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Power of 3

Ride For Life presents CSHL with $300,000 for ALS research: from left, CSHL Director of Annual Giving and Donor Relations Karen Orzel, CSHL Assistant Professor Molly Hammell, Ride for Life Founder Chris Pendergast, Stony Brook Associate Professor Josh Dubnau and Ride for Life board member Frank Verdone. Photo by Jessa Giordano, Cold Spring Harbor Laboratory

By Daniel Dunaief

The past can come back to haunt us, even in the world of genetics. Over the course of millions of years, plants and animals have battled against viruses, some of which inserted their genes into the host. Through those genetic struggles, explained Molly Hammell, an assistant professor at Cold Spring Harbor Laboratory, cells develop “elaborate ways to fight back,” even as they continue to make copies of these pieces of DNA.

Sometimes, when our defenses break down, these retrotransposons, or jumping genes, can become active again. Indeed, that appears to be the case in a fly model of amyotrophic lateral sclerosis, also known as ALS or Lou Gehrig’s disease.

Working on a fruit fly model of ALS, Joshua Dubnau, an associate professor at Stony Brook University, Lisa Krug, who earned her doctorate at Cold Spring Harbor Laboratory and is now working at Kallyope in New York, and Hammell showed that these ancient genetic invaders play an important role in the disease amid activation by a protein often linked to ALS called TDP-43.

A recent study, published in PLOS Genetics, “really proves that retroviral reactivation (as a consequence of TDP-activity) is … central to either causing or accelerating neuronal cell death when TDP-43 inclusions are present,” explained Hammell in an email. If TDP-43 plays the same role for humans, this would suggest that targeting this protein or the jumping genes, it activates could lead to potential treatment for ALS.

These collaborators showed that an aggregation of this protein turned on jumping genes. These genes can make copies of themselves and insert themselves in other parts of the genetic code. In this case, TDP-43 expression disrupts the normal immune-like system that silences retrotransposons such as gypsy, which is a particular type of jumping gene in the fruit fly.

When gypsy was activated, the fruit fly exhibited many of the features of ALS, including protein pathology, problems with movement, shortened life span and cell death or glia and neurons in the brain. The scientists were also able to turn gypsy off, which improved the health and extended the life span of the fly.

Mimicking this protein results in broad activation of several retrotransposons. If this also occurs in people, the disease may activate a retrotransposon that is the human analog to gypsy, called HERV-K, as well as other retrotransposons. The study also suggests that DNA damage caused by retrotransposons may active a cell suicide mechanism. Finally, this effort showed a means by which the protein disrupts the normal immune surveillance that keeps retrotransposons quiet.

To be sure, Dubnau cautioned that animal models of a disease may not translate when returning to people. Researchers need to look at more patients at all the retrotransposons in the human genome to monitor its prevalence, Dubnau suggested. If the link between retrotransposon activation and the development of ALS is as evident in humans as it is in the fruit fly, scientists may take an approach similar to that which they took to battle the human immuno-deficiency virus, or HIV. Retrotransposons have an RNA genome that needs to be copied to DNA. This, Dubnau explained, is the step in the process where researchers attacked the virus.

In a small subset of HIV patients who have motor neuron symptoms that are similar to ALS, Avi Nath, a senior investigator at the National Institutes of Health discovered that treating patients with the typical HIV medication cocktail helped relieve their ALS symptoms as well.

“What is not known is whether, for some reason, this subset of patients had an ALS syndrome caused by HIV or they were curing them” by treating HIV, Dubnau said. Nath is currently involved in one of two clinical trials to see if HIV medications help ALS patients. The next step for Dubnau and Hammell is to screen the tissue of numerous ALS patients after their death to see if their retrotransposons were elevated.

In addition to NIH funding, the scientists received financial support from Ride for Life, which is a not-for-profit organization started in 1997 that raises funds for research to find a cure for ALS, supports patients and their families through patient services and raises awareness of ALS. Every May, Ride for Life conducts a 12-day, 100-mile patient wheelchair ride across Long Island. Dubnau and Hammell, who received a $300,000 grant from Ride for Life in 2015, said they have been inspired by Ride for Life founder Chris Pendergast.

Meeting Pendergast “has had a big impact,” Dubnau said. “He’s a force of nature. He’s an incredibly strong and intelligent person.” Receiving funds from Ride for Life created a sense of personal obligation to Pendergast and many other people who “had raised that money through sweat and effort.”

Without funding from the Ride for Life Foundation, “We would not have the resources to obtain these samples and do the sequencing experiments necessary to prove that this is a clinically relevant phenomenon in a large number of ALS patients,” Hammell said.

Through an email, Pendergast explained that Ride for Life chose to fund the work by Dubnau and Hammell because the research met several criteria, including that it might lead to new strategies to treat ALS and the research was on Long Island, which is a “powerful affirmation for our generous donors.”

Pendergast emphasized the importance of funding basic ALS research. “We need to know why it develops, how it progresses [and] how it can be diagnosed and monitored,” he urged.

A resident of Huntington, Dubnau and his wife Nicole Maher, who works at the Nature Conservancy as a climate scientist, have a nine-year-old daughter, Caitlin. Reflecting both of her parents’ professional interests, Caitlin is going to a statewide science fair, where she is presenting her work on how temperature affects the life span of insects.

As for his research, Dubnau hopes a further exploration of TDP-43 might reveal an important step in the progression of ALS. He hopes this discovery may suggest a strategy researchers and clinicians can take that might “stop the cascade of events” in ALS.

Percy Zahl. Photo courtesy of BNL

By Daniel Dunaief

When he was in high school in Negenborn, Germany, Percy Zahl built his own computer, with some help from one of his father’s friends. Nowadays, Zahl spends considerable time improving the computer capability of an open-source community drive software project that helps researchers see structures and interactions at a subatomic level.

