Dr. Anne Comi watches a technician pasting dozens of wires to the boy’s scalp. She’s betting on those electrodes to tell her if the fire has spread to the boy’s tender brain – and whether she might be able to prevent the terrible damage it can do. At 40, Comi is one of the world’s few experts on Sturge-Weber syndrome, an obscure neurological disorder that affects roughly one of every 20,000 children.

She’s among a handful of doctors who devote their lives to fighting and treating “orphan diseases,” conditions that afflict so few victims that drug companies have no financial incentive to study them.

With relatively little research funding and few patients, she’s the scientific equivalent of a captain sailing a tiny boat across an uncharted ocean. As a doctor, she takes on the responsibility for treating desperately ill children whose parents have few places to turn.

“I wanted to do it in a big sort of way,” she said of her work. “If my family was going to make the sacrifices, I wanted it to mean something.”

Observers of her career draw comparisons to the late Dr. Hugo Moser, a Krieger researcher depicted in the 1992 film Lorenzo’s Oil.

Moser, who worked until his death in January at 82, spent his career searching for a cure for adrenoleukodystrophy, or ALD – a rare and potentially fatal neurological disorder that leaves young boys deaf, blind and unable to control their bodies.

His work led to blood tests that allowed an earlier diagnosis, as well as to evidence that Lorenzo’s oil, a mix of common olive oil and rapeseed oil, prevented onset of the disease.

“Hugo got this incredible passion about this really rare disorder,” said Dr. Gary Goldstein, Kennedy Krieger’s president. “Whether Anne can achieve what he did, I don’t know … but she’s taking the whole thing on.”

Outsiders often assume that Comi’s commitment stems from a moving encounter with one endearing child. But like a scientific breakthrough, her journey has been equal parts vision, perseverance and luck.

Difficult path

After earning a medical degree from the State University of New York, Buffalo in 1993, she came to Baltimore for a pediatric neurology residency at Johns Hopkins Hospital. There she resolved to be a doctor-scientist, a demanding dual career, but one in which she could simultaneously treat patients and attack a medical mystery.

She considered a focus on autism but found the field crowded with prestigious scientists whose long shadows would be difficult to avoid.

Dr. Michael Johnston, Kennedy Krieger’s chief medical officer and a pediatric neurology researcher who supervised her rounds at Hopkins, found Comi’s combination of skills and ambition particularly impressive.

“She’s unusual in that she combines great intellect and curiosity with great social skills,” he said. “And she’s got the fire in the belly to make things happen.”

Those skills allow her to switch from stern-faced, scientific authority in the lab to cooing caregiver as she handles infants in the examining room.

A disciple of scientific detachment and modesty, she refuses to make broad claims about her scientific findings.

She also refuses to wear a white coat in the examining room, worried that it might distance her from her young patients.

Johnston steered Comi to a 1999 conference on Sturge-Weber sponsored by the National Institutes of Health. She understood the basics of the disorder, but what she learned there caught her attention.

Wine-colored marks

She knew that the birthmarks result from abnormal capillaries growing under the surface of the children’s skin.

The marks can be disfiguring, and glaucoma can develop in the affected eye.

Far worse, the abnormal vessels can also invade a child’s brain. Creeping over its delicate surface like tentacles, the vessels block normal blood flow, starving the delicate tissue of oxygen and nutrients.

As the brain shrinks and hardens, children can suffer epileptic seizures, mental retardation and stroke.

The seizures, which often start during the first year of life, can occur dozens of times a day and last for hours.

At the conference, Comi realized that the harbinger of the disorder, wine-colored facial marks that affect about 1 in 5,000 children, might be their salvation as well. If doctors could determine which children with the birthmarks also suffer from brain involvement, they might be able to protect the brain before seizures start.

Back in Baltimore, Comi started seeing more Sturge-Weber patients at Hopkins, where she was considering a staff position. She was drawn deeper with each wine-stained child she examined.

“The children are beautiful and the families dear,” she said. “I fell in love.”

But could she piece together a viable scientific enterprise? She still needed the support of a hospital, access to enough patients to produce meaningful research and funds from the few sources available.

The key to attracting patients, she decided, was one-stop shopping, a place where they could see neurologists, eye doctors and skin specialists in one trip.

She sought help from Karen Ball, a New Jersey mother with a daughter who has Sturge-Weber. Ball started the Sturge-Weber Foundation, a patient advocacy group that had helped establish several Sturge-Weber centers around the country.

Ball sensed that Comi was different from other doctors and scientists familiar with the disorder. For them, it was one of several they studied, but Comi was willing to commit everything to solving this one terrible puzzle.

Ball was impressed but concerned, too.

“It’s a lot of responsibility,” Ball said. “Sometimes when you’re young, you think only you can do it.”

Still, she offered to help Comi establish a center and to give her access to the foundation’s registry of Sturge-Weber patients. The foundation also gave Comi a $30,000 grant to do preliminary research. In 2001, Comi told Ball she felt the pieces falling into place.

“I can do this,” Comi recalls assuring Ball – and herself.

She decided that Kennedy Krieger, with its mission to study and treat childhood developmental disorders, would be the right home for her center. But Goldstein, Krieger’s president, was skeptical.

“I didn’t see how she could make a career out of it,” Goldstein said. “I can’t say I was encouraging.”

Yet he had seen Moser build a great career studying one disease. More importantly, Comi had made up her mind.

