood the proper viscosity and slowly dissolve the clot.

Too much of the drug could’ve caused him to bleed internally. Too little wouldn’t have helped at all.

After five stressful days the clot dissipated and he was allowed to go home. When I asked him why it took so long, he said that doctors don’t really know how much warfarin to give patients at first because everyone reacts to it differently.

Carolina biologist Darrel Stafford found out why, and he has developed a way to test patients before they receive the drug.

His team isolated the gene that encodes vitamin K epoxide reductase (VKOR), the enzyme that warfarin targets to inhibit normal blood coagulation. Stafford then devised a method to check patients for certain types of mutations on the VKOR gene that make people less or more sensitive to warfarin.

“Being able to predict whether someone is likely to be a bleeder might help get someone started on a warfarin regimen,” Stafford says.

Isolating the VKOR gene could also help researchers make better blood thinners with fewer side effects.

Warfarin has been in use for a long time, but until now scientists knew very little about the genetics behind coagulation.

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n the 1920s, farmers in Canada and the northern United States reported that a mysterious disease was killing their cattle. Some cows bled to death from only minor injuries. Some showed no signs of external injury but still died of internal hemorrhaging.

“Turns out the cows were eating fermented sweet clover,” Stafford says, “which inhibited coagulation.”

In the 1940s, scientists at the University of Wisconsin discovered the anticlotting culprit in the moldy clover and named it

dicoumerol. The lead investigator, Karl Paul Link, synthesized a stronger version of the drug and named it warfarin after his funding agency—the Wisconsin Alumni Research Foundation. Link’s main goal was to use warfarin as rat poison. Today a version of dicoumerol is still used for just that, but researchers also turned the compound into a blood thinner that was approved for use in humans in 1954. A year later doctors prescribed warfarin to President Dwight D. Eisenhower after he had a heart attack, and it became a commonly prescribed drug.

Warfarin—or Coumadin, the most popular brand of the drug—is now the fourth-most-prescribed heart drug and eleventh-most-prescribed drug overall in the United States.

In 1978 researchers discovered that warfarin inhibited the VKOR enzyme and foiled proper vitamin K metabolism. But no one had been able to isolate the VKOR gene, which researchers suspected caused some patients to be more sensitive to warfarin.

Stafford’s team gathered all the previous studies on VKOR and managed to narrow down its location to one region of a chromosome. Still, that region contained 194 genes. Instead of using older, more timeconsuming methods to find the right gene, they decided to use a new technique.

First, the team took sixteen different cell lines, ruptured the cells, and used highpressure liquid chromatography to check them for measurable amounts of epoxide reductase. Second, graduate student Tao Li used a computer program to translate the 194 genes into protein sequences. This helped Stafford narrow his search to thirteen likely candidates for the production of epoxide reductase. Third, Stafford’s team made small interfering RNA (siRNA) for each gene. SiRNA is found in many organisms, and in 2001 scientists figured out how to make synthetic siRNA for specific genes to turn off or reduce gene expression.

Stafford made siRNA to turn down the expression of epoxide reductase. When he added the siRNA to the genes, he saw that one had a significant decrease in reductase activity.

“So then we put that gene into cells and it had a gigantic increase in epoxide reductase activity,” he says.

This was the first time anyone had used siRNA as a screening technique to isolate a gene. Stafford’s discovery made the cover of

Nature, which published his paper alongside an article by Johannes Oldenburg, a German scientist who had used an older, more laborious method to isolate the same gene.

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fter this, Stafford wanted to isolate the enzyme that completes the vitamin K metabolism cycle. But his wife, a physician, pushed him to figure out why certain people are extremely sensitive to even low doses of warfarin.

“She just said, ‘Look, this is a big deal.

Millions of people are on warfarin. You’ve got to go ahead and figure this out.’”

Thanks to Stafford’s long-standing friendships with several blood researchers at Carolina, including Harold Roberts and Roger Lundblad, he knew that UNC had a lot of patients’ records that he could check for warfarin resistance.

“Some of these patients required thirtyfive milligrams of warfarin and some needed two milligrams,” he says. “We took the data and looked for genetic polymorphisms in these patients—places on the gene where there were differences.”

He found that patients were less or more sensitive to warfarin depending on their sequence of genetic mutations. Researchers can use a polymerase chain reaction, a common genetic-testing method, to determine if a patient has one kind of nucleotide sequence or a different kind at a particular site in the genome. This, essentially, is how Stafford’s patent-pending diagnostic test works. It has been licensed to four different companies who are developing tests for clinical use.

Stafford is now setting his sights back on vitamin K enzymatic activity. He’s trying to figure out which enzyme is responsible for actually reducing the VKOR at the end of each cycle—a reduction that is crucial for proper blood coagulation.

“We’ve used a lot of techniques to try to figure this out,” he says. “But so far we still don’t know.” e Darrel Stafford, who came to Carolina in 1965, is a professor of biology in the College of Arts and Sciences. He was a 2007 recipient of the North Carolina Award for Science.

Prior to isolating VKOR, Stafford’s team purified the gene that encodes gamma-glutamyl carboxylase, another key enzyme within the vitamin K cycle. This discovery is helping other researchers develop cheaper clotting agents for hemophilia patients. endeavors 33

seeds of

Invasion

What does this weed tell us about the spread of human disease?

by Beth Mole CHARLES MITCHELL

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In the past two hundred years, the green, bunchy

grasses that once grew over eleven million acres of California grasslands have been usurped by carpets of invasive golden weeds.

Only 1 percent of the native grasslands remain, and they now top the list of the most disturbed and endangered ecosystems in North America. This transformation has baffled scientists, and attempts to restore the grasslands have largely failed. Charles Mitchell, a disease ecologist, thinks a virus is to blame. If he’s right, he holds the key to restoring the California grasslands— and could help explain how both plant and human diseases transition from emerging threats to full-blown epidemics.

