Power of 3

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Understanding the basic properties of mixing fluids

As a child in France, Thomas Cubaud grew up watching rivers, waves in the ocean, tides, and even the vortex that formed as bathwater ran down a drain.

Fast forward to now and the assistant professor at Stony Brook University has turned his passion for understanding the way fluids move and interact with each other into an award-winning developing career in mechanical engineering.

Cubaud works in a field called microfluidics. That means he mixes tiny amounts of different kinds of fluids (often very viscous or thick liquids with less viscous liquids or solvents). In addition to producing magnificent images, he also tries to understand the nature of the way these liquids mix.

Microfluidics is a relatively new science that was developed about 30 years ago. It has applications in a wide range of fields and helped produce such products as inkjet printheads, DNA chips, and microthermal technologies.

While aware of the potential applications of his research, Cubaud is much more focused on understanding the basic properties of mixing.

When researchers like Cubaud mix a very viscous liquid with a solvent in small amounts, they maximize the surface area (or points of contact) between the two liquids. While that could be an advantage in mixing, they also see what’s called laminar flow, where those two liquids form parallel layers and glide past each other, rather than mixing.

Enter viscous buckling. To picture this, take honey from a pantry and pour it on toast. As it comes out of a jar held a few inches above the toast, the honey falls in lines back and forth, looking like coiled rope. If the honey were falling through another thick liquid instead of air, the buckling back and forth would promote turbulent flow (converting the laminar flow — not good for mixing — into turbulent flow — much better for mixing).

One of the goals of Cubaud’s research is to understand the role of different properties, such as viscosity and surface tension, on the flow of fluids on a small scale.

In his experiments, Cubaud varies the speed at which he injects one fluid into another, the pressure and the thickness of the liquids.

Cubaud’s research showed sufficient promise that he recently won the Career Award from the National Science Foundation, which will give him $400,000 over a five-year period.
The award is given to promising young faculty members at universities around the country to support their teaching and research.

“The challenge is to find the best operating condition. We need to do experiments with different materials and new methods to characterize the flows,” he said.

Jon Longtin, an associate professor at Stony Brook and Cubaud’s mentor, sees considerable promise in his junior colleague.

“He is a genuine top-notch scholar,” Longtin said. “When he gets his arms around an idea, he wrestles it to the ground until he figures out exactly what is going on.”

Longtin said microfluidics has become a hot topic in science, which means there is increased competition for funding.

“He has carved out a niche for himself,” Longtin described. “He’s looking at fluids that have disparities in thickness. He found interesting things that happen that are not necessarily obvious. He’s had a lot of success.”

Cubaud’s research also examines a process called carbon sequestration, where carbon dioxide is removed from the air and absorbed into liquids.

“Injecting carbon dioxide gas with liquids in microgeometries permits us to significantly increase the surface area of contact between the fluids,” he said. “The knowledge that will be gained during the project will help frame future carbon sequestration applications.”

Cubaud pointed to a biological system that already uses microscale interactions between gases and liquids: the lungs, where blood gives up carbon dioxide and takes in oxygen.

Microfluidics allows scientists to achieve a basic understanding of new physical interactions, he said.

“A key aspect of miniaturization technology is that, up until recently, we could only observe phenomena,” he said. “Today, not only can we observe, but we can also directly intervene on small-scale mechanisms.”

Echoing the observations of the young boy in France who watched rivers, oceans and whirlpools in a bathtub, Cubaud said: “When you just do an experiment, you find unexpected results. It’s very exciting to see something possibly unexpected occurring.”

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Cold Spring Harbor scientist’s discoveries also focus on cancer treatment

One Sunday in the fall of 2010, Alea Mills needed a break from one of her more mundane jobs — writing proposals to get money. She decided to check on her mice.

When she did, she couldn’t contain her excitement. She’d worked with mice for years and yet these were clearly different. She called her husband Ross Maddalena, an actor who doesn’t particularly enjoy visits to her lab — especially during a football Sunday.

“Please, please, please,” she begged. “You have to come. I need somebody else to observe this.”

Maddalena, an extra in movies like “Mr. Popper’s Penguins” and “Salt” who has taken cues from his wife’s career as he followed her from California to Texas to Long Island, drove to her lab at Cold Spring Harbor, where she has conducted research since 2001.

Even without any scientific expertise, Maddalena recognized the changes. Mills had created a mouse model for autism. Using a hand-held video camera, he recorded the mice. Mills said she has watched the movie dozens of times.