“She was persistent,” Goldstein said. “I told her, `I don’t quite know how you can pull this off.’ She said, `Well, thank you, but I’m going to do it anyway.’”

She persuaded several specialists at Krieger and Hopkins to work with her – including skin, eye and brain doctors – to treat the various ailments that afflict Sturge-Weber patients.

“I was struck that she was able to get all of these really senior people to work on this,” Goldstein said. “You just can’t say no.”

In 2002, the Sturge-Weber Syndrome Center opened in Baltimore with Comi, then 35, at its helm.

Patients followed, and so did money from foundations, families and the NIH. In addition to treating Krieger patients for other ailments, each week Comi sees about four children with Sturge-Weber, often from out of state.

The disease still takes its toll.

In May 2005, one of her patients, a blue-eyed 5-year-old from Colorado named Hunter Nelson, was scheduled to have half his brain surgically removed in a last, desperate effort to stop his seizures. On the day he was supposed to fly in, Hunter died from a massive seizure.

His picture now hangs in Comi’s office, and her organization was renamed the Hunter Nelson Sturge-Weber Center.

This year, Comi began seeing an infant whose seizures started during a family trip to Mexico, where no anti-seizure drugs were available.

The seizures “essentially halted” the boy’s mental development, Comi said.

Although her theory is unproven, Comi thinks prompt, aggressive treatment at the first sign of the seizure might have protected the boy’s brain and allowed him to develop more normally.

“If they’d met me,” Comi said of the family, “they probably wouldn’t have gone to Mexico.”

`It’s become my life’

Comi’s research aims at preventing these nightmare scenarios.

She’s testing low-dose aspirin as a possible treatment, and she has developed a method to mimic a stroke in mice, paving the way for future studies that can’t be done with children.

She’s also looking for ways to diagnose Sturge-Weber sooner and more accurately.

“It’s become my life,” she said. “Other than when I’m with my family, it’s what I think about all the time.”

The infant sleeping in the hospital bed with wires attached to his head is part of an experiment to see whether an EEG, or electroencephalogram, will allow diagnosis in children before their first seizure.

Ryan McKinney of Frederick has been seizure-free in his first 10 months of life, but the flame-like birthmark is a sign that, if he has the disease, it could reach into his brain.

As his tiny chest rises and falls, the EEG machine scouts the landscape of his mind for the first signs of electrical storms.

The research into the disease is in its early stages, but the test has predicted which children with facial birthmarks will also develop seizures – and might benefit from preventive treatment.

“It’s going to take time before I can stand up and say, `Look, we’ve proved it,’” she said. “But so far, it’s working.”

Reason to cheer

While the machine scans Ryan’s brain (it would ultimately find no abnormal activity), Comi walks two floors down to examine Christian King, a 20-month-old boy from Dundalk.

His mother, Kristina Amos, sits beside him on the exam table, a worried expression on her face.

Christian’s brown skin makes the birthmark harder to see, but appearances are deceiving: He has been diagnosed as having Sturge-Weber syndrome, suffering seizures and showing signs of developmental delays.

As Comi looks him over, Christian smiles and eats plump grapes, leaving light-purple juice stains down the front of his white T-shirt.

During the exam, Comi notices more signatures of the disorder – his foot turns outward slightly when he walks, and he has stopped gaining weight.

But he’s putting words together, and as Comi leans in close and waves her hands next to his face, she finds another sign of improvement.

“He’s blinking now, on both sides,” she tells Christian’s mother. “I think he’s seeing more off to his side, so that’s good.”

Amos brightens at the news that her son’s medications might be helping.

“Yay!” she says, raising Christian’s hands over his head in a victory cheer.

“Yay,” echoes Christian, his chin shiny with grape juice.

Comi smiles and cheers with them at the small sign of progress.

But the moment is fleeting. The exam finished, she hurries down the hall to her next appointment.

(Printed on the front page of The Baltimore Sun, Sept. 30, 2007.)

Yi Qi, a postdoctoral researcher at Princeton University, holds a piece of silicone rubber imprinted with super-thin material that generates electricity when flexed. The technology could provide a source of power for mobile and medical devices. (Photos: Frank Wojciechowski)

The material, composed of ceramic nanoribbons embedded onto silicone rubber sheets, generates electricity when flexed and is highly efficient at converting mechanical energy to electrical energy. Shoes made of the material may one day harvest the pounding of walking and running to power mobile electrical devices. Placed against the lungs, sheets of the material could use breathing motions to power pacemakers, obviating the current need for surgical replacement of the batteries that power the devices.

A paper on the new material, titled “Piezoelectric Ribbons Printed Onto Rubber for Flexible Energy Conversion,” was published online Jan. 26 in Nano Letters, a journal of the American Chemical Society. The research was funded by the U.S. Intelligence Community, a cooperative of federal intelligence and national security agencies.

The Princeton team is the first to successfully combine silicone and nanoribbons of lead zirconate titanate (PZT), a ceramic material that is piezoelectric, meaning it generates an electrical voltage when pressure is applied to it. Of all piezoelectric materials, PZT is the most efficient, able to convert 80 percent of the mechanical energy applied to it into electrical energy.

“PZT is 100 times more efficient than quartz, another piezoelectric material,” said Michael McAlpine, an assistant professor of mechanical and aerospace engineering at Princeton, who led the project. “You don’t generate that much power from walking or breathing, so you want to harness it as efficiently as possible.”