The devastating effects of more familiar epidemics are well known. Diseases such as bubonic plague, the Spanish Flu, Dutch elm disease, and the potato blight of the Great Famine all swept through populations and drastically altered ecosystems long after their initial outbreaks. But what conditions allowed these diseases to spread so well?

Scientists have identified a lot of variables that contribute to a disease’s success: transmission routes, duration of contagiousness, mortality rate. Epidemiologists have figured out mathematical models that take all of these factors into account, and have used them successfully in fighting the spread of endemic diseases such as HIV/AIDS and malaria. But these models don’t yet exist for emerging diseases such as avian flu and SARS. The California grasses may change that.

Mitchell and his team of researchers are studying the spread of a virus called the barley yellow dwarf virus (BYDV) in California grasslands. They hope modeling BYDV will help us understand how diseases interact with their environments to become epidemics.

JASON SMITH

Charles Mitchell: we can do experiments with plants that would be unethical or impossible with animals or people.

Below: Mitchell’s group infected native California brome with barley yellow dwarf virus, causing the leaves to turn red.

MEGAN RĂšA

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“We’re interested in understanding the causes of disease spread, and we can do manipulative experiments with plants that would be either unethical or just impossible with animals, let alone humans,” Mitchell says.

BYDV and the California grasslands make a great system for studying the spread of disease. “It’s a classic example of a major biological invasion,” he says.

Stowaway seeds

It started in the 1500s, when Spanish settlers arrived in California, bringing with

them the seeds of Mediterranean grasses.

The settlers may have planted some grass intentionally for grazing livestock, making medicines, or for ornamentation. Other seeds may have been brought accidentally as stowaways in ship ballast, hay, or crop seed.

The golden annual grasses not only set up shop, but took over the place, spreading over more than 10 percent of the state of California. More than three hundred species of native, perennial green grasses were forced out of their habitats.

As the golden grasses spread, ecosystems lost the benefits of the native grasses, which

JASON SMITH

At this field site just north of Chapel Hill, Mitchell and graduate students Miranda Welsh (left) and Megan Rúa (right) run experiments on native and exotic grasses.

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have deep roots that stabilize the soil and filter pollutants. The native grasses also produce nutrient-rich material for foraging animals, and provide nests and harbors for native mammals and insects.

“Ecologists have long puzzled over why the invasion was so successful that there could be a wholesale replacement of a native flora by an exotic one,” Mitchell says.

At first researchers thought the success of the golden grasses was a case of classic competition—new species edging out old ones by monopolizing resources. But now researchers think that BYDV led to a situation ecologists call apparent competition— when one species acts as a food source for a predator, increasing the predator population and allowing it to reduce the numbers of a second species.

BYDV is the most widely spread virus of grasses, and causes significant damage to cereal crops such as wheat, oats, and, of course, barley. The virus spreads when an aphid punctures the stem of an infected plant to suck out sap, and then carries BYDV to an uninfected plant. Almost all grasses are susceptible to aphids and BYDV, but not all have the same rate of infection and severity of disease.

“Whenever you have transmission of a disease between a native and an introduced species, it raises the question of which species will transmit the disease more effectively and what are the relative impacts of the disease on the different species—which species will be on the winning end and which will be on the losing end?” Mitchell says. In California, the golden exotic grasses won and continue to win. But how’d they do it?

Researchers have to take more into account than just the disease. “The old frontier in disease ecology was predicting the dynamics of a single pathogen species infecting a single host species,” Mitchell says. This strategy has been useful in making mathematical models for the spread of pathogens such as HIV. “But most pathogens infect multiple host species—for example, over sixty percent of human pathogens also infect nonhuman animals—and hostpathogen interactions occur in complex environments,” he says.

To understand the apparent competition between exotic and native grasses, researchers have to understand the relative populations of each species, their rates of BYDV infection, the preferences of the aphids for

JAMES CRONIN

feeding, and how changes in these factors feed back into the system. This is exactly what Mitchell is trying to do to understand how this disease—and others—spread.

Aggressive exotics

Mitchell hypothesizes that nutrient cycling and the way grasses grow are key factors for modeling diseases such as BYDV. The native, perennial grasses are slowgrowing and conservative in their uptake and use of nutrients. The exotic annuals are fast-growing and quick to use resources from their environment. California grasslands are rich in nitrogen, and Mitchell speculates that this environment gives the fast-growing, exotic grasses an advantage.

Aphids grow and thrive on the booming exotic grasses. But because the exotics can quickly take up the nutrients available to them, they’re more tolerant of aphid attacks and viral infection. The slow-growing, conservative perennials are less tolerant and come in contact with the virus more often as neighboring exotics become aphid havens.

The exotic annuals die out each year, which gives them the opportunity to clear the virus from their population. Some of the native perennials, such as purple needlegrass, may live as long as a thousand years, carrying the virus far longer than the exotics do.

So far this is Mitchell’s hypothesis. He and his team are trying to pinpoint quantifiable traits that they can use to establish a model for BYDV. First they must measure specific traits and physical features of the grasses. How fast do they perform photosynthesis? How long do they live? What are the concentrations of nutrients in their leaves? How tough and dense are their leaves? Then the team will see if the data they collect can predict disease trends. “We have the general idea,” Mitchell says, “but we’re still a step away from having a concrete, robust model of how those epidemiological traits predict disease dynamics in a community.”

So they’ve set up experiments to start taking measurements in the greenhouse and at field sites. By nailing down the traits that explain the community changes and disease spread, they hope to create a model that can be applied to other community changes and diseases.

Trait measurements such as photosynthetic capacity and leaf toughness might not seem like useful data for countering human

Mitchell’s research group isolated barley yellow dwarf virus from naturally infected grasses.