A researcher who has made important cancer discoveries, Mills took the unusual step of using her expertise in chromosome engineering — changing the genetic blueprint of an animal — to study autism.

“I saw [autism] as a genetic problem,” Mills said. “We can generate models where we can make the same precise changes as in various diseases.”

By using a form of molecular scissors, Mills took out a 27-gene region on chromosome 16 in mice.

“We didn’t know what to expect,” Mills recalled. “Could we see anything different with respect to the behavior or the brain anatomy of the mice? The answer is yes. Those genes are regulating fundamental processes that are evolutionarily conserved to some degree and are causing the same type of changes.”

Indeed, these genetically altered mice also showed eight regions in their brains that were larger than normal.

Her results, which were published last October in the prestigious journal Proceedings of the National Academy of Sciences, created a buzz in the world of autism research.

At this point, Mills, who is a resident of Lloyd Harbor, is fine-tuning her autism research to look at even smaller areas within that genetic region. She is also looking more closely at the brains of these mice to see if she can connect some of the more severe behaviors to the biggest changes in brain structures.

While extending this research to understanding the development of autism in humans remains a challenge and will require considerably more work, Mills said this could prove an important step in diagnosis and treatment.

People typically show signs of autism at around 2 or 3 years old, Mills said. In mice, Mills and her postdoctoral research fellow Guy Horev can often detect changes in one to two days after birth.

Researchers like Mills need to figure out the mechanism in which these genes might lead to autism and, once they do, work on a potential clinical model to correct it. Mills cautions that there is considerable work left to do to understand the pathways that lead to autism in humans.

While she will continue to oversee autism research, Mills will also direct and conduct studies on cancer, where she discovered Chd5 and p63. Scientists had long sought Chd5, a gene that produces a protein that prevents cancer. Indeed, the amount of Chd5 protein a patient has is a predictor of treatment outcome for cancer patients. The p63 gene, meanwhile, produces some proteins that suppress cancer, while it manufactures others that promote it. The effect of p63 depends on the type of cell.

Perhaps Mills’ upbringing on a 60-acre piece of property in upstate New York made her comfortable looking out to the horizon for answers to a wide range of questions. The only girl in a family of five children, she said she and her siblings “ran rampant.”

At the same time, when Mills was as young as 3, her mother often encouraged her to slow down and look closely at a small piece of grass, where she could study a flower or a worm.

Those days of watching worms brought her to Cold Spring Harbor, where she witnessed the excitement of her own breakthrough with the first mouse model of autism one Sunday in 2010.

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Working to lower heating bills, pollution and dependence on foreign oil

Tom Butcher doesn’t just stand around at the water cooler and complain every time he gets a heating oil bill — he’s doing something about it. The head of the Brookhaven National Laboratory’s Energy Resources Division, Butcher is conducting the kind of research he hopes will lower our heating oil bills, create less pollution, and reduce our dependence on foreign oil.

For starters, he is working on ways to displace import petroleum with domestic biodiesel. As it stands now, fuel that heats our homes can have 5 percent biodiesel — or fuel made from substances like soybeans and waste from restaurants. Butcher has his sights set on a much higher target.

“The legal definition of heating oil has changed so that it can have as much as 5 percent biodiesel,” Butcher explained. “Getting that done was a big step. Where our research is focused is on increasing that limit and going well beyond it. From a technology perspective, there are some challenges in doing that.”

Butcher and his colleagues at BNL and his counterparts at Stony Brook have been examining numerous technological hurdles. One of those. Butcher said, is looking at the reliability and safety of existing equipment designed to house oil-based fuels when liquid fuels, including fuels from soybeans and waste oils pass through them.

The “rubbers in a pump shaft may degrade and lead to leaking components,” Butcher said. “The key issue” in raising biofuel content is that there is a “lack of experience in some important areas, including the compatibility of field materials, including elastomers and rubbers,” Butcher said.

Butcher is also interested in examining how to reduce pollution and improve the efficiency of burning wood as a heat source.

“In rural New York state, wood burning is the number one source of air pollution,” he warned. “On the track we’re on, [wood burning] threatens to become a dominant source of air pollution in the Northeast.”

Burning wood is something consumers generally warm to because it “puts people to work and is a renewable energy source,” Butcher described. “A lot of our work is focused on how to burn wood cleanly. How do you develop test methods that can accurately capture the performance of the currently available leading-edge wood conversion combustion technology?”

Butcher is examining the effectiveness of electrostatic precipitators, which use a high-voltage field across the exhaust gas, where captured particles migrate to a wall, fall down and get removed. He is also examining heat exchangers that can be used to condense water vapor from the exhaust gas and wash the particles out.