Fabrication starts with the researchers producing PZT nanoribbons — strips so narrow that 100 fit side-by-side in a space of a millimeter. In a separate process, they embedded these ribbons into clear sheets of silicone rubber, creating what they call “piezo-rubber chips.” Silicone, which is used for cosmetic implants and medical devices, already is biocompatible. “The new electricity-harvesting devices could be implanted in the body to perpetually power medical devices, and the body wouldn’t reject them,” McAlpine said.

In addition to generating electricity when it is flexed, the opposite is true: The material flexes when electrical current is applied to it. This opens the door to other kinds of applications, such as use for microsurgical devices, McAlpine said.

“The beauty of this is that it’s scalable,” said Yi Qi, a postdoctoral researcher who works with McAlpine. “As we get better at making these chips, we’ll be able to make larger and larger sheets of them that will harvest more energy.”

Qi and McAlpine collaborated with Habib Ahmad of the California Institute of Technology along with Noah Jafferis, a Princeton graduate student in electrical engineering; Kenneth Lyons Jr., an undergraduate at Morehouse College who worked in McAlpine’s lab; and Christine Lee, an undergraduate at Princeton.

McAlpine joined the Princeton faculty in 2008 after completing a postdoctoral fellowship at Caltech, where he focused on nanotechnology-enabled hybrid sensors for medical applications. He received his doctorate in chemistry from Harvard University in 2006.

(Posted on the Princeton Engineering website on January 28, 2010.)

Now, scientists at the Salk Institute for Biological Studies are using new tools they developed to chart that world, a key step in revolutionizing research into the neurological basis of vision.

For the first time, the scientists have produced neuron-by-neuron maps of the regions of the mouse brain that process different kinds of visual information, laying the groundwork for decoding the circuitry of the brain using cutting-edge, genetic research techniques only possible in mice.

“In the field of cognitive research, this puts the mouse on the map – by putting the map on the mouse,” says James Marshel, a Salk research associate. Marshel and Marina Garrett, a graduate student at University of California San Diego, were lead authors on a paper reporting the advance in the December 22 issue of Neuron.

To understand the extraordinarily complex computations of the human brain, including those behind visual cognition, scientists have mostly relied on studies on primates, such as monkeys, our closest relatives in the animal kingdom, and the most like us in terms of cognitive ability.

Researchers have identified what portions of the primate brain process different aspects of the sensory information they gather from the outside world. In particular, a great deal is known about what regions of the primate brain process certain visual information, helping them identify objects and follow their movements in three-dimensional space.

“We’ve learned a lot about how our eyes feed information to our brains, and a huge portion of our brain is devoted to processing this information,” says Edward Callaway, a professor in Salk’s Systems Neurobiology Laboratory, whose laboratory conducted the research. “Vision is a terrific system for understanding how the brain works and, ultimately, for studying mental diseases and consciousness.”

Powerful new scientific tools are emerging that could allow scientists to better understand the human brain by studying the relatively simpler brains of mice. These methods allow scientists to alter genes, the instructions in DNA that control the behavior of cells – including the neurons that form brain circuits. By using genetic methods for mapping brain connections and controlling the activity of cells, scientists hope to generate detailed wiring diagrams of the brain and probe how these circuits function.

“While mice can not replace the work that is being done in monkeys, these research techniques are much further along in mice than in monkeys,” Callaway says. “The ability to modify neural activity using genetic tools and to study the resulting changes in brain and nerve activity is revolutionizing neuroscience.”

Although such genetic engineering techniques in mice offer huge potential, little was known about what areas of the mouse visual cortex – the high-level brain region that computes the meaning of signals from the eyes – were responsible for processing different elements of the visual information.

To remedy this, Callaway and his colleagues set out to chart a map of the mouse’s visual processing system. They injected mice with a calcium-sensitive fluorescent dye that glows when exposed to a certain color of light. The amount of calcium in nerve cells varies depending on the activity level of the neurons, so the scientists could measure the activity of brain cells based on how brightly they glowed.

The scientists then displayed different types of visual stimulus on a television monitor and recorded what parts of the brain glowed. To make the recordings, they used a high-resolution camera capable of discerning the activity of individual nerve cells.

They found that a mouse’s visual field, the area of three-dimensional space visible through its eyes, is represented by a corresponding collection of neurons in its brain. The researchers precisely recorded which neurons were associated with which area of the animal’s visual field.

The scientists studied seven different areas of the animal’s visual cortex containing full neuronal “maps” of the visible outside world, and found that each area has a specialized role in processing visual information. For instance, certain areas were more sensitive to the direction objects move in space, while other areas were focused on distinguishing fine detail.

With these maps of brain function in hand, the Salk researchers and others now have a baseline against which they can compare the brain function of mice in which circuit function is manipulated using genetic methods. Ultimately, Callaway says, understanding in detail how the mouse brain works will illuminate the workings of the human mind.

“This gives us new ways to explore the neural underpinnings of consciousness and to identify what goes wrong in neural circuits in the case of diseases such as schizophrenia and autism,” Callaway said.

Originally published by the Salk Institute for Biological Studies

One of the technologies, dubbed RECAP, is an extension for the Firefox browser that gives users free access to records from PACER, the pay-per-page system for accessing records of the U.S. Federal District and Bankruptcy Courts. PACER stands for Public Access to Court Electronic Records; RECAP is PACER spelled backward.