They used feeding aphids to transfer the viruses to crop oat plants that reliably propagate the virus. To contain the aphids, each plant is temporarily kept in a ventilated clear plastic tube.

infectious diseases, but Mitchell’s research addresses the most serious challenges epidemiologists face: BYDV infects multiple hosts, causes apparent competition, and is carried by an insect vector. “Across host species from plants to wildlife to domesticated animals to humans,” he says, “insect-transmitted generalist pathogens are at high risk of causing emerging infectious diseases—diseases that are of greatest concern for conservation, agriculture, and human health.

“We’re trying to move toward recognizing disease spread early when there are more unknowns. It’s tricky.” e

Beth Mole is a doctoral student in the department of microbiology and immunology in the School of Medicine.

Charles Mitchell is an assistant professor in the department of biology and the curriculum in ecology in the College of Arts and Sciences. He is working on this project in collaboration with Elizabeth Borer and Eric Seabloom at Oregon State University, Alison Power at Cornell University, and Andrew Dobson at Princeton University. Funding comes from the National Science Foundation’s Ecology of Infectious Disease program. endeavors 37

SOUNDING OUT

THE WHITE HOUSE Terry Sullivan leads an all-volunteer team charged with finding out what outgoing presidencies have learned. The goal: to ease the transition for the incoming team.

by Mark Derewicz

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s soon as Bill Clinton won the 1992 election he made a serious blunder—he failed to name a White House chief of staff right away. In fact, he waited until December to name longtime friend Mack McLarty chief of staff and until January to pick his senior advisors. Clinton instead focused on choosing his cabinet and figuring out how to boost the economy. As a result, his inexperienced staff were still trying to get organized during their first one hundred days in office. The West Wing got bogged down in side issues such as gays in the military. The administration didn’t gain its footing until the following year.

“Everyone recognizes Clinton’s as one of the absolute worst White House transitions ever,” says political scientist Terry Sullivan.

“There was an enormous amount of uncertainty and as a result there was a whole bunch of stuff screwed up in Clinton’s first term.”

This year, with an economy on the brink and two wars to win, the last thing we need is a wobbly West Wing. So it was no wonder most people praised Barack Obama for naming Rahm Emanuel as 38 endeavors

JASON SMITH

Terry Sullivan and his team have talked to a who’s who of former White House staffers, interviewing nearly every major player since the Nixon administration. The lessons the staffers have learned—often the hard way—fill stacks of binders in Sullivan’s office and make up the reports he prepares for incoming administrations.

White House chief of staff two days after the election. Emanuel was an advisor to Bill Clinton for five years. He witnessed the sluggish start and served under all four Clinton chiefs of staff, including John Podesta, who served as codirector of the ObamaBiden transition.

Still, Sullivan says, even a good transition won’t be perfectly smooth for three major reasons. Few people under Emanuel know what it’s like to work in the White House. No one knows what it will be like to work in the Obama White House—not even Obama. And finally, each administration is so enormous that getting it up and running takes time the country simply doesn’t have.

Sullivan, who’s an expert on White House transitions, helps ease the growing pains.

I

n 1997, Sullivan led a group of scholars to create an archive on presidential transitions. All they wanted was a tool to help other researchers. But the project quickly grew into a public service to help public servants, new White House staffers in particular.

Sullivan and Towson University professor Martha Kumar started the White House Transition Project, a nonpartisan group of twentyfour scholars who have interviewed nearly every former White

House chief of staff, press secretary, director of communications, and senior advisor since the Nixon Administration. The goal is to find out what each White House office is responsible for. What were their common mistakes and greatest successes? What were the most important lessons they learned, and what did they wish they had known before they entered the West Wing?

The resulting answers fill twelve thick binders that the scholars use to write twenty- to forty-page briefing memos. Sullivan and Kumar give the memos and binders to the president’s transition team, but anyone can read them at www.whitehousetransitionproject.org. Kumar also has an office in the White House lower press office and is available to work with a transition team, as she did in 2000 when she met with Clay Johnson, President Bush’s transition director.

In 2003, Kumar and Sullivan included many of their findings in the book The White House World. And in 2004, Sullivan wrote Nerve Center: Lessons in Governing from the White House Chiefs of Staff.

After an election the winners often say that working for a campaign is like being a minor league baseball player, and working in the West Wing will be like joining the major leagues—the fastball will be a little faster. Sullivan says the analogy is comforting, but flat wrong. “It’s more like going from a ninety-two-mile-per-hour fastendeavors 39

The conversations were kept under the radar so that the candidates wouldn’t be accused of measuring the White House drapes.

ball to trying to hit a twelve-hundred-mileper-hour fastball. The scale of the American government is just so much bigger than any other job. And you’re under enormous pressure not to make mistakes.” But the pace of each job is so fast that staffers are bound to make mistakes, especially if their ideas of the job don’t comport with reality.

Despite this, typical incoming White House staff members won’t seek advice from their immediate predecessors, who are often members of the other political party. “So we talk to them,” Sullivan says.

In April 2008 both the Obama and McCain campaigns contacted Sullivan’s team, though conversations were kept under the radar so that the candidates wouldn’t be accused of measuring the White House drapes.

“A lot of times the campaigns ask, ‘What is our appropriate level of ignorance, and how do we get rid of it?’” Sullivan says. That’s a tough one because even former West Wingers have trouble explaining how the White House is organized, how it can or should be organized, the sort of confidence each job demands, and the sheer amount of work each job entails. It’s not a coincidence that, on average, a White House staffer burns out after sixteen months.

But Sullivan’s binders do help banish a good deal of ignorance.

In one example, Marlin Fitzwater, press secretary for Ronald Reagan and George H.W. Bush, said this about White House operations: There’s always this kind of feeling when you bring in businessmen or women with experience that they’ll bring some professionalism to the organization. And they always fail because they think in line-staff structural relationships and in business they don’t have to worry about personal relationships because they have the power. They give orders; they take away your salary; they can fire you. And in the White House all those normal management techniques go out the window. Oftentimes you can’t fire people.