“If we are going to continue to use wood for heating, this is a road we have to go down,” Butcher insists. “I don’t think we’re going to have a choice.”

The BNL investigator said there are already technologies on the market that are much better than the average pellet burners, some of which keep fuel from smoldering, especially during periods when a house doesn’t need heat. A key to this system is thermal storage, where systems run at their optimal condition and charge the storage. The stored energy can heat the home while the burning system is off.

Butcher and his wife Donna, who works in a dental office and as a real estate agent, have raised four children who have all shown interest in technical fields. Their eldest, Kim, is an aerospace engineer who works for NASA on the technology for future space travel. Matt is working on his Ph.D. in biology at Eastern Virginia Medical School and is focused on heart disease. Jon will complete his doctor of pharmacy degree at Long Island University at the Brooklyn campus in just over a year and is, in the words of his father, “a fanatic fisherman.”

Not to be outdone, Jamie, who worked at BNL last summer on radiation detectors, is at Geneseo and “will undoubtedly develop a career that involves something technical in collaboration with something international.”

As for Tom Butcher, who lives in Port Jefferson with Donna, the common theme for the work he’s tackling now is “given the high price of oil, what do we do?”

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Studying both brain and bone cells to defeat two mountains: Alzheimer’s, osteoporosis

Lisa Miller lives a life of extremes. At work, she looks inside brain and bone cells through some of the highest-tech equipment in the country, checking the chemistry of diseases like Alzheimer’s and osteoporosis. In her free time, the Brookhaven National Laboratory’s Associate Division Director climbs mountains, looking out at the world from the planet’s highest peaks.

Using mid-infrared light, Miller, who is in BNL’s Photon Sciences Directorate, has shown that some areas of the brains of people afflicted with Alzheimer’s disease have high amounts of metals like copper and zinc.

“Metals in our body are tightly regulated and are bound to proteins,” Miller explained. On their own, the metals could be “toxic and can kill cells.”

The brains of people who suffer from Alzheimer’s have amyloid plaques, where brain cells are folded over and clumped together. These plaques have high amounts of these metals.
Using the National Synchrotron Light Source (one of only four such Department of Energy funded tools in the country), Miller wanted to examine how the metals might build up in the brains of those with Alzheimer’s.

Because the concentration of iron in the amyloid plaques is ten times higher than normal, the presence of this metal could be an important diagnostic tool.

MRIs and other tools in doctors’ offices can measure the concentration of iron in a person’s brain.

“It’s possible to image patients who don’t have symptoms yet for high iron content,” Miller offered. Miller cautioned that it’s unclear whether there is a direct connection between the presence of these metals and the onset or course of Alzheimer’s disease.

Indeed, the BNL faculty plans to examine the link between copper in the plaques with disease severity. If the presence of metal is an important part of the progression of the disease, it shouldn’t show up in people who have amyloid plaques but don’t have symptoms. Miller is helping to hire scientists and engineers at BNL to build the next generation light source that uses x-ray, ultraviolet and infrared light. The NSLS-ii, which will be complete in March of 2014, will produce x-rays that are more than 10,000 times brighter than the ones from the current NSLS.

“She’s taken an active role in managing the facility,” said Antonio Lanzirotti, a senior research associate at the University of Chicago who collaborated with Miller on her Alzheimer’s studies. “She’s incredibly impressive in terms of her breadth of knowledge. People respect her opinion at the highest level of management.”

In addition to Alzheimer’s, Miller has also used the NSLS to study osteoporosis.
Partnering with biomedical engineer Stefan Judex at Stony Brook University, Miller and her lab have looked at how osteoporosis drugs affect the chemistry and strength of bones.
Fosamax and Actonel “work really well, not only in slowing down the resorption of bone,” she said, but also in helping the body produce “good, quality bone.”

When she’s not studying the chemistry of bones, brains and other tissues, Miller is an enthusiastic backpacker. She has climbed to highest point in 48 of the 50 U.S. states. Last year, she trekked to the top of Mt. Kilimanjaro.

A native of Cleveland, Miller took her first hike when her father “dragged us to the top of Mount St. Helens” when she was in graduate school at the Albert Einstein College of Medicine. Once she got the climbing bug, she couldn’t stop.

Miller believes in helping the next generation of researchers reach its own scientific peaks.
She helped start a new BNL program called Introducing Synchrotrons into the Classroom (called InSynC) that allows high school students to design research studies that use BNL’s synchrotron.