The other, FedThread, is a website that helps people parse the Federal Register, a daily publication of the federal government that provides highly detailed coverage of important rules, proposals and actions taken by the government.

Felten and Schultze are the director and associate director, respectively, of the Center for Information Technology Policy (CITP), a joint venture of the Woodrow Wilson School of Public and International Affairs and the School of Engineering and Applied Science that addresses crucial issues at the intersection of society and computer technology.

“Both of these projects evolved from a paper we published in the Yale Journal of Law and Technology,” said Felten, a professor of computer science and public affairs. “In that paper, we argued that the best way for the government to be transparent with digital information is to make it available in a raw but usable format and let the public decide what to do with it. The idea was to do more by doing less. The government can’t predict and shouldn’t limit what people will do with the data. So make it accessible but don’t insist on processing it for them.”

In developing the two systems, Felten and Schultze led groups of Princeton computer science graduate students that included Joe Calandrino, Ari Feldman, Harlan Yu, Bill Zeller and Timothy Lee.

After the U.S. Government Printing Office announced in September that it planned to release the Federal Register in the Web language XML, the Princeton students scrambled to build FedThread. The site, which allows users to more easily find and share documents and to follow certain policy issues, went live on Oct. 5, the same day the XML feed was released.

“The graduate students built the entire system from scratch in 10 days,” Schultze said. “They literally worked around the clock, with one or two of them dropping off every few hours to grab some sleep and then return to their computer screens. They showed remarkable teamwork in a marathon relay race of coding.”

In announcing the release of the new XML format, the White House blog and the administration’s “Open Government Progress Report to the American People” mentioned FedThread and Public Resource, a nonprofit transparency organization that uses the new feed to publish its own version of the register.

“The Center for Information Technology Policy and other organizations, such as Public Resource, demonstrated the tremendous value of this collaboration between government and the American people,” said Beth Noveck, the White House’s deputy chief technology officer for open government. “Together, we’re innovating to transform the Federal Register — the newspaper of our democracy — into a new platform for citizen engagement and participation.”

The RECAP project originated with a talk in February at Princeton by Schultze, who was then a fellow at Harvard University’s Berkman Center for Internet and Society before joining the CITP staff in the fall. The talk focused on the fact that people who want to access federal court records through the PACER system have to pay a fee for them, a hurdle that makes the information inaccessible to those who can’t afford the fees.

“It seemed like something was very wrong that the public did not have free access to court records,” Felten said.

In August, the CITP team, in collaboration with Schultze, launched RECAP, which allows people who purchase digitized court records from the PACER system to contribute the documents to a freely accessible repository stored by the Internet Archive in San Francisco. Other RECAP users can then search the repository and download the files for free and legally avoid paying the government-imposed fees for public records. In addition, the system offers a more comprehensive search function.

While other organizations, including Public Resource, have republished PACER documents online for free, RECAP harnesses the power of online social networking to allow people to share federal court documents. The repository currently holds more than 1.5 million court documents and is being used by lawyers, academics, students and journalists among others.

“The system is humming along now, and we’re building the document repository,” Felten said.

The projects to improve government transparency and provide easier access to public information inspired Felten and Schultze to organize a two-day workshop that will examine how digital technologies are transforming citizen access to government. The workshop, titled “Open Government: Defining, Designing and Sustaining Transparency,” will take place from 8 a.m. to 5 p.m. Thursday and Friday, Jan. 21-22, in the Friend Center Convocation Room.

Felten also has been teaching a course during the fall semester called “Civic Technologies,” which focuses on designing and building technologies that serve the public good. Students have worked on a range of projects, including a system to help UNICEF researchers in Senegal to conduct health surveys through mobile phones. Another project has involved creating a website that provides scientists and health organizations with better access to important malaria data.

“It’s not written in stone what the students will build,” Felten said. “Given access to raw data, people can do things you don’t expect.”

Originally published by Princeton University

Catherine Peters, an associate professor of civil and environmental engineering, tours the Homestake Mine in South Dakota, where she plans to test whether the greenhouse gas carbon dioxide can be stored safely underground. (Photo: Bill Harlan/Sanford Underground Laboratory)

Hoping to help fix the Earth’s atmosphere, Catherine Peters recently found herself 4,100 feet underground.

Peters, a Princeton associate professor of civil and environmental engineering, rode an elevator down a deep shaft into the Homestake Mine, a defunct South Dakota gold mine being transformed into an underground science laboratory. She toured the mine to plan for a research project that will explore whether factories that emit carbon dioxide, the gas primarily responsible for global warming, could instead safely pump it into the ground.

“They warned us that people who are claustrophobic may have problems,” Peters recalled later. “The elevator was an open cage and they warned us to keep our hands and fingers inside. It took us about 10 minutes to go down, and we could feel our ears pop.”

Together with collaborators at Lawrence Berkeley National Laboratory, Peters has received $750,000 in initial funding from the National Science Foundation to design an experimental facility in the mine to test what would happen if carbon dioxide stored underground were to leak up toward the surface.

“One of the main uncertainties and what is hindering this strategy for carbon mitigation is what will happen if there is a leak and it migrates upward,” Peters said. “What we are trying to do is reproduce the kind of processes that would happen in an actual sedimentary basin, the kind of geological formation where we might store carbon dioxide.”

Located in the state’s Black Hills region, Homestake was operated as a gold mine from 1876 to 2001 and reaches a depth of 8,000 feet. It was first used for scientific research in the 1960s, when physicist Raymond Davis of Brookhaven National Laboratory led a Nobel Prize-winning experiment to detect neutrinos emitted by the sun.