40 endeavors

The chief of staff doesn’t set the salaries; the special assistant to the president for White House management and administration handles that. The chief of staff can’t fire people without the president’s say-so. A chief of staff who’s hired mid-term might not be able to bring in his or her own people despite the fact that, according to former chiefs of staff, loyalty to the chief is crucial to the success of the president’s agenda.

All this leads Sullivan to believe that Rahm Emanuel will be a good chief of staff. He knows how to be loyal to an agenda above his own. He and Obama won’t be afraid to hire people as smart or smarter than they are, Sullivan says. Emanuel knows what it’s like to work in the West Wing. He knows he might not last the entire first term, and he’ll know how to prepare for that. “Emanuel has a reputation for having sharp elbows,” Sullivan says. “The White House needs someone like this, especially in the first one hundred days and in times of crisis. So this is a classic time for a smart, pushy, demanding guy like Emanuel to step in.”

These qualities will help Emanuel push Obama’s agenda in the West Wing and on Capitol Hill. They will also help Emanuel manage Obama’s time, which Sullivan found won’t be as easy as one might think.

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very president’s appointment secretary keeps track of who enters the Oval Office, who calls, and when. Every time the president leaves a room a Secret Service agent whispers into his sleeve so that the service’s command center can track the president’s every move. These minuteby-minute accounts are made public at the National Archives. Sullivan scoured the records from Dwight Eisenhower to George H.W. Bush. In 2008, Sullivan wrote Presidential Work During the First Hundred Days, a report he handed over to Obama’s transition team and which is available at the White House Transition Project website.

“We did this research because campaigns have been building their plans for the first one hundred days in office based on what they think the president does,” Sullivan says.

“And they’ve been doing an absolutely lousy job.” For example, they may think the president will talk to the congressional leadership two or three times during the first one hundred days in office, but the president actually sees them thirteen to sixteen times.

Sullivan says this is the kind of underestimation that forces the president’s staff to cancel appointments, which can be a risky proposition depending on who’s being cancelled. Or the staff will make the president’s already long day much longer. Both possibilities add stress and tension to an already pressure-packed work environment.

According to Sullivan’s report, there are about ten people who see the president three or more times a week. There are just five people the president sees every day—the secretary of state, the chief of staff, the national security advisor, the vice president, and either the senior domestic policy advisor or the press secretary, but not both. Obama can change this formula, but no president will ever change the huge volume of people to be seen every day. Sullivan’s research shows that Obama can expect to see eight thousand people in his first one hundred days in office.

That’s eighty people a day in meetings. This doesn’t include phone calls.

“Karl Rove calls this being a fire hydrant in a world of dogs,” Sullivan says.

Back in 1994, when Clinton’s West Wing was more like a dog pound and Republicans were gaining popularity, Clinton consulted with senior advisor Leon Panetta, who bluntly told the president that his White House lacked order. McLarty resigned and Clinton promoted Panetta, who immediately became the strong enforcer Clinton needed in order to push his agenda. That’s not to say everything was McLarty’s fault.

The president does define the chief’s role to a certain extent, according to the former chiefs of staff Sullivan contacted. But Clinton was the quintessential policy wonk who liked to spend hours analyzing one issue.

Sullivan says that Panetta told Clinton he couldn’t do that because there were simply too many other decisions he had to make.

Even before taking power, the presidentelect has to learn how to make good decisions as quickly as possible. First he has to figure out how to fill eight thousand federal

jobs, twelve hundred of which are policymakers, who must be nominated by the president and then approved by the Senate.

Sullivan says this is where Obama probably took a cue from George W. Bush, who knew which posts he needed to fill first and how many he would likely be able to fill in a given amount of time. Sullivan says that Bush was planning all this well before the 2000 election. Given Obama’s sleek campaign organization and his choice of Emanuel as chief of staff, it looks like he’s keen to all this.

Sullivan says Obama picked his core cabinet positions—secretaries of State, Defense, Treasury, and the Attorney General—faster than any president in the past thirty years.

Still, completing the transition will take much longer than anyone would like.

According to Sullivan, in the first one hundred days in office no president has been able to fill more than twenty-five of those

twelve hundred jobs. We’re talking the State Department, the Departments of Defense, Treasury, Commerce, Education, Energy, Homeland Security—you name it. By the end of the first year, no president has been able to appoint more than 360 people.

There are several reasons for this slow pace. One is political infighting over the nominations; Senators sometimes try to hold up the appointment process, forcing the new president to nominate someone else for a job. There’s little anyone can do about this. Sullivan, though, wrote a report called Rescuing the Presidential Appointment Process which outlines several steps the government could take to help speed things up.

Right now, each nominee must divulge approximately twenty-eight hundred personal details in answering three hundred questions. Sullivan found so many repetitions in these inquiries that discarding them

ON TEAM OBAMA

I

n an interview with 60 Minutes in November 2008, Barack Obama was asked what he was reading. He answered with a smile: briefing papers. No doubt a lot of them. And this was before his transition team gathered more papers on everything from national security to the National Endowment for the Arts. UNC professor Bob Adler cowrote one of these papers.

Adler, a UNC business school professor, joined Obama’s transition team in October 2008. After the election, Adler was one of two people asked to review the Consumer Product Safety Commission (CPSC), which is in charge of making sure our stores don’t sell defective products such as toys with lead paint.

The CPSC is considered an independent agency, though it is part of the federal government. The president appoints the agency’s three commissioners and names the chairperson, and Congress funds it. Over the past several years, the commission has been widely criticized for its perceived lack of power to protect consumers. Adler’s job was to document how the agency functions and give advice about how it could be improved.

Adler was a lawyer for the commission from 1973—when it was created—until 1984. Then he worked for the congressional committee in charge of CPSC oversight before joining UNC’s faculty. In October 2008 former CPSC executive director Pamela Gilbert, a longtime colleague of Adler’s, asked him to help review the hurting agency for Obama.