Recently, Zahl, who is an associate scientist in the Proximal Probe Microscopy facility at the Center for Functional Nanomaterials at Brookhaven National Laboratory, completed an extensive upgrade to software called Gnome X Scanning Microscopy, or GXSM, that adds a whole suite of new features. Zahl re-coded about half of the original 300,000 lines of code during this project.

The software, which is used to operate any kind of scanning probe microscopy system which includes atomic force microscopy and scanning tunneling microscopy, has a wide range of applications, from understanding catalysts that facilitate chemical reactions, to capturing gases, to biomedical sensors.

Oliver Monti, a professor of chemistry and biochemistry and a professor of physics at the University of Arizona, has been working with Zahl for over four years and has been using this system to explore atomic and molecular-scale processes that determine efficiency in plastic solar cells and other next-generation low-energy-use technologies. He said he uses the GXSM for data analysis.

Zahl “often introduces modifications and upgrades as instantaneous response to some scientific need,” which has “helped us solve specific problems efficiently,” Monti explained in an email. A former student of Monti’s needed to analyze molecule-to-molecule interactions. The two came up with an algorithm to study that and, unprompted, Zahl “introduced a version of this algorithm to his software.”

Percy Zahl (front of line) during a Tour of Somerville race in 2011. Photo by Anthony Skorochod.

Monti said he is “very much aware of the most recent release,” which he considers a “major upgrade” and he is in the process of installing it. The new software allows the export of images in formats such as PDF and SVG, which are editable and resolution independent, Zahl explained. A PDF output of a graph has publication quality, while the images with high-resolution displays are enhanced and sharper than the previous bitmap PNG files.

The upgrade also includes making a remote control process for automating scanning and manipulation tasks “easy to use,” which is a “big plus for less experienced users,” Zahl explained. It can help automate complex or tedious repetitive jobs. As an example, Zahl said the need to scan an image that takes 10 minutes each for 20 different settings creates a laborious task. “I can either sit there and enter manually a new number every 10 minutes” or he can program a script that he made to use a list of bias voltages and hit execute in the new remote console, he explained, leaving him time to work on other projects for the next two hours and 20 minutes.

Recently, Zahl ran a spectra covering the area of a molecule, which is a task he can do reliably without worrying about user typos or errors. An additional noncontact atomic force microscopy simulation plug-in module provides researchers with a more efficient way to generate data. The new approach measures the force between atoms and molecules of the surface of a sample and a probe smaller than the diameter of an atom. Zahl has calculated and simulated forces between atoms, taking into account all atoms of a molecule and the probe atom and finds the equilibrium position of his probe. Using that three-dimensional force field, he can extract an image that he compares to the model.

Zahl spends about three quarters of his time working with users like Monti, while he dedicates the remaining time to his own projects. He appreciates the opportunity to work with many different systems and with people in a wide range of scientific disciplines.

“It’s really as diverse as it can get in this particular field of fundamental surface science — a specialty of solid state physics,” Zahl explained in an email. He has the experience to work with many different sample types while still continuing to learn “all the tricks on how to get the best images possible.”

Monti appreciates Zahl’s dedication to his work. “Data processing and analysis can be challenging,” he explained. His students often compare a trip to BNL to drinking from a firehose.

Zahl has been “essential in helping us figure out how to sift through the data and quickly focus on the most important observations,” Monti added. That appreciation extends well beyond Monti’s lab. “Whenever I meet colleagues across the world who had the pleasure to interact with [Zahl], they lavish praise on his scientific and technical expertise,” Monti said.

Bruce Koel, a professor in the Department of Chemical and Biological Engineering at Princeton University, appreciated Zahl’s contribution to his research on chemical reactions at surfaces. Zahl has “enabled us to do very high impact research,” Koel explained in an email. This work would “not have been possible without [Zahl’s] technical support and guidance about what experiments could be done.”

A resident of Rocky Point, Zahl rides the 20 miles to work as often as he can on one of several of his bicycles. An avid cyclist, Zahl has a high-end racing bike, a commuter bike and a mountain bike from those “beloved times” riding mountain trails in Switzerland.

In Chile, he reached a top speed of around 56 miles per hour descending the Osorno Volcano. In a YouTube video of his ride, he can be seen passing a car in a clearing along the windy road.

As for his work, Zahl remains committed to continuing to improve the software scientists use to enhance their visual understanding of the small surfaces of the substances they study. “I am pretty much always working on some new details or fixing this and that tiny issue,” he said. “No software is ever done. It’s evolving.”

Jun Wang in her laboratory with a transmission x-ray microscope. Photo from BNL

By Daniel Dunaief

The first time is most definitely not the charm. That’s what Jun Wang and her colleagues at Brookhaven National Laboratory discovered about sodium ion batteries.

Wang, a physicist and lead scientist at the facility, looked deep into the inner workings of a sodium ion battery to determine what causes structural defects as the battery functions. As it turns out, the first time a sodium ion battery charges and discharges, it develops changes in the microstructure and chemical composition of iron sulfide. These changes, which degrade the performance of the battery, are irreversible during the first charging cycle.

“We found that the cracks happened during the first cycle, then, after that, the structure kind of reached equilibrium,” said Wang, who published her research in the journal Advanced Energy Materials. “All these changes happen during the first cycle.”

Collaborators from Brookhaven’s Photon Sciences and Sustainable Energy Technologies groups stand behind the new transmission x-ray microscope (TXM) at BNL’s National Synchrotron Light Source. From left: Yu-chen Karen Chen-Wiegart, Can Erdonmez, Jun Wang (team leader), and Christopher Eng. Photo from BNL

Sodium ion batteries are considered an alternative to lithium ion batteries, which are typically found in most consumer electronics. Like lithium, sodium is an alkali metal, which means that it is in the same group in the periodic table. Sodium, however, is more abundant and, as a result, considerably less expensive than lithium.

Using a synchrotron-based hard X-ray full-field microscope, Wang was able to see what happened when sodium ions moved into and out of an iron sulfide electrode through 10 cycles. “We can see this microstructure evolution,” she said.