In recent years, a nonprofit organization, Sanford Underground Laboratory, re-established research facilities in the mine. Sanford’s efforts laid the groundwork for the National Science Foundation and Lawrence Berkeley National Laboratory to convert larger portions of the mine into the Deep Underground Science and Engineering Lab (DUSEL). The facility will be the world’s deepest laboratory, hosting physics, engineering, geoscience and biology experiments that can only be conducted under thousands of feet of rock.

The mine presents a unique opportunity to study the leakage of carbon dioxide through the ground, but not for the reasons one might expect. The regions actually being considered for storing carbon dioxide gas underground are sedimentary basins, such as those in Michigan, Illinois and Alberta, Canada, which boast vast layers of porous sandstone. Homestake’s tunnels cut through a more varied collection of rock and are inappropriate for underground gas storage. But the mine offers plenty of vertical space along with horizontal tunnels, known as “drifts,” that provide access at different depths and are perfect for Peters’ experiments.

Princeton engineers plan to build a laboratory in an old South Dakota goldmine to test whether carbon dioxide can be safely stored in the earth’s crust. The facility will consist of tall pipes (red) filled with sand to simulate the stone under which carbon dioxide gas might be stored. The pipes will pass through several vertical layers of mine tunnels (beige), which will allow scientists to more easily track how fast gas pumped into the bottom of the pipes moves upward. (Graphic: Dave Plate/Lawrence Berkeley National Laboratory)
Her team plans to build up to four pipes that are about two feet wide and nearly one-third of a mile high. To simulate a carbon dioxide leak from an underground reservoir into sandstone, they will fill the pipes with sand and water, pump carbon dioxide into the bottom of the pipes and track what happens as the buoyant gas travels upward. The pipes will intersect three or four of the drifts, allowing the researchers access to the pipes at various heights so they can easily measure the progress of the gas with sensors mounted at each level.

“It’s not something that we could study in some smaller system in the laboratory,” Peters said. “The physics don’t scale down.”

Scientists disagree on what will happen in the case of a CO2 leak. Some say the gas will diffuse into the sandy sediments as it rises and “fizzle out” before it reaches the surface. Others predict it will expand and become more buoyant as it moves upward, accelerating the leakage. Whether a leak involves large or small volumes of gas might also play an important role in how quickly the gas rises. “One can simulate with a computer both of these scenarios happening, but without experimental validation of those models we’re left wondering what’s going to happen,” Peters said.

She also hopes to address another matter of debate: how carbon dioxide will interact with layers of harder rock that might serve as caps to the gas reservoirs. When it dissolves in water, carbon dioxide creates an acid that some scientists propose will eat away at the cap rocks and eventually rupture the protective seal. On the other hand, the acid could react with chemicals in the rock to form hard deposits that reinforce the seal.

Peters is working with several colleagues in her department, including George Scherer, Michael Celia and Jean Prevost. Tullis Onstott, of the Department of Geosciences, also plans to use the facility to study how microorganisms found deep underground might provide insight into the origins of life.

The team is working to design for the facility, which will be called DUSEL CO2, within the next few months. Peters expects construction of their portion of the DUSEL facility to begin around 2016 and to see results from their first experiments as early as 2017.

In the meantime, general improvements will be made to prepare the mine to serve as a full-time research facility. “The first thing they’re going to do,” Peters said cheerfully, “is refurbish that elevator.”

Originally published by Princeton University

Researchers led by Olga Troyanskaya (right), an assistant professor in the Department of Computer Science and the Lewis-Sigler Institute for Integrative Genomics, have developed a website that brings together genetic data from various sources to help scientists better understand ailments such as Alzheimer's disease, diabetes and cancer. Curtis Huttenhower, a postdoctoral researcher in Troyanskaya's lab, developed the site. The two are shown here with the website projected on the display wall behind them in Icahn Laboratory. Photo: Brian Wilson

Princeton researchers have created a Rosetta Stone for the human body, a website that offers clues to the role DNA plays in aging and disease by helping scientists make sense of the vast jumble of information emerging from genetics research.

By mashing up genetic data from disparate sources and interpreting it with the help of computer algorithms informed by biological principles, the online system allows scientists to predict which genes might be involved in ailments such as Alzheimer’s disease, diabetes and cancer.

“The scientific community has produced millions of points of genetic data in recent years, but has not achieved an equivalent understanding of how genes work,” said Olga Troyanskaya, the Princeton professor who led the project. “We need to translate this into knowledge about disease.”

Reflecting Troyanskaya’s joint appointments as an assistant professor in the Department of Computer Science and the Lewis-Sigler Institute for Integrative Genomics, the new website exists at the nexus of computers and genomics, the field of biology concerned with mapping organisms’ entire DNA and understanding how genes interact to keep an organism healthy or cause disease.

“Olga has now emerged as a world leader in analyzing and displaying vast amounts of functional data so that the ordinary biologist can understand them,” said David Botstein, the Anthony B. Evnin Professor of Genomics and director of the Lewis-Sigler Institute.

In conjunction with launching the new site — which was developed by Curtis Huttenhower, a postdoctoral researcher in Troyanskaya’s lab — the team’s paper on its methodology, titled “Exploring the Human Genome With Functional Maps,” was published in the May issue of the journal Genome Research.