“I was totally surprised to be asked to serve,” Adler says, “but very excited about having some input on what the policy of the agency ought to be.”

would reduce the burden on the nominee by 30 percent.

Congress could also amend the Presidential Transition Act of 2001 to give the national campaigns, or at least the presidentelect, access to the personnel operation system that the White House uses to process all the information it gathers on nominees.

As it stands now, the new White House staff can’t process nominees until after Inauguration Day. “All this takes a surprisingly and frighteningly long time,” Sullivan says.

“Mainly, the government is empty chairs for two years.” e Terry Sullivan, executive director of the White House Transition Project, is an associate professor of political science in the College of Arts and Sciences. Martha Kumar, professor of political science at Towson University, is the director of the White House Transition Project.

He spent several days interviewing commission employees, members of Congress, industry people, and consumer groups.

Over Thanksgiving and Christmas and in between classes, Adler read volumes of CPSC reports and other articles about the agency.

Then he helped Gilbert write the briefing paper for Tom Perez, the director of Obama’s health and human services transition team.

When Endeavors interviewed Adler, he was unable to divulge any of his findings or advice because his work was for internal review only. But during the presidential campaign, Obama vowed to make several changes to the CPSC, including filling top posts with people who had not previously worked for companies the commission oversees. Obama also wants to double funding for the agency and hire more investigators in charge of keeping our stores free of defective stuff.

According to the CPSC website, the agency has about 420 employees. In 1980 it had 978. Since then its budget has been reduced while the rate of products entering the United States has skyrocketed. The agency now monitors fifteen thousand kinds of products. Yet until 2008 it had only one stationary machine that could scan products for lead, even though handheld scanners have been on the market for ten years. When toys with lead paint landed on our shelves last year, people started pointing fingers at the CPSC, its organization, and why it lacks the regulatory power to act quickly in emergencies.

In this economy, no one is sure if the CPSC will be restructured, but Adler cowrote the blueprints in case Obama wants to try.

—Mark Derewicz Robert Adler is the Luther Hodges, Jr., Scholar in Ethics and Law at the Kenan-Flagler Business School. endeavors 41

boning up on stem cells

by Susan Hardy FROILAN GRANERO-MOLTO

Fractures that received mesenchymal stem cells that were treated with the growth factor show more cartilage growth (right) than fractures that did not receive treatment (left).

42 endeavors

As a pediatrician, Anna Spagnoli

spent a lot of time monitoring kids’ heights and weights. “It’s a major sign of the health of a child,” she says. “Are they growing okay? That’s the first thing a parent usually wants to know.”

But the parents Spagnoli talked to had more than the usual concerns. They came to her because their kids were growing too slowly and breaking too many bones. Some had bone fractures that just wouldn’t heal. Many of these children suffered from osteogenesis imperfecta, a genetic disorder that makes bones fragile. Children with the disorder heal very slowly after a fracture, and may have to stay immobile during the process to prevent a rebreak.

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genetic bone disease is just one of many reasons why a patient might have trouble healing from fractures. Osteoporosis, diabetes, and other conditions also prevent normal bone formation. Of all fractures, about 20 percent don’t heal on their own.

That’s six hundred thousand fractures in the United States each year.

The number seems high, but Spagnoli contrasts it with the millions of fractures that do heal normally. “This is a tissue that, 80 percent of the time, functions correctly. So if your bone isn’t repairing itself, what does it not have that other bones do?”

She and her colleagues think they know.

And their research might lead to a new treatment for fracture nonunions—the broken bones that just won’t heal.

For a patient who has a fracture nonunion, the best option available today is bone graft surgery. A graft, usually taken from the patient’s pelvis, is reshaped and placed in the fracture site. But if a patient is young or has low bone density, there might not be enough healthy bone from which to take a graft. Even when a graft can be done, healing takes a long time. “One year after the graft surgery, many of these patients still have pain,” she says.

Spagnoli looks at fracture treatments through the eyes of a pediatrician. In healthy children, fractures heal well and quickly— maybe, Spagnoli says, older bones can be persuaded to act like young ones. “We want to supplement the bone’s natural healing process,” Spagnoli says.

That’s the goal of regenerative medicine, a field that looks beyond drugs and artificial transplants to produce new treatments for diseases and injuries. “Something in your own body is used to regenerate the tissue that’s not working,” Spagnoli says.

She thinks this new approach is a good one for fracture healing because bones regenerate themselves all the time. Bones aren’t static tissue: no matter what age we are, our bones are in a continuous cycle of resorbing old bone cells and forming new ones. The same process occurs during fracture healing. A web of cartilage and weak but quick-forming bone forms across a fracture site; the web is then slowly resorbed and replaced by stronger bone.

Spagnoli’s supplement for this process is a type of adult stem cell found inside bones themselves. Scientists have known about the

potential of bone marrow stem cells since around 1970, shortly after the first bone marrow transplants were performed. When researchers examined the different types of cells found in the marrow, they found mesenchymal stem cells (MSCs).

“In a dish, MSCs from bone marrow turned into bone, muscle, cartilage, and other cells. What we didn’t know was whether we could get them to perform that way in a body,” Spagnoli says.

Working in pediatric endocrinology, Spagnoli had learned a lot about the hormone called insulin-like growth factor 1 (IGF-1). It’s particularly active in growing children, and it’s also known to be lower than normal in adults with osteoporosis. Spagnoli hypothesized that when MSCs treated with IGF-1 encountered a bone fracture, they would turn into cartilage cells, an early step in the fracture-healing process.

It’s a test that would have been difficult to do just five years ago. The problem, Spagnoli says, was that scientists couldn’t see what cells do and where they go once they’re inside a nonhuman animal. “Until five or six years ago, injecting cells into an animal was like putting them in a black box. You couldn’t see what the cells did until you sacrificed the animal. So you missed everything that happened in between.”