Wang monitored the evolution as a function of time while the battery is charging and discharging. The results are the first time anyone has studied a sodium-metal sulfide battery with these tools, which provides information that isn’t available through other methods. “It is challenging to prepare a working sodium ion battery for the in operandi/in situ TXM study to correlate the microstructural evolution with its electrochemical performance,” she said.

Other researchers suggested that Wang has developed a following in the scientific community for her ground-breaking research. “She has a very good reputation in the area of X-ray nanotomography, applied to a wide range of different materials,” Scott Barnett, a professor of materials science and engineering at Northwestern University, explained in an email. “I am most familiar with her work on fuel cell and battery electrodes — I think it is fair to say that this work has been some of the best pioneering research in this area,” he said.

Barnett, who started collaborating with Wang in 2010 on measuring fuel cell and battery electrodes with X-ray tomography, suggested that Wang’s work on capacity loss “could certainly lead to new breakthroughs in improved batteries.”

In her most recent work with sodium ion batteries, Wang found that the defects start at the surface of the iron sulfide particles and move inward toward the core, Wang said. The microstructure changes during the first cycle and is more severe during sodiation. The particles don’t return to their original volume and shape. After the first cycle, the particles reach a structural equilibrium with no further significant morphological changes, she said.

In other cycles, the material does not show further significant morphological changes, reach a structural equilibrium and electrochemical reversibility. Wang and her colleagues confirmed these observations with X-ray nanotomography, which creates a three-dimensional image of the battery material while recording the change in volume.

Wang suggested that a way to reduce these structural defects could be to reduce the size of the iron sulfide particles to create a one-phase reaction. She will work with other collaborators on modeling and simulations that will enhance the design of future battery materials.

In addition to conducting research on batteries, Wang is an industrial program coordinator in the Photon Science Directorate at BNL. She works with industrial researchers and beamline staff to find and explore new opportunities in industrial applications using synchrotron radiation. She leads the industrial research program, interacting with user groups through consultation, collaboration and outreach.

To manage her research, which includes a lab of three other researchers, and to accomplish her mission as manager of an industrial research program, Wang jokes that she “spends 100 percent of her time” with each responsibility. “I try to do my best for the different things” she needs to do with her time, she said.

Jun Wang with her husband Qun Shen and their 11-year old son Sam in Waikiki last year. Photo from Jun Wang

A native of Wuhu, China, Wang earned her bachelor’s degree in physics from Anhui University in China and her doctorate in physics from the Chinese Academy of Sciences in Beijing. She worked at the Beijing Synchrotron Radiation Facility, which was the first synchrotron light source in China. During her doctoral training, she studied multilayer films using X-ray diffraction and scattering.

A resident of Poquott, Wang is married to Qun Shen, who is the deputy director for science at the NSLS-II. The couple has an 11-year-old son, Sam, who is a sixth-grade student at Setauket Elementary School. Shen and Wang met at an international X-ray crystallography conference in the early 1990s.

Shen trained in the United States after he graduated from Beijing University in 1980, when he went to Purdue University for his doctorate through the China-US Physica Examination and Application Program. The couple have worked together a few times over the years, including publishing a paper in Nature Communications. Wang is hoping that her work with battery research will lead to improvements in the manufacture and design of sodium ion batteries.

Above, members of the New York Chapter of The Children’s Heart Foundation present CSHL Research Assistant Professor Michael Ronemus with a $50,000 check from The Children’s Heart Foundation for his recently funded research grant on Feb. 23. Photo courtesy of ©C. Brukin, 2017/Cold Spring Harbor Laboratory

By Daniel Dunaief

Just before he took a holiday break in December, Michael Ronemus received a welcome surprise. “In the last afternoon before the holidays, I got a call from William Foley. He said, ‘Congratulations,’” recalled Ronemus, a research assistant professor at Cold Spring Harbor Laboratory. “I submitted the application in May and I didn’t know what to expect.”

Foley, the executive director at the Children’s Heart Foundation, was reaching out to Ronemus to let him know he was one of seven researchers — six in North America and one in Europe — to receive funding for his research. Ronemus received a check for $50,000 at a presentation ceremony on Feb. 23.

Scientists are seeking out private foundations more as they search for sources of funding, said Ronemus. The funds will help Ronemus use next-generation sequencing to look closely at 120 families for evidence of copy number variation in their genes.

 

When a person has a different number of copies of a part of a specific gene, that can be a positive, neutral or negative event, depending on the consequence for the individual. Most copy number variations are neutral, which is why people have hundreds of them in their genes. Copy number variations can contribute, however, to de novo mutations, presenting changes in a genetic code that can make the genes of an offspring different from those of his or her parents. If these mutations damage a gene that’s essential for normal development of the heart, they can contribute to congenital heart defects.

Michael Ronemus explains the relevance of his research to the community at the check presentation event on Feb. 23. Photo courtesy of ©C. Brukin, 2017/Cold Spring Harbor Laboratory

Indeed, the Children’s Heart Foundation has contributed $8.7 million to research, hoping to improve the ability to prevent, diagnose and treat the 40,000 people born each year in the United States with a heart defect. Of the children born with a heart defect, about one in four, has a form of critical congenital heart disease, said Jon Kaltman, the chief in the Heart Development and Structures Diseases Branch of the National Heart, Lung and Blood Institute. That means he or she will most likely require surgery within the first year of life, although most have it within the first month.

At this point, doctors and researchers understand the genetic cause of congenital heart disease for a small percent of people. The work of the Pediatric Cardiac Genomics Consortium hopes to make this true for a larger number of people with a congenital heart defect, Kaltman said.

Knowing the genetics of a patient and his or her family could be “helpful for that family to understand what might have caused the congenital heart disease” said Kaltman, who has been a pediatric cardiologist since 2005. “If that family were to have another child” the genetics could help assess the “risk that a second child will also have a congenital heart defect.”