The site is based on the principle of “functional mapping.” The term is shorthand for mapping out the tangled web of relationships among genes, based on how they work together in cellular function. A single gene, for example, might help a cell become heart or brain tissue, but a cell’s overall function emerges from the interactions of many genes.

Understanding these functional relationships is key to developing new medical treatments, since most medications target proteins — the primary product of genes. Proteins are complex molecules that serve as cogs in the cellular machinery or, in the case of disease, wrenches in the works.

Genomics researchers seek to understand which genes and proteins are involved in certain aspects of cell function. Is a protein part of the mechanism that produces energy for the cell? Does it work in concert with other genes to control aging? Does it help control the metabolic rhythms that serve as the basis of humans’ biological clocks?

Working out how genes keep cells running normally helps scientists understand what goes wrong in the case of a harmful genetic mutation. Discovering a link between a gene and a disease can tell researchers what cellular processes are involved in the disease, which in turn fingers other genes involved in those processes as potential culprits.

But discerning these connections is no easy feat. Discoveries of genes resemble early discoveries of Egyptian hieroglyphs: Finding a new one doesn’t mean researchers understand its purpose or how it fits into the larger system.

While Egyptologists struggled to decode the meaning of around 2,000 hieroglyphs, genomics researchers are faced with an estimated 20,000 to 25,000 human genes that could potentially interact with each other in 300 million different ways.

With so many genes and so many possible avenues of inquiry, predicting which genes and relationships are important in certain diseases, and therefore worthwhile to study, presents an enormous challenge. It involves a lot of guesswork.

This is where computers come in handy. The computer program created by Troyanskaya and the other computational biologists working on the project sorts through 350 sets of genome data from thousands of separate experiments.

The program relies on artificial intelligence algorithms, similar to those used by government intelligence agencies to sort through the data collected as part of anti-terrorism programs and by online commerce websites, such as Amazon and Netflix, to recommend products to customers.

Dubbed the Human Experimental/Functional Mapper, or HEFalMp, the site focuses on discerning connections among genes, biological processes and diseases to help scientists determine which relationships are most important.

Entering “breast cancer,” for instance, returns a list of all the genes in the site’s database ordered by the probability that they are involved in the development of the disease. Three genes at the top of the list — BRCA1, BRCA2 and TP53 — are known to play an important role in the development of breast cancers, but other genes high on the list also could be involved. The site allows researchers to explore how these genes work together and the likely reasons they play a role in breast cancer.

“Knowing which genes are most likely to be involved helps researchers choose where to focus,” Troyanskaya said. “The program determines the significance between a gene and a disease based on a rigorous analysis of published data.”

“This is a magnifying glass,” she said, “that shows you what is trustworthy and what is relevant.”

Troyanskaya anticipates that molecular biologists will begin using the site following publication of the paper. Hilary Coller, an assistant professor of molecular biology at Princeton who co-wrote the paper with Troyanskaya, used the site to link genes to an important cellular process, known as autophagy, by which nutrient-starved cells digest parts of themselves to ensure survival. The results of the laboratory tests were published in the paper.

Members of Coller’s research group continue to use the site to understand the results of their laboratory experiments and to provide clues to new avenues of research.

“In the past, everyone did their own experiments and came to their own conclusions,” she said. “It was rare that anyone actually compared results, in part because it was overwhelming. There was always this sense that if someone pulled all of this information together it would be valuable. The new site does an intelligent job of mining a lot of data and putting it into an intelligible form.”

Originally published by Princeton University

The researchers modified algal chlorophyll to create a molecular structure similar to chlorosomes, the antennae that photosynthetic bacteria use to harvest sunlight for energy.

While the light-driven chemical reaction by which the chlorosomes convert sunlight to chemical energy has not yet been replicated, engineering the basic structure of the antennae helps pave the way to pigments that could be spread on flat surfaces to collect energy from sunlight and used as engine fuel.

“The scope of our research is solar fuel – non-fossil fuels made by direct solar energy conversion”, says Huub de Groot, a biophysicist at Universiteit Leiden (The Netherlands). “We are aiming for renewable fuels from solar energy, using water as the raw material. The introduction of new CO2-lean fuel concepts, based on renewable resources, is spurred by worries about global warming and decreased availability of oil and gas.”

Chlorosomes in bacteria evolved to harvest the tiny amount of light found in dark places, such as the deep sea, and are the fastest light-collecting antennae in nature. However, the color of the chlorosomes is wrong for the chemical processes required to make artificial pigments for use as solar fuels.

To get around this limitation, German researchers in de Groot’s team, from the University of Würzburg, used a chemical process to modify chlorophylls from the Spirulina alga to resemble the chlorosomes found in ultra-efficient bacteria.

De Groot’s group in Leiden then studied the structure of the semi-synthetic chlorosomes using a combination of imaging technologies – nuclear magnetic resonance (NMR) and x-ray diffraction. The x-ray technique enabled them to determine the overall structure, whereas NMR allowed them to understand the detailed molecular makeup of the antennae.

According to de Groot, the pigments could one day be used to convert sunlight to fuel at special facilities, or by spreading it on flat surfaces of existing infrastructure, such as roads, parking lots, or buildings.

“In the US, to cover land the size of Wyoming would not be a problem”, he says, “but in Europe, space is an issue, and integration [with existing infrastructure] will always be beneficial”.