In the past few years, imaging technologies used on humans, such as CT and MRI, have become available on a smaller scale for use on animals. And scientists learned how to use the gene that codes for luciferase—the harmless enzyme that makes fireflies glow— as a tracker to watch the movement of cells inside an animal’s body.

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roilan Granero-Molto, a member of Spagnoli’s lab, extracted MSCs from the bone marrow of mice that had the luciferase gene. After treating the glowing cells with IGF-1, he injected them into mice that had fractured leg bones. The injured mice didn’t have the luciferase gene, so the injected cells stood out brightly in their blood. “You can’t see them with the naked eye, but they show up clearly in photos taken with a CCD camera,” Spagnoli says.

“This way, we could track the movement of the cells hour by hour through the mice,” Granero-Molto says. “We found that after three days, the cells got to the fracture.”

They also found that the cells used CXCR4, a molecule that can home in on bone marrow, to find the fracture site. Cells that lacked CXCR4 didn’t arrive at the fracture.

After two weeks micro-CT scans showed that mice treated with stem cells had more cartilage and bone growth at the fracture sites than did mice that didn’t receive the stem cells. The repaired bone in the treated mice was three times stronger than the repaired bone in the untreated mice. The animal model for the stem cell treatment had worked.

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uccess in an animal model is a crucial step toward developing a treatment for humans. But Spagnoli and her colleagues need evidence that stem cells would address a deficiency in human patients with nonunion fractures. Right now they’re planning a study of patients who have the same kind of leg fractures they studied in mice. They’ll test blood and bone marrow samples from the patients to examine their levels of stem cells, and track how well the fractures heal.

They want to find out if patients whose fractures heal poorly have fewer MSCs or defective MSCs. Spagnoli anticipates that stem-cell treatments to regenerate tissue are not far off—or at least much closer than many of the other goals of stem-cell research. “A lot of the interest in stem cells has been to treat diseases like diabetes, where there is a total degeneration of an organ—or very complex diseases like Alzheimer’s or Parkinson’s.

How to cure these diseases will be a very difficult question. But how to use stem cells to help the body with a repair process it’s usually good at, such as bone healing—this is a question we may be able to answer much sooner.” e Anna Spagnoli is an associate professor of pediatrics and biomedical engineering in the School of Medicine. Froilan Granero-Molto, who presented the results of the study in June 2008 at the annual meeting of the Endocrine Society, is a postdoctoral student in pediatrics in the School of Medicine. Assistant professor of pediatrics Lara Longobardi in the School of Medicine and Vanderbilt University collaborators Michael Miga, Jared Weis, Benjamin Landis, and Lynda O’Rear were coauthors on the study. Funding came from the National Institutes of Health. endeavors 43

in print

the letters he kept Every Day Lasts a Year: A Jewish Family’s Correspondence from Poland.

By Christopher Browning, Richard Hollander, and Nechama Tec. Cambridge University Press, 285 pages, $28.00.

44 endeavors

by Margarite Nathe photos by Paul Fetters

The attic,

Rich Hollander decided, would be the least painful place to begin. He walked past the refrigerator (still full of food) and the thermostat (still humming), and up the stairs. The house was just as his parents had left it.

Months earlier his seventy-year-old mother Vita had been driving, with his father Joseph in the passenger seat, when the car had veered off the road and into a storefront. “My parents, who were profoundly in love after forty-one years of marriage,” Hollander writes, “died almost instantly, and within seconds of each other.”

Up in the third-floor attic, Hollander looked around at the old suitcases and bags, and began sifting through them. One old briefcase, though, was surprisingly heavy. He sat down with it, pulled the tabs apart, and the clips sprang open.

Inside, stacked neatly and held together by rubber bands, were hundreds of letters and postcards, all addressed to Joseph. They were written in Polish and German, and so Hollander couldn’t read them. But the hand-stamped swastikas and Nazi imprints in the upper corner of each letter were clear. There were dozens of old photographs of strangers, along with the beginnings of Joseph’s autobiography, which cut off at around 1939. There were old passports in the attic, too, and receipts, telephone records, business cards, household inventories—the kinds of things his father usually threw out.

Neither of his parents had ever mentioned the attic archive before, Hollander says, “but I knew exactly what it was.”

Joseph probably stowed the letters in the attic because he wanted to forget about them, but he would never have thrown them out—they were all that was left of the family, friends, language, culture, and history that he had lost during the Holocaust.

Finding the archive then was unbearable for Hollander. He closed the briefcase and tucked it away in his own house. It stayed there for fourteen years.

…

As a child, Hollander knew that

his father had moved to the United States from Poland and that he had no other family. “But my father never talked about any of this,” Hollander says. “I knew only the most fragmentary stuff about it.” His mother was a strict gatekeeper for her husband’s sensibilities—even during the 1970s and 80s, when Holocaust books and movies were becoming more common, never did a single one enter their home.

“I had the letters translated when I finally had the courage to do it,” Hollander says. He took them to Polish professor Barbara Bernhardt at American University. When he returned months later to pick up the translations, he found Bernhardt sobbing. “You don’t understand what you have here,” she said to him.

“I’ve done many translations in my life, but not like this,” Bernhardt says. She’d spent months pulling the fragile bits of paper

from the envelopes and getting to know the family. The letters, she says, are powerful testimonies from a Jewish family who lived under constant threat and still managed to have hope, humor, and gentleness. “In situations of crisis we’re usually reduced to instinct,” Bernhardt says. “But they weren’t reduced to scared little creatures, especially not the women.”