A greater awareness of the genes involved in heart disease could also provide a guide for the way the defect might react to treatment. “We see patients with identical looking hearts [on an echocardiogram] from different families in which they undergo surgery” and have different reactions, Kaltman said. “One does well and has few complications and the other develops arrhythmias at 15 and heart failure at 25.”

The differences in respones to treatment for those patients may be genetic. “For the patient with the genetic signal for the complicated course, we can do more interventions early on,” Kaltman said, which could include earlier valve replacements or more aggressive arrhythmia surveillance.

Working with Bruce Gelb, a professor in pediatrics and cardiology at Mount Sinai Hospital, Ronemus is focusing on a group of patients with a condition called tetralogy of Fallot. Children with this defect develop a bluish color in their skin and can have trouble breathing when they exercise.

New York Chapter president of the Children’s Heart Foundation Jackie Pecora speaks at the check presentation event. Photo courtesy of ©C. Brukin, 2017/Cold Spring Harbor Laboratory

Doctors treat people with this condition with open heart surgery, which fixes a hole between the ventricles and opens up a narrowed right ventricular outflow tract. “Early diagnosis can lead to a straightforward procedure and good outcome,” Ronemus said. “If there is any reason to suspect [that a developing fetus has this condition], we’d like to know.”

By studying copy number variation, Gelb and Ronemus can search for signatures or markers in prenatal screening, which doctors can do through amniocentesis or cell-free fetal DNA analysis, which is a noninvasive form of prenatal testing. A definitive diagnosis even before birth could help doctors prepare for quick intervention that could be more effective, Ronemus said. If not diagnosed, a third of the children with the condition die within the first year and 50 percent in the first three years, Ronemus explained. If doctors know a child has the condition, they can take precautions, like have supplementary oxygen or drugs nearby.

Ronemus, who started his career in plant genetics and then became involved in the study of autism, is applying a genetic technique he co-developed at CSHL for copy number variation detection called SMASH. He applied for the Children’s Heart Foundation grant because of a meeting at CSHL with Jackie Pecora, a resident of East Northport, who is New York Chapter president of the Children’s Heart Foundation. The foundation has 11 chapters throughout the country and raises funds through events like the Long Island Congenital Heart Walk, which will take place on May 21 in Sunken Meadow State Park. Ronemus will be an honorary co-chair for the walk.

Foley said Ronemus’ approach is a “unique way” of looking at congenital heart defects. During the medical advisory board’s discussion of which projects to fund “there was a lot of enthusiasm” for this project. Ronemus is the first New York researcher to receive CHF funds since 2009.

A resident of East Meadow, Ronemus lives with his wife Ana Rodriguez-Fernandez, who is an associate professor of microbiology at the NYU School of Medicine. The couple has three children, Martin, 14, Silvia, 12, and Daniel, 11.

Pecora has family experience with congenital heart disease. After she gave birth to twins 18 years ago, doctors discovered that her daughter Chloe had a heart defect that required surgery. Nine days after she was born, Chloe died from an infection. Pecora got involved because of a bumper sticker for another grassroots fundraiser for a baby with the same heart condition as Chloe. That led her to the Children’s Heart Foundation. While the awareness among the public is improving, there’s still a way to go to combat a prevalent condition, Pecora said. “Look at the clock: Every 15 minutes a baby is born with congenital heart disease. People don’t realize the magnitude.”

Joseph Schwartz, right, with a collaborator, Daichi Shimbo, the director of the Translational Lab at the Center for Behavioral Cardiovascular Health at Columbia University Medical Center, in front of a poster they presented at an annual meeting of the American Society of Hypertension in New York City in 2013.Photo by John Booth, III

By Daniel Dunaief

The cardiovascular skies may be clear and sunny, but there could also be a storm lurking behind them. About one in eight people who get a normal reading for their blood pressure have what’s called masked hypertension.

That’s the finding in a recent study published in the American Journal of Epidemiology led by Joseph Schwartz, a professor of psychiatry and sociology at Stony Brook University and a lecturer of medicine at the Columbia University Medical Center. Schwartz said his research suggests that some people may need closer monitoring to pick up the kinds of warning signs that might lead to serious conditions.

“The literature clearly shows that those with masked hypertension are more likely to have subclinical disease and are at an increased risk of a future heart attack or stroke,” Schwartz explained in an email.

Tyla Yurgel, Schwartz’s lab manager from 2005 to 2016 who is now working in the Department of Psychiatry, wears the ambulatory blood pressure cuff that was a part of the study. Photo by Arthur Stone

Schwartz and his colleagues measured ambulatory blood pressure, in which test subjects wore a device that records blood pressure about every half hour, collecting a set of readings as a person goes about the ordinary tasks involved in his or her life. Through this reading, he was able, with some statistical monitoring, to determine that about 17 million Americans have masked hypertension, a term he coined in 2002.

Schwartz, who started studying ambulatory blood pressure in the late 1980s, has been actively exploring masked hypertension for over a decade. Ambulatory blood pressure monitoring is more effective at predicting subclinical disease such as left ventricular hypertrophy and the risk of future cardiovascular events, said Schwartz. “There was some rapidly growing evidence it was a better predictor of who would have a heart attack or stroke than in the clinic, even when the blood pressure in the clinic was properly measured,” he said.

To be sure, the expense of 24-hour monitoring of ambulatory blood pressure for everyone is unwieldy and unrealistic, Schwartz said. The list price for having an ambulatory blood pressure recording is $200 to $400, he said. Wearing the device is also a nuisance, which most people wouldn’t accept unless it was likely to be clinically useful or, as he suggested, they were paid as a research participant.

Schwartz said he used a model similar to one an economist might employ. Economists, he said, develop simulation models all the time. He said over 900 people visited the clinic three times as a part of the study. The researchers took three blood pressure readings at each visit. The average of those readings was more reliable than a single reading.