The research team is currently studying the process by which the chlorosomes convert light to chemical energy and hopes to have a working prototype of an artificial pigment in about 5 years.

Published in Frontiers in Ecology and the Environment

Employing modern genomics and proteomics techniques, the researchers found that Shewanella, an adaptable genus of bacteria found both in the oceans and on land, was more diverse than traditional microbiology approaches would suggest (P Natl Acad Sci USA 2009; doi:10.1073/pnas.0902000106).

“With many classical techniques, some of these bacterial strains would be indistinguishable from one another”, explains lead researcher Kostas Konstantinidis (Georgia Institute of Technology, Atlanta), “but when we gave them different heavy metals to grow on, some
expressed completely different proteins, even though they supposedly belong to the same genus.”

Because of their ability to metabolize a variety of metals and compounds, Shewanella holds promise as an environmental cleanup organism that could mitigate toxic spills or serve as
a pollution indicator. Determining which species of Shewanella would work best for cleaning up a certain toxin requires understanding their ability to metabolize certain the toxins into something not harmful to other organisms.

Using traditional microbiology techniques that focus on genetic material in the ribosome, the site of protein synthesis in bacteria, Konstantinidis and his colleagues found ten different strains in the Shewanella genus. But when they analyzed the bacteria using genomics (an analysis of the entire genome) and proteomics (an analysis of the full range of proteins produced by the bacteria), the researchers found greater diversity.

Some bacteria that were lumped into a single strain shared only 70% of the same genes. Nearly half of the 10,000 genes in the genus were found only in certain strains, and the assortment of proteins each strain produced was greater than that predicted by their genetic differences.

“We’re trying to get more scientific about doing this”, continues Konstantinidis. “During the past couple of decades, we mostly studied one gene at a time, but now we study a whole cell at a time, with all the genes and all the protein pathways that are expressed.”

Konstantinidis points out that systems-level approaches – as whole organism approaches that employ genomics and proteomics are typically called – could be used to determine which Shewanella strain might best be used for cleaning up certain toxic compounds.

Conversely, by measuring the activity of certain Shewanella genes or proteins, scientists might be able to use the bacteria to determine whether a toxin is present in a certain location.

Published in Frontiers in Ecology and the Environment

Princeton engineers, assistant professor Michael McAlpine and graduate student Manu Mannoor, have developed an electronic chip that may replace horseshoe crab blood for testing drugs and medical devices for contamination and could relieve pressure on two threatened species of animals. (Photo: Frank Wojciechowski)

Princeton engineers have developed a sensor that may revolutionize how drugs and medical devices are tested for contamination, and in the process also help ensure the survival of two species of threatened animals.

To be fair, some of the credit goes to an African frog.

In the wild, the African clawed frog produces antibacterial peptides — small chains of amino acids — on its skin to protect it from infection. Princeton researchers have found a way to attach these peptides, which can be synthesized in the laboratory, to a small electronic chip that emits an electrical signal when exposed to harmful bacteria, including pathogenic E. coli and salmonella.

“It’s a robust, simple platform,” said Michael McAlpine, an assistant professor of mechanical and aerospace engineering at Princeton and the lead researcher on the project. “We think these chips could replace the current method of testing medical devices and drugs.”

McAlpine collaborated on the project with Manu Mannoor,  graduate student who works in his laboratory, and with James Link, an assistant professor of chemical and biological engineering, and Siyan Zhang, a graduate student in chemical and biological engineering.

A paper outlining their development of the sensor was published online October 18 in the Proceedings of the National Academy of Science. The research was funded by the American Asthma Foundation and by the Air Force Office of Scientific Research.

The current testing method has a major drawback: It relies on the blood of the horseshoe crab, a species that is roughly 450 million years old. The horseshoe crab population has declined in recent years, and as a result, so too has the population of a bird that feasts on the crab.

The crab became desirable for testing because its immune system has evolved to cope with the constant threat of invasion from its bacteria-rich environment. Its blue-colored blood contains antimicrobial cells, known as amebocytes, that defend the crab against bacteria — similar to the way the peptides protect the African frog’s skin.

For almost 40 years, an aqueous extract made from horseshoe crab blood cells, called Limulus amebocyte lysate (LAL), has been used for testing drugs and medical devices for contamination.

In the era before the use of these animal extracts for testing, although drugs and medical devices were sterilized, they would sometimes cause patients to develop fevers due to an immune reaction to endotoxins, which are remnants of bacteria destroyed by the sterilization process. When a sample from a drug or device is added to LAL and the solution hardens into a gel, it indicates the sample is contaminated and not safe for human use.

New approach could help save animal populations

To produce LAL, the crabs are captured and roughly 30 percent of their blood drained before they are returned to the ocean. There is disagreement on how many crabs die as a result of the procedure, but their estimated mortality rate can be as high as 30 percent, according to the United States Geological Survey.

A conservative estimate puts the number of horseshoe crabs on the Atlantic Coast between New Jersey and Virginia at between 2.3 to 4.5 million, according to the Ecological Research & Development Group. In recent years, the populations of the horseshoe crab and shore birds that rely on them for food both have been in decline, with the red knot, a rust-colored species of shore bird, of particular concern.

Each spring the bird migrates 20,000 miles from the islands of Tierra del Fuego, off the southern tip of South America, to the Delaware Bay on the east coast of the United States. From April to May, the bird feasts on horseshoe crab eggs found on beaches, nearly doubling its body weight to sustain its health for the long flight south.