After talking with Bernhardt, Hollander realized he had work to do. “That’s when I began peeling back of the leaves of the artichoke,” he says. He asked around, and finally a professor at Columbia led him to contact Christopher Browning at UNC. Browning, a historian whom the New York Times calls “the master of Holocaust scholarship,” had never seen anything like Hollander’s letters. In fact, he says, Holocaust historians have never had access to anything like this before—an uninterrupted, two-year narrative from an entire family living under the Nazi boot. “You have nine people—three generations, six women, three men—that are writing,” he says. “You’re getting the whole family, with their different perspectives and their different personalities.” And unlike authors of Holocaust-survivor memoirs, these writers had no idea how their story would end. Their letters are filled with anxiety, uncertainty, and hope, which, Browning says, is a very different way to tell a story. An early letter from Joseph’s sister Klara reads: Here, thank God, not much changes. We all are healthy and that’s the most important thing… I cook every day for many people. Sometimes I start distributing dinner at 1 p.m. and end at 4. I can do it in such a way that it’s never too little. Maybe I have a profession for America? Only my hands are not good for the piano anymore. I would like it to be my only worry…

Browning immediately wanted to help Hollander learn more about the letter-writers and eventually publish the correspondence.

“But not all the letters had been translated yet,” Browning says. A few were typed, but the rest were handwritten; the oldest family members had scribbled their letters out in a nineteenth-century German hand that was so illegible that translators had trouble identifying the language. And even the translated letters weren’t ready to publish; most were undated, and used a lot of code. Joseph’s family knew the Nazis were reading Poland’s outgoing mail, and to avoid attracting attention to themselves—risking “getting their names on a list,” as Browning says—they referred to Russia as “Uncle Tolstoy” and to the Germans as a “horrible old aunt”; “out-of-town guests” was code for other Jewish families who’d been forced to squeeze into the Hollanders’ tiny apartment in the Krakow ghetto.

“A few of the letters were lost,” Browning says, “but these letters were crossing the Atlantic in the middle of the war. It’s remarkable how many of them actually got there. And that Joseph saved them.”

Even so, only half the correspondence survives—the letters Joseph wrote back to his family are lost. “And Joseph’s is an extraordinary story in its own right,” Browning says, “because he’s the one who got out.” endeavors 45

If Joseph’s autobiography left Hollander stunned, it was nothing to what he found after a little more investigation: in the archives of the American federal court were hundreds of pages of transcripts and documentation, all about Joseph. Hollander approached an immigration historian about it and was surprised to hear that she already knew about Joseph’s dramatic landing in the United States.

“Your father was the Elian Gonzalez of 1940,” she told him.

Joseph had a successful life in Krakow; he had a law degree and was the director of a Polish travel agency before he fled. But the anti-Semitic rumblings he heard during his business travels around Europe were unsettling. When Hitler ordered all Jews to leave Germany, droves of them came to Joseph for help. So Joseph did what he could for them: he bribed officials in the Interior Ministry in Warsaw to revalidate expired passports, and paid huge sums for visas to Nicaragua, Cuba, and other Latin American countries whose gates hadn’t yet been slammed shut. He helped hundreds of Jews escape before Germany closed its fist over Poland.

When word came in August of 1939 that Germany was massing an army on Poland’s border, Joseph and his first wife made secret plans to leave Poland. He urged his family to do the same. They decided to stay, and that haunted him for the rest of his life.

Joseph’s plan was to reach Portugal, a neutral country, and wait for the war to end. But Joseph, his wife Luisa, and a boy they’d taken in during the trip weren’t allowed to disembark in Lisbon, despite their carefully procured paperwork. They were forced to stay on the ship until it came to port, finally, in New York. When they reached Ellis Island, the port authority ordered their immediate deportation back to Poland, where by that time Jews were being deposed from their businesses and funneled into ghettos. The three threw themselves on the mercy of the U.S. Immigration and Naturalization Service (INS), which was not inclined to be merciful.

But Joseph was methodical and relentless; for months, he worked with translators and lawyers to wade through U.S. immigration laws. He pleaded with the INS and the federal courts, appealed the deportation order several times, and wrote letters to senators, the secretary of state, and even Eleanor Roosevelt (to which she responded). The press picked up the story; the New York Times ran a news story about them.

While Joseph was fighting deportation in the States, his family was struggling against deportation in Krakow. “Krakow was different from other European cities,” Browning says. The Nazi governor of Poland chose it as his colonial capital, and so there were no uprisings or battles there like the ones that destroyed Warsaw.

“While other cities brought Jews in from all over and concentrated them in the ghetto, the Nazi governor didn’t want the clean air of Krakow spoiled by so many Jews,” he says. So the city’s Jewish ghetto was smaller and more frequently culled than those in other cities. Joseph’s family, like some other Krakow Jews, strove to stay and make their living there. They realized only later that it would mean living in the ghetto.

Throughout Joseph’s legal struggles, he was still scrambling to help his family back in Poland. He paid for care packages from companies in neutral countries that would, for an arm and a leg, 46 endeavors

send food and toiletries into Poland. At first, the letters from his family assured Joseph that they had enough food to be comfortable. Before long, though, the letters became detailed, desperate thank-you notes that read like inventories (“Thank you so much for the rice…the canned milk…the three ounces of tea…the five ounces of coffee…”)

By the time Joseph managed to secure several expensive Nicaraguan visas for the family, it was too late—the Nazis were no longer recognizing even legitimate paperwork for Polish Jews. The letters from his family trailed off in December of 1941. Joseph’s Polish wife left him and remarried, but Joseph won the right to stay in the country by enlisting in the Army. He went back to Europe in 1945 wearing an American uniform, and searched for months through concentration camp ruins and records. He picked up the trail of several of his family members and found that they were deported to Auschwitz among the last trainload of Jews whose papers did not stand up to examination.

…

That day in 1986 was the first time Hollander

ever saw the photographs of his family. “It only hit me later,” he says, “that my father’s survivor guilt was so extraordinary that he couldn’t even display the photographs in our house.” Many of them are included in the book Every Day Lasts a Year: A Jewish Family’s Correspondence from Poland.