The study participants then provided 30 to 40 blood pressure readings in a day and averaged those numbers. He collected separate data for periods when people were awake or asleep. A patient close to the line for hypertension in the clinical setting was the most likely to cross the boundaries that define hypertension. “You don’t have that far to go to cross that boundary,” Schwartz said.

After analyzing the information, he came up with a rate of about 12.3 percent for masked hypertension of those with a normal clinic blood pressure. The rate was even higher, at 15.7 percent, when the researchers used an average of the nine readings taken during the patient’s first three study visits.

William White, a professor of medicine at the Calhoun Cardiology Center at the University of Connecticut School of Medicine in Farmington was a reviewer for one of these major studies. “They are excellent,” said White, who has known Schwartz for about a decade. “We should be monitoring blood pressure more outside of the clinical environment.”

Indeed, patients have become increasingly interested in checking their blood pressure outside of the doctor’s offices. “We have a 200 to 300 percent increase in requests for ambulatory blood pressure monitoring from our clinical lab during the last five to ten years — in all age groups, genders and ethnicities,” explained White.

The challenge, however, is that tracking hypertension closely for every possible patient is difficult clinically and financially. “There are no obvious clinical markers for masked hypertension other than unexpectedly high self-blood pressure or unexplained hypertensive target organ damage,” White added.

Schwartz himself has a family history that includes cardiovascular challenges. His father, Richard Schwartz, who conducted nonmedical research, has a long history of cardiovascular disease and had a heart attack at the age of 53. His grandfather had a fatal heart attack at the same age. When Schwartz reached 53, he said he had “second thoughts,” and wanted to get through that year without having a heart attack. He’s monitoring his own health carefully and is the first one in his family to take blood pressure medication.

Schwartz, who grew up in Ithaca, New York, came to Stony Brook University in 1987. He called his upbringing a “nonstressful place to grow up.” He now lives in East Setauket with his wife Madeline Taylor, who is a retired school teacher from the Middle Country school district. The couple has two children. Lia lives in Westchester and works at Graham Windham School and Jeremy lives in Chelsea and works for Credit Suisse.

As for his work, Schwartz said the current study on masked hypertension was a part of a broader effort to categorize and understand pre-clinical indications of heart problems and to track the development of hypertension.

Now that he has an estimate of how many people might have masked hypertension, he plans to explore the data further. That analysis will examine whether having masked hypertension puts a patient at risk of having cardiovascular disease or other circulatory challenges. “We are very interested in whether certain personality characteristics and/or circumstances (stressful work situation) makes it more likely that one will have masked hypertension,” he explained.

David Matus in his lab at Stony Brook University. Photo courtesy of SBU

By Daniel Dunaief

At first look, the connection between a roundworm, a zebrafish and cancer appears distant. After all, what can a transparent worm or a tropical fish native to India and the surrounding areas reveal about a disease that ravages its victims and devastates their families each year?

Plenty, when talking to David Matus and Benjamin Martin, assistant professors in the Department of Biochemistry and Cell Biology at Stony Brook University whose labs are next door to each other. The scientific tandem recently received the 2017 Damon Runyon–Rachleff Innovation Award, which includes a two-year grant of $300,000, followed by another renewable grant of $300,000 to continue this work.

In the first of a two-part series, Times Beacon Record Newspapers will profile the work of Matus this week. Next week the Power of Three will feature Martin’s research on zebrafish.

Long ago a scientist studying dolphin cognition in Hawaii, Matus has since delved into the world of genetic development, studying the roundworm, or, as its known by its scientific name, Caenorhabditis elegans. An adult of this worm, which lives in temperate soil environments, measures about 1 millimeter, which means it would take about 70 of them lined up end to end to equal the length of an average earthworm.

From left, David Matus and Benjamin Martin. Photo courtesy of SBU

Matus specifically is interested in exploring how a cell called the anchor cell in a roundworm invades through the basement membrane, initiating a uterine-vulval connection that allows adult roundworms to pass eggs to the outside environment. He is searching for the signals and genetic changes that give the anchor cell its invasive properties.

Indeed, it was through a serendipitous discovery that he observed that the loss of a single gene results in anchor cells that divide but don’t invade. These dividing cells are still anchor cells, but they have lost the capacity to breach the basement membrane. That, Matus said, has led the team to explore the ways cancer has to decide whether to become metastatic and invade other cells or proliferate, producing more copies of itself. In some cancers, their hypothesis suggests, the cells either divide or invade and can’t do both at the same time. It could be a cancer multitasking bottleneck.

Mark Martindale, the director of the Whitney Laboratory at the University of Florida in Gainesville who was Matus’ doctoral advisor, said a cell’s decision about when to attach to other cells and when to let go involves cell polarity, the energetics of motility and a host of other factors that are impossible to study in a mammal.

The roundworm presents a system “in which it is possible to manipulate gene expression, and their clear optical properties make them ideal for imaging living cell behavior,” Martindale explained in an email. Seeing these developmental steps allows one to “understand a variety of biomedical issues.”

Last year, Matus and Martin were finalists for the Runyon–Rachleff prize. In between almost getting the award and this year, the team conducted imaging experiments in collaboration with Eric Betzig, a group leader at the Janelia Research Campus of the Howard Hughes Medical Institute in Ashburn, Virginia. Betzig not only brings expertise in optical imaging technologies but also has won a Nobel Prize.

“We really appreciate the opportunity to work with [Betzig] and his lab members on this project,” said Matus, who also published a review paper in Trends in Cell Biology that explored the link between cell cycle regulation and invasion. He and his graduate student Abraham Kohrman explored the literature to find cases that showed the same switching that he has been exploring with the roundworm.

Yusuf Hannun, the director of the Stony Brook Cancer Center, said the work is highly relevant to cancer as it explores fundamental issues about how cells behave when they invade, which is a key property of cancer cells. Hannun said the tandem’s hypothesis about division and invasion is “consistent with previous understandings but I believe this is the first time it is proposed formally,” he suggested in an email.