Studies have discovered a precipitous decline in the red knot population. One study by researchers at the University of Toronto found that the Tierra del Fuego population of red knots declined from 53,000 birds to 27,000 birds between 2000 and 2002.

The decline has been linked to the reduction in the number of horseshoe crabs, as a result of harvesting their blood for medical testing and their use as fishing bait for eel and conch.

In response, Delaware, Maryland and New York have limited the number of crabs that can be harvested each year to less than 150,000, and New Jersey has implemented a moratorium on harvesting the crabs. In 2009, since implementing the measures, the number of red knots visiting Delaware Bay was estimated at 24,000, up from 18,000 the year before, but still far lower than the population of 100,000 to 150,000 of two decades ago.

The researchers hope that technology based on their electronic chip will eventually replace LAL as the standard for contamination testing, obviating the need for horseshoe crab blood and helping both the crabs and the red knots rebound.

At the same time, producing this new sensory device would not put pressure on the frog species. “No frogs were harmed in the making of this sensor,” he said.

Published on the Princeton University website.

“For the first time we have used stem cells to rewire part of the nervous system,” said Dr. Douglas Kerr, the lead researcher.The multipronged procedure, which requires the use of drugs and proteins as well as implanted stem cells, re-established the electrical path from the rats’ brains, down their spinal cords and out to their muscles, Kerr said.

The results, released yesterday, are to be published in the journal Annals of Neurology. The study was funded by several organizations, including the National Institutes of Health and the Muscular Dystrophy Association,

One obstacle to applying the treatment to people is the length of the spinal cord, said Clive N. Svendsen, a researcher at the University of Wisconsin. He said implanted stem cells would have to grow farther to reach inactive muscles and that it is difficult to get spinal neurons to survive when transplanted into humans.

“It is a great proof-of-concept paper, but it doesn’t address everything,” Svendsen said of the Hopkins study.

Kerr said he is planning a study in pigs to determine whether his team’s technique will work in larger mammals.

Clinical trials in humans are a possibility within five years, said Kerr, but he cautioned that human therapy is years away.

Yet, he says the work is a big step forward in the quest for a cure for paralysis and other neurological disorders.

“It’s not imminent, but it is a realistic hope,” he said. “It used to be science fiction, but it is now a realistic possibility.”

He said the speed at which his research progresses would in large part be dictated by the availability of funding, which has become more difficult to obtain in the face of political opposition to research on human embryos.

In their Baltimore laboratory, Kerr and his colleagues inserted mouse stem cells into the spinal cords of paralyzed rats that had little or no use of their hind limbs. Kerr and his team initially paralyzed the rats with a virus that killed the neurons that connected their spinal cords to their leg muscles.

The scientists then used a cocktail of proteins and drugs to coax the implanted nerve cells to make connections with spinal nerves coming from the brain and to grow out of the spinal cord to connect with the animals leg muscles.

Of the 15 rats that received the full treatment in the study, 11 showed significant improvement in their ability to control their hind limbs 24 weeks after the stem cells were implanted.

The scientists found that if any one of the factors was removed from the treatment – the stem cells or any of the two proteins and three drugs they used – the rats showed no improvement in their ability to stand and walk. The most important finding, Kerr said, was that all of the factors were needed for the animals to regain function.

“This is a blueprint for how to rewire part of the nervous system,” he said.

He said the results suggest that embryonic stem cells may one day be used to treat human neurological disorders such as Lou Gehrig’s disease, multiple sclerosis and spinal injuries.

The researchers used embryonic stem cells because they possess the unique ability to become any other type of cell.

Before the cells were implanted, the researchers stimulated them with a cellular protein and Retin-A, an organic compound that plays a role in the growth and development of embryos. That prompted some of the stem cells to begin developing into nerve cells.

The researchers then implanted tens of thousands of the cells into the rats’ spinal cords. Next, the team injected another protein near the rats’ leg muscles to coax the cells to grow out of the spinal cord and attach to the muscles.

“This is very different than a lot of what’s been reported on in recent years,” said Naomi Kleitman, a neurology researcher at the National Institute of Neurological Disorders and Stroke. “I haven’t seen anything like it before.”

She said most studies have focused on the nerve cells in the spinal cord that connect to the brain. Kerr’s protocol focuses on cells known as lower motor neurons, which connect the spinal cord to muscles.

“If I want to move my arm or my leg, my brain has to tell my spinal cord and my spinal cord has to tell my muscles,” she said. “This research looks at fixing the problem of what happens when nobody is there to answer that call.”

Despite the success of the study, Kerr expressed concern that he might struggle to obtain funding if he tries to extend his research to humans.

“The amount of money required to take this into clinical trials is ultimately hundreds of millions of dollars,” he said. “Without federal funding, that money is going to be difficult to find.”

Early last year, President Bush restricted federal funding of embryonic stem cell research. Bush and some other religious conservatives oppose research using embryonic stem cells, citing ethical concerns.

But Kerr said his team had to use embryonic stem cells because adult stem cells could not be coaxed into developing into spinal neurons and healthy adult neurons die when implanted into the spinal cord.

To make up for the loss of federal money, several states – including Maryland – have begun offering state funding to embryonic stem cell researchers.

This spring, the General Assembly voted to provide $15 million in state funding to stem cell researchers in Maryland.

Kerr said he plans to apply for state funding once the commission that is to administer the research grants has been formed.

Published in The Baltimore Sun