The projects, which go through a competitive review process, give students and teachers a chance to test their ideas using the NSLS. Miller credits her advisors with guiding her career and wants to pass that long.

“I always had good mentors,” she recalls. “If you’re excited about something, you want others to be as well.”

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Some people like slamming things together, whether it’s a young child sitting on a floor crashing two matchbox cars into each other or an adult behind the wheel of a bumper car at a fairground.

Gene Van Buren gets to do the same thing, although he’s not using cars. He’s propelling a gold nucleus along a 2.4-mile track at speeds approaching that of light and slamming it into another gold nucleus.

The effects of the collision are more spectacular, albeit on a miniature scale, than watching the bumper pop off a matchbox car. The temperatures in these crashes climb to 4 trillion degrees Celsius. That’s 250,000 times hotter than the temperature in the center of the sun.

“The day when we get to see what [such a collision] looks like on a computer screen, we are all like a bunch of kids,” said Van Buren, an experimental nuclear physicist at Brookhaven National Lab. “It’s so cool. It’s what we’ve been working for for the past decade to do. We remember how exciting this is.”

Besides doing it because they can, nuclear physicists like Van Buren who work at the Relativistic Heavy Ion Collider (RHIC) study the results of those nuclear mash ups to gain a better understanding of the way nature works at very small scales.

When they’ve jammed these tiny particles together, they’ve been able to examine the way smaller ones, like quarks and gluons, interact. Quarks are the building blocks for protons (matter with a positive charge) and neutrons (those with a neutral charge). Gluons, which don’t have mass, serve as the “glue” that holds quarks together.

“From a theoretical calculation, we expected that once you got these gluons and quarks really hot, they wouldn’t want to interact with each other,” he said. Their collisions, however, showed the opposite, that these subatomic particles “still want to stick to each other.”

What that means is that the parts of the nucleus of an atom behave much more like a liquid than a gas. In a gas like air, Van Buren explained, molecules tend to flow freely away from each other. Liquids like water, on the other hand, tend to bind together. That is why water forms droplets when it is spilled.

“For us, this is very exciting because it has implications for the nature” of how these particles behave, “under normal, everyday conditions that we don’t necessarily observe from our perspective of everyday life,” Van Buren said.

At the same time, these experiments may simulate the kinds of conditions that existed during the beginning of the universe, at least according to the big bang theory. At RHIC, colliding these nuclei at such high speeds is similar to making a “little bang.”

The biggest difference, however, is that RHIC doesn’t collide matter with as much “stuff.”
“In the big bang, the universe started out dense and hot with a lot of material and energy. In our case, we have two out of those three” conditions, Van Buren said. “We have the density and heat.”

Still, by examining high temperatures and density, the scientists at RHIC may be able to see “how the universe evolved during that particular epoch.”

Van Buren said down the road, maybe decades of even a hundred years from now, other scientists can use the knowledge he and others are generating at RHIC to engineer new products.

“It was like that with electricity,” he said. “The first people studying it had no idea how this would affect their everyday life. Over 100 years later, look what electricity does. We can learn to engineer things with the knowledge we gain about the universe.”
Physicists like Van Buren are inspired by the first dozen years that RHIC has been operating (its first experiment was in the summer of 2000).

The scientists “have the pioneering spirit of climbing to the top of Mount Everest,” offered Jim Thomas, a visiting physicist from Lawrence Berkeley Lab in California who has worked closely with Van Buren for several years.

In addition to designing collision experiments, Van Buren has helped create computer programs that analyze the results of the collisions.

Van Buren “understands a lot about computers and a ton about physics,” said Thomas. “He’s able to make the physics/ computer connection very nicely.”

If Van Buren ever needs to consult with a computer-programming expert, he doesn’t have to look far. His wife Marie Van Buren, whom he met when he was at graduate school at the Massachusetts Institute of Technology, is a computer programmer at BNL.

The couple met when they joined a volleyball league at MIT. Marie, who is around 5 feet tall, sometimes sets up her 5-foot-10-inch nuclear physicist husband to spike the ball when they are on the same team.

Sports have always been an important part of Van Buren’s life, whether it was soccer in high school, track and racquetball in college or volleyball and, in summer, ultimate frisbee.
Residents of Middle Island, the Van Burens have lived on Long Island since 1998, when Gene did his post-doctoral work for UCLA at Brookhaven National Lab.

As for his research, Van Buren said his primary goal is “pure research,” in which the end result is knowledge, not a product. The basic knowledge of nuclear physics may one day pave “the way for new developments that perhaps no one today can dream.”