Their work could apply to invasive epithelial cancers, suggested Scott Powers, a professor in the Department of Pathology at Stony Brook and the director of Clinical Cancer Genomics at the Cancer Center. That could include breast, colon, prostate, lung and pancreatic cancers, noted Powers, who is a recent collaborator with Matus and Martin.

The additional funding allows Matus and Martin to focus more of their time on their research and less on applying for other grants, Matus said.

Back row from left, David Matus and his father in law Doug Killebrew; front row from left, Maile 9, Bria, 7, and Matus’ wife Deirdre Killebrew. Photo by Richard Row

Matus lives in East Setauket with his wife Deirdre Killebrew, who works for Applied DNA Sciences. The couple met when they were working with dolphins in Hawaii. Matus’ first paper was on dolphin cognition, although he switched to evolutionary and developmental biology when he worked in Martindale’s lab at the University of Hawaii.

Martindale described Matus as prolific during his time in his lab, publishing numerous papers that were “profoundly important in our continued understanding of the relationship between genotype and phenotype and the evolution of biological complexity,” Martindale wrote in an email.

Following in Martindale’s footsteps, Matus replaced his middle name, Samuel, in publications with a Q. Martindale said several of his colleagues adopted the phony Q to pay homage to the attitude that drove them to pursue careers in science. Matus has now passed that Q on to Korhman, who is his first graduate student.

Matus and Killibrew have two daughters, Bria and Maille, who are 7 and 9 years old. Their children have a last name that combines each of their surnames, Matubrew. Matus said he feels “fortunate when I got here three years ago that they had me set up my lab next to [Martin]. That gave us an instantaneous atmosphere for collaboration.”

By Daniel Dunaief

 

Adrian Krainer with Emma Larson earlier this year. Photo from Dianne Larson

The prognosis hit Dianne Larson of Middle Island hard. Within three weeks, anxiety attacks, a lack of sleep and fear caused her weight to plummet from 135 to 120 pounds. She found out her daughter Emma, who was 17 months old at the time, had a potentially fatal genetic condition called spinal muscular atrophy in which the motor nerve cells of the spinal cord progressively weaken. Normally, the SMN1 gene produces the survival of motor neuron protein, which, as its name suggests, helps maintain motor neurons. People with SMA, which has four types and severity, produce a lower amount of the functional protein.

“My mind went to the darkest of dark places,” said Larson, whose daughter couldn’t crawl or sit up to eat. “There was no hope. There was nothing I could do.”

At the time of Emma’s diagnosis, there was no treatment for a disease that is the leading genetic cause of death among infants and affects about 1 in 10,000 newborns. Thanks to the work of Adrian Krainer, a professor and program chair of cancer and molecular biology at Cold Spring Harbor Laboratory, that changed early enough to alter the expectations for Emma and children around the world battling a genetic condition that causes progressive weakness and can make moving and even breathing difficult.

Turning to a back up gene called SMN2, Krainer hoped to fix a problem with the way that gene is spliced. On SMN2, exon 7 is normally skipped and the resulting protein has a different sequence at the end. Krainer developed an antisense olignocleotide that binds to a sequence in the intro following exon 7, blocking the splicing receptor. The treatment, which is called Spinraza, helps guide the splicing machinery, which carries out one of the steps in gene expression that is necessary to build a functional protein.

The Larson family of Middle Island, from left, Dianne, Emma and Matthew. Photo from Dianne Larson

Larson had heard of Krainer’s work and was eager to see if his success with animal models of the disease would translate for humans. As soon as Emma reached her second birthday, Larson enrolled her daughter in a clinical trial for Spinraza. After her daughter had a few shots, Larson was stunned by the change. “I was in the master bedroom and she was in the den and I heard a voice getting closer,” Larson recalls. “Next thing I know, she was in my bedroom. I couldn’t believe she crawled from the den to the bedroom. I put her in the den and told her to do it again,” which she did.

The SMA community and Krainer received an early holiday present in late December when the Food and Drug Administration not only approved the treatment, but it also gave doctors the green light to prescribe it for all types of SMA and for patients of all ages. While the SMA community, doctors and Krainer have been delighted with the FDA approval, the excitement has been tempered by concerns about the price tag Biogen, which manufactures and commercializes Spinraza and funded the drug’s development, has placed on the treatment.

For the first full year of injections, the drug costs $750,000. Every year after that will cost $375,000, which Biogen has said publicly is consistent with the pricing for other drugs for so-called orphan diseases, which affect a much smaller percentage of the population.

Knowledge Ecology International, a nonprofit advocate for affordable medicines, sent a letter to the Office of the Inspector General at the Department of Health and Human Services, seeking an investigation. The letter claims that the inventor and maker of Spinraza failed to disclose that the treatment received federal funding. KEI urges the government to use that alleged disclosure failure to end the patent and authorize a generic manufacture of the treatment.

Biogen didn’t return a call and email for comment. Patients and their families, meanwhile, are looking for immediate access to a life-altering treatment. “To be honest, I really don’t know what we’re going to do,” said Larson, whose daughter has four injections left as part of the extension trial soon. “I’m hoping insurance will cover it.”

Insurer Anthem announced late in January that the treatment was only medically necessary for patients with Type 1 SMA, which include people diagnosed with the disease within six months of birth. Anthem created a pay for performance model, which will require patients or their families to prove that the treatment is improving the lives of the recipients.

Larson said she has been in touch with a personal liaison at Biogen, which has been “helpful and supportive,” she said. “They have been going out of their way to reach out to the community to make sure everyone gets access.”

Larson, who is a financial advisor, said she understands the need for the company to generate a profit. “A lot of money goes into” research and development Larson said. “If they’re not gong to make money, they’re not going to” support the efforts to create a treatment.