Almost every letter from the briefcase is included too, following chapters by Hollander, Browning, and sociologist Nechama Tec. The letters don’t talk about politics; they mostly discuss family matters. “Everyday family difficulties continue even in terrible circumstances,” Browning says. “All the things that are part of family life didn’t just disappear because the Holocaust was about to happen.” And even though the family had to write around the bigger issues looming over them, there’s no denying the growing sense of desperation in their tone and, Browning says, “the growing strangulation that they feel as the noose tightens around them.”

Reading the Hollander letters one after another is a throattightening experience. There’s something eerie in the repetition— “We are okay.” “Please don’t worry about us.” “We are all healthy.”

“We are okay.”

Others are more poetic. One of the last letters reads: Dearest Józiu [Joseph], Our mail to you reminds me of our prayers to God. One never knows if they really reach Him. e Christopher Browning is the Frank Porter Graham Professor of History at Carolina. He’s now collecting firsthand accounts of factory slave-labor during the Holocaust in Starachowice, Poland. Richard Hollander is a former television and newspaper journalist, and the author of Video Democracy: The Impact of Interactive Technology on American Politics; he is now president of Millbrook Communications in Baltimore, Maryland.

Rich Hollander’s father Joseph never spoke of his escape from Poland.

But through the family letters Joseph left behind after his death, “I was able to see my father as a young man,” Rich says, “which is a really extraordinary thing.”

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A troubled man in troubled times

Above: Walter Lenoir’s grandfather built the family home, Fort Defiance, in the sparsely settled Yadkin River valley. Below: As a student at UNC, Walter Lenoir was dismayed that other students liked to drink and steal the horses of people attending revivals down the street.

Images: Happy Valley, History and Genealogy, North Carolina Collection, UNC-Chapel Hill

The Making of a Confederate: Walter Lenoir’s Civil War. By William L. Barney. Oxford University Press, 272 pages, $12.95.

I

n 1860, just before the Civil War began, Walter Lenoir was straddling a lot of fences. A lawyer who thought he might be happier on a farm, a slaveholder who planned to move to a free state, a well-to-do Southerner who wanted North Carolina to stay neutral if war came, Walter didn’t fit the stereotype of a member of the South’s landed class.

That’s why historian William Barney wanted to tell about the Civil War from Walter’s perspective. “Walter Lenoir’s South lies outside the South of the popular imagination,” Barney writes.

North Carolinians today recognize the name Lenoir from the city of Lenoir near the family home in Caldwell County, and from Lenoir County, North Carolina. Both are named after the Lenoir family patriarch, William, a Revolutionary War general and later a North Carolina politician and member of UNC’s first Board of Trustees.

Living in the foothills of the Blue Ridge Mountains, William’s descendents were set apart from many Southerners both geographically and ideologically. Walter and his family were prodevelopment Whigs. When the party fractured along the Mason-Dixon line—antislavery Republicans in the North versus Southerners who would come to support the Confederacy—the Lenoirs at first stayed Whig and pro-Union.

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Before the Civil War, the Lenoirs’ politics were actually the majority view in North Carolina’s western counties. Unlike tobacco and rice planters in eastern North Carolina and cotton planters in the Lower South, most white people in the mountain region owned few or no slaves. “Families like the Lenoirs tried to stake out a middle ground between those they denounced as extremists in both sections—ambitious, hotheaded radicals in the Lower South, and the meddling, fanatical abolitionists in the North,” Barney writes.

The family’s ambivalence about slavery comes across in hints scattered through their letters. Walter bluntly advised his brother Rufus to buy slaves because they were likely to gain in value. Yet in other letters, Walter said the institution of slavery had “defects of the greatest character” and was “wrong in the abstract.” When Walter’s mother learned that one of her sons had sold a slave,

she reminded him that he had an obligation to keep his slaves unless they behaved badly or wanted to be sold.

Walter wrote of “the evil of being the master of slaves.” He wanted to live in a free state, and went to Minnesota to scout for land. But growing tensions convinced him to stay near home and advocate for moderation. As late as March 1861, Walter hoped that North Carolina, Maryland, Virginia, and other middle states might form a central confederacy that could eventually make peace between the North and the South.

In April, when Lincoln called up the state militias, Walter and other Southerners who had wanted to avoid secession began to see the conflict in a new way. By gathering troops, Lincoln showed that he was ready to use force against states that seceded. That realization changed everything for Walter.

He had tried his best to prevent the war.

Now it was coming, and he couldn’t stop it.

In his mind, the choice became whether he would fight for his homeland.

This account of Walter’s life helps us understand not just one man, but other Southerners who were reluctant to secede.

“If they’d had their druthers, they would have ended slavery, but they figured there wasn’t a lot they could do,” Barney says.

“Walter was more than happy that the war was going to bring an end to slavery. It was going to solve the problem for him.”

—Susan Hardy William Barney is a professor of history in the College of Arts and Sciences.

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CAMERON MOSELEY

Before enrolling at Carolina, Cameron Moseley spent four months at the Jubilee Children’s Center, an orphanage in Nairobi, Kenya, where he taught a math class, helped build a library, and took pictures. Moseley is a first-year student from Charlotte, North Carolina.

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Office of Information & Communications Research & Economic Development CB 4106, 307 Bynum Hall Chapel Hill, NC 27599-4106

NONPROFIT ORG. US POSTAGE PAID RALEIGH, NC PERMIT NO. 2483

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Page 18: After David Mora-Marin laid eyes on

Page 28: James Evans teaches genetics to U.S.

Page 24: Mark Zylka was puzzled when he found

the Western world’s oldest piece of writing, he couldn’t stop thinking about how to read it. Photo

by Michael Coe

judges—his hands-on lessons demystify DNA and help the judges make courtroom decisions backed by science. Photo by Jason Smith

a prostate protein in pain-sensing neurons. Then he found that the protein was stunningly effective at relieving pain. Image by Bonnie Taylor-Blake

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