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When their son Dylan was under a year old, Debbie and Ron Cuevas noticed he couldn’t support his head and had trouble rolling over. They brought him to a pediatrician, who diagnosed Dylan with spinal muscular atrophy.

The doctor said he likely had two years to live. Determined to make every day count, the Cuevas family of Rockville Centre has rallied around their son, who is now 8 and in third grade.

A genetic disease with varying severity that weakens muscles in the central nervous system, spinal muscular atrophy (or SMA) has no current cure. Some with the disease die because they can’t breathe or swallow. SMA is the leading genetic cause of death among infants and affects about 1 in 6,000 newborns.

Researchers, including Dr. Adrian Krainer at Cold Spring Harbor Laboratory, however, have been working to find a treatment. Krainer has unlocked a potential solution. His work with antisense oligonucleotides (or ASOs) has been impressive enough in the lab and on mice that California-based Isis Pharmaceuticals started using his treatment in the first phase of clinical trials in December. It’s too early to determine the effectiveness of this approach.

SMA is a genetic disorder and is caused by a defective SMN1 gene, which is on the fifth chromosome. That gene produces the survival of motor neuron protein. Without enough of that protein, the motor neurons in the spinal chord gradually die and the muscles they control cease to function.

The solution to this recessive genetic disease may be in the genes themselves. There is a backup gene, called SMN2, that produces the same protein. The problem in children with the disease is that the backup often doesn’t produce enough protein or the protein isn’t complete or breaks apart.

Krainer’s lab has aimed one of its efforts at improving the function of SMN2. The problem with SMN2 is in something called splicing, a process where important pieces of genetic information (exons) are linked together while white noise (introns) is spliced or cut away. The exons are like the proverbial wheat and the introns are the chaff.

As DNA and its cousin RNA go from the genetic blueprint stage to the protein-building stage, there are signposts along the way that indicate whether the next set of genetic instructions is an exon or an intron. A repressor sits on SMN2 at exon 7 that mistakenly sends the cell’s RNA machinery away. The repressor acts like a “Do Not Enter” sign, making it hard for the cell’s machinery to recognize an exon.

Krainer’s lab has created a synthetic molecule called antisense oligonucleotide that replaces that “Do Not Enter” sign and encourages the gene splicing tools to include the information from exon 7 when it builds the survival of motor neuron protein.

In the lab, ASO has done its job, making SMN2 act like its much more effective SMN1 cousin. When Krainer injected ASO into mice with severe SMA, he found that they not only lived longer, but they also were able to grow and develop the same way as mice without the genetic defect.

Krainer’s lab is “changing how the splicing machinery” works, he offered. “We took the repressor out of the picture.”

Krainer has been working on SMA for over a decade. The Uruguay-native who has been at Cold Spring Harbor Lab since 1986 is on the advisory board for two SMA foundations.

He said he quickly moved from understanding SMA as an abstract cell mechanism problem to the urgent need to “do something about it. When [a disease] affects children and very young infants in particular, it is something even more touching.”
Residents of Huntington Station, Krainer and his family have made the Cold Spring Harbor Lab a family affair over the years.

Krainer’s wife Denise Roberts (who met Adrian when they were Ph.D. students at Harvard in the 1980s) is the deputy administrative director of the cancer center at Cold Spring Harbor.
All three of their children — Emily, 22, Andrew, 19 and Brian, 18 — have pitched in at different labs over the years. After she graduates from Brandeis this year, Emily plans to attend medical school and has shown an interest in pediatric neurology. Some day, if her father’s treatment proves effective, Emily may be able to do more for children like Dylan Cuevas than doctors have been able to do up until now.

“I definitely hope [Krainer’s treatment] leads to an improvement,” said Debbie Cuevas, who runs the Families of SMA Greater New York Chapter. “I’m happy to see that it’s going into clinical trials.”

A full-time mom to Dylan and Heather, 5, Debbie Cuevas gave up her job at AIG to take care of her children. Cuevas and her husband, Ron, who works for Chips Technology Group in Syosset, have been through some harrowing times. Dylan has had respiratory failure several times and breathes with the assistance of a respirator.

Still, Cuevas remains positive. “Every day we’re on this Earth is a gift,” she said.

Even if Krainer’s research doesn’t provide the single, definitive solution to SMA, Cuevas believes his research, and that of others, can move science and medicine in the right direction.

Some day, for all the families who pray for a cure, she hopes “someone won’t have to utter the words SMA as a diagnosis.”

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