Emma Larson will be turning 4 this month. Photo from Dianne Larson

Joe Slay, who is the chairman of FightSMA, a group he and his wife Martha founded in 1991 after they learned their son Andrew had Type 2 SMA, sounded hopeful that people who need this treatment will receive it. “I understand there’s constructive, good conversations between insurance companies and Biogen,” Slay said. “We’re monitoring that.”

While Andrew, who is now 30, considers the potential benefits of Spinraza, Slay is pleased the treatment is an option for people and is proud of Krainer’s work.Krainer is “by any definition of the word a hero,” Slay said. “He’s taken his natural gifts, his brilliance in science, his discipline year in and year out approach to his work and has applied himself 100 percent.”

Slay and FightSMA, which has raised over $8 million since its founding, helped provide seed money to Krainer more than 15 years ago, attracting a promising scientist to what was then an intractable medical challenge.

Tom Maniatis, who is the chairman of the Department of Biochemistry and Molecular Biophysics at Columbia University, said Krainer, who did his doctoral work in Maniatis’s lab, showed considerable scientific promise early in his career. Krainer “clearly had the intelligence, drive and experimental skills to make important contributions,” Maniatis said. His work is “a perfect example of how deep basic science studies can lead to profound understanding of a disease mechanism and that, in turn to the development of a treatment,” explained Maniatis in an email.

Within Krainer’s own family, there is a connection to patient care. Krainer’s daughter Emily, who is a pediatric neurology resident at Rochester, may one day prescribe a treatment her father developed. “It will be quite something for me if she eventually prescribes Spinraza to one of her patients,” Krainer said. Even as other scientists and companies like AveXis continue to search for ways to treat SMA, Krainer enhances and refines his research.

“We continue to work on understanding aspects of SMA pathophysiology, the role of SMN levels outside the central nervous system and the potential for prenatal therapy,” he explained in an email. “We are also working on antisense therapies for other genetic diseases and cancer.”

Larson, who is overjoyed with her daughter’s progress, calls Krainer her “superhero” who “saved my daughter’s life.” “It’s such a different feeling when you know you can do something,” she said. When she found out that the FDA approved the treatment, it was “the best day.”

By Daniel Dunaief

Born in Berlin just before World War II, Eckard Wimmer has dedicated himself in the last 20 years to producing something that would benefit humankind. A distinguished professor in molecular genetics and microbiology at Stony Brook University, Wimmer is hoping to produce vaccines to prevent the spread of viruses ranging from influenza, to Zika, to dengue fever, each of which can have significant health consequences for people around the world.

Using the latest technology, Wimmer, Steffen Mueller and J. Robert Coleman started a company called Codagenix in Melville. They aim to use software to alter the genes of viruses to make vaccines. “The technology we developed is unique,” said Wimmer, who serves as senior scientific advisor and co-founder of the new company.

Mueller is the president and chief science officer and Coleman is the chief operating officer. Both worked for years in Wimmer’s lab. Despite the potential to create vaccines that could treat people around the world facing the prospect of debilitating illnesses, Wimmer and his collaborators weren’t able to attract a pharmaceutical company willing to invest in a new technology that, he estimates, will take millions of dollars to figure out its value.“Nobody with a lot of money may want to take the risk, so we overcame that barrier right now,” he said.

Eckard Wimmer in his lab. Photo by Naif Mohammed Almojarthi

Codagenix has $6.2 million in funding. The National Institutes of Health initially contributed $600,000. The company scored an additional $1.4 million from NIH. It also raised $4.2 million from venture capital, which includes $4 million from TopSpin and $100,000 from Accelerate Long Island and a similar amount from the Center for Biotechnology at Stony Brook University.

Stony Brook University recently entered an exclusive licensing agreement with Codagenix to commercialize this viral vaccine platform. Codagenix is scheduled to begin phase I trials on a vaccine for seasonal influenza this year.

The key to this technology came from a SBU collaboration that included Wimmer, Bruce Futcher in the Department of Molecular Genetics & Microbiology and Steven Skiena in the Department of Computer Science. The team figured out a way to use gene manipulation and computer algorithms to alter the genes in a virus. The change weakens the virus, giving the attack dog elements of the immune system a strong scent to seek out and destroy any real viruses in the event of exposure.

Wimmer explained that the process starts with a thorough analysis of a virus’s genes. Once scientists determine the genetic code, they can introduce hundreds or even thousands of changes in the nucleic acids that make up the sequence. A computer helps select the areas to alter, which is a rapid process and, in a computer model, can take only one afternoon. From there, the researchers conduct experiments in tissue culture cells and then move on to experiment on animals, typically mice. This can take six months, which is a short time compared to the classical way, Wimmer said.

At this point, Codagenix has a collaboration with the Universidad de Puerto Rico at the Caribbean Primate Research Center to treat dengue and Zika virus in primates. To be sure, some promising vaccines in the past have been taken off the market because of unexpected side effects or even because they have become ineffective after the virus in the vaccine undergoes mutations that return it to its pathogenic state. Wimmer believes this is unlikely because he is introducing 1,000 changes within a vaccine candidate, which is much higher than other vaccines. In 2000, for example, it was discovered that the polio vaccines involve only five to 50 mutations and that these viruses had a propensity to revert, which was rare, to the type that could cause polio.

Colleagues suggested that this technique was promising. “This approach, given that numerous mutations are involved, has the advantage of both attenuation and genetic stability of the attenuated phenotype,” Charles Rice, the Maurice R. and Corrine P. Greenberg professor in virology at Rockefeller University explained in an email.

While Wimmer is changing the genome, he is not altering the structure of the proteins the attenuated virus produces, which is exactly the same as the virus. This gives the immune system a target it can recognize and destroy that is specific to the virus. Wimmer and his associates are monitoring the effect of the vaccines on mosquitoes that carry and transmit them to humans. “It’s not that we worry about the mosquito getting sick,” he said. “We have to worry whether the mosquito can propagate this virus better than before.” Preliminary results show that this is not the case, he said.

Wimmer said there are many safety precautions the company is taking, including ensuring that the vaccine candidate is safe to administer to humans. Wimmer moved from Berlin to Saxony after his father died when Wimmer was 3. He earned an undergraduate degree in chemistry in 1956 at the University of Rockstock. When he was working on his second postdoctoral fellowship at the University of British Columbia in Vancouver, he heard a talk on viruses, which brought him into the field.

A resident of Old Field, Wimmer lives with his wife Astrid, a retired English professor at Stony Brook. The couple’s daughter Susanne lives in New Hampshire and has three children, while their son Thomas lives in Portland, Oregon, and has one child. “We’re very happy Long Islanders,” said Wimmer, who likes to be near the ocean and Manhattan.

Through a career spanning over 50 years, Wimmer has won numerous awards and distinctions. He demonstrated the chemical structure of the polio genome and worked on polio pathogenesis and human receptor for polio. He also published the first cell-free creation of a virus.

“This was an amazing result that enabled a number of important mechanistic studies on poliovirus replication,” Rice explained. Wimmer has “always been fearless and innovative, with great enthusiasm for virology and discovery.”

With this new effort, Wimmer feels he will continue in his quest to contributing to humanity.

From left, Robert Catell, chairman of the board, Advanced Energy Research and Technology Center; Vyacheslov Solovyov; Sergey Gelman, a Stony Brook engineering student; and Yacov Shamash, vice president for economic development at Stony Brook University. Photo from Stony Brook University

By Daniel Dunaief

It’s lighter, cheaper and just as strong. In the age of manufacturing the latest and greatest high-technology parts, that is a compelling combination. Indeed, the Department of Energy recently awarded the Brookhaven Technology Group, a business incubator tenant of the Advanced Energy Research and Technology Center at Stony Brook University, $1.15 million to develop a high-temperature superconductor cable with a new architecture. The grant supports the research of Vyacheslav Solovyov, an adjunct professor in the Department of Electrical Engineering at SBU and the principal investigator at Brookhaven Technology Group.

“Very few projects are funded, so we’re very excited that ours was chosen,” said Paul Farrell, the president at BTG. The potential applications for Solovyov’s Exocable, as the new architecture is called, span a wide range of uses, including in high field magnets for a new breed of accelerator. The work entails creating a high-temperature superconducting cable that is an integral ingredient in creating the superconducting machinery. The BTG process produces a high-temperature superconducting cable after removing the substrate, which is a single-crystal-like material. Solovyov transfers the superconducting layer to a supporting tape that can be engineered for strength and not for crystallinity.

This work reduces the weight of the tape by as much as 70 percent per unit length for the same current capacity. The potential for this new cable is that it can contribute to the growing field of research at Stony Brook and Brookhaven National Laboratory on superconductivity, said Jim Smith, assistant vice president of economic development at Stony Brook. “Maybe this is the next industry that replaces the Grummans and the aerospaces that have left,” he said. Semiconductors are of particular interest to manufacturers because they transmit energy with no resistance. Right now, about 6.5 percent of energy transmitted around the United States is lost in distribution wires, Smith said. Maintaining the energy that’s lost in the wires would have “tremendous benefits.”

To be sure, while the research at BTG could contribute to lower cost and improved efficiency in high-temperature superconductivity, there are hurdles to making this process and the applications of it work. For starters, the company needs to produce kilometers of ExoCable. “The challenge is to demonstrate that the properties will be as uniform as they were before the substrate removal,” explained Solovyov, who has been working in superconductivity since 1986.

Recently, Smith said he, Farrell and Solovyov met to discuss the wiring for their facility. “A lot of power and wiring will be installed in the next four to five weeks,” Smith said. Scientists who worked with Solovyov expressed admiration for his work and optimism about his results. Solovyov’s “new activity will definitely advance the long-promised practical application of superconductivity electrical power transmission, as well as in the development of high-field magnets for both industrial and scientific application,” David Welch, a former collaborator and retired senior materials scientist at Brookhaven National Laboratory, wrote in an email. Welch explained that Solovyov focused on methods for making composites of superconducting material with normally conducting metals in the form of wires, tapes and cables necessary for their practical application. “Such a combination of talents is unusual,” Welch continued. Early on, it was clear “that [Solovyov] was going to become an important member of the scientific staff at BNL.”

Solovyov started working on this process with BTG about a year and a half ago. When he first started collaborating with BTG, the company was working on a superconducting project funded by the army. When that work ended, Solovyov and BTG worked together to submit new proposals to the DOE. According to Solovyov, Stony Brook has been “very helpful in terms of providing facilities and lab space.” Stony Brook’s goal, Smith said, is to help companies like BTG succeed and measures that success in the number of new jobs created in the energy field.

Solovyov, who grew up in the Ukraine, said he has had several breakthroughs in his career. He helped develop a patented technology that can speed up the processing of superconducting materials by a factor of 10. “That has been used in production and I’m very proud of it,” Solovyov said. The professor lives in Rocky Point with his wife Olena Rybak and their two children, Natasha, 19, who attends Suffolk County Community College, and Dennis, 14, who is in high school. Solovyov said he enjoys Long Island, where he can fish for striped bass and bluefish. He pan fries what he catches.

As for his work, Solovyov has four patents and applications for three more. He and Farrell said the company is looking for opportunities for expansion. He is exploring ways to work with large-scale generators and wind turbines. Farrell explained that BTG has ambitions to become a larger company. BTG would “like to become a major contributor in this field,” Farrell said. That could include adding staff and developing more products that can be sold and used worldwide. “If our product is successful, in the sense that it improves the capability of superconductors to be used commercially, we’ll be adding people.” This work will need more funding, which the company plans to get either from the Department of Energy, from private investors or both.

“If you can improve the usefulness of superconductors and reduce the cost of the wire, there’ll be wider use than there is right now,” Farrell said.

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