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Power of 3

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Pavel Osten. Photo by Joelle Wiggins

By Daniel Dunaief

Male mice, as it turns out, might also be from Mars, while female mice might be from Venus. Looking at specific cells in the brain of rodents, Cold Spring Harbor Laboratory Associate Professor Pavel Osten has found some noteworthy differences in their brain cells.

In the scientific journal Cell, Osten presented data that showed that in 10 out of 11 subcortical regions of the mouse brain, female mice showed greater flexibility and even more cells. These regions of the brain are responsible for reproduction, and social and parenting behaviors. “There were more cells [in these regions] in the female brain, even though the brains tended to be bigger in the males,” Osten said.

These results are part of a multiyear collaboration called the National Institutes of Health’s Brain Initiative Cell Census Network.

In the recent Cell article, Osten indicated that his analysis offered a surprising result in the number of cells of specific types in various regions of the cortex. “Those areas that have higher cognitive functions have different compositions,” he said. The ratios of cell types “vary according to the level of cognitive function.” In retrospect, Osten indicated that he saw the logic in such a cellular organization. “It makes sense that different cortical areas would have different cell type composition tuned to the specific cortical functions,” he explained.

In an email, Hongkui Zeng, the executive director of structured science at the Allen Institute for Brain Science, in Seattle, Washington, suggested that “people never looked at this issue carefully before. She added that the “sexual dimorphism was somewhat expected, but it is still interesting to see the real data.”

Pavel Osten sailing in St. Barts and St. Martin last summer. Photo from Pavel Osten

Osten used a system called qBrain to see and count inhibitory neurons in the mouse brain. Over the next five years, he and his collaborators will build an online resource database for other researchers that will have distribution maps for numerous cell types throughout the mouse brain.

Osten estimates that there could be hundreds or even a thousand cell types within the brain that are largely uncharacterized in their specialized functions. A cell type is defined by its function in terms of its morphology, including dendritic and axonal branches. These cells are also defined by their physiology, which includes spiking properties, and connectivity, which indicates which cell is talking to other cells.

The anatomy and physiology of the cells will validate these transcriptome single-cell RNAseq studies, which probe for the variability between cells based on their gene expression, which includes differences due to day-to-day variability and differences from distinct cell types.

By analyzing the location and modulatory functions of these cell types, Osten would like to determine ways human brains differ from other animal brains. “In the human, we can mainly analyze the location and distribution which includes the ratios of specific cell types and our hypothesis is that fine-tuning the ratios of neuronal cell types may be a powerful evolutionary mechanism for building more efficient circuits and possibly even for distinguishing between human and other animals,” Osten explained in an email.

Humans, he continued, don’t have the largest brains or the most neurons. At one point, spindle neurons were considered unique to humans, but other researchers have shown that great apes, elephants and cetaceans, which is a group that includes whales and dolphins, also have them.

Osten’s hypothesis is that one of the differences is that the ratios of cells of different types built a computational circuit that’s more powerful than the ones in other species.

When he studies mouse brains, Osten collects information across the entire brain. With humans, he explores one cubic centimeter. The human work is just starting in his lab and represents a collaboration with Zsófia Maglóczky from the Hungarian Academy of Sciences at the Institute of Experimental Medicine in Budapest.

Each mouse brain dataset is between 200 gigabytes and 10 terabytes, depending on the resolution Osten uses to image the brain. He can process 10 terabytes of data in about a week.

Osten uses machine learning algorithms that develop with guidance from human experts. This comes from a long-standing collaboration with Sebastian Seung, a professor of computer science at Princeton University.

He suggested that the research has a translational element as well, offering a way to study cellular and wiring elements characteristic of diseases. “We are looking at several of the models that are well established for autism.” He is also planning to write grants to find funds that supports the analysis of brains from people with schizophrenia and Alzheimer’s disease.

The analysis is a promising avenue of research, other scientists said. “It will be extremely interesting to compare the ratio of different cell types in various diseased brains with normal healthy brains, to see if the diseases may preferentially affect certain cell types and why and how,” Zeng explained in an email. “This could be very helpful for us to devise therapeutic means” to treat diseases.

Zeng has known Osten for about seven years. Last year, she began a collaboration using qBrain to quantify cell types.

A current resident of Williamsburg, where his reverse commute is now about 40 minutes, Osten works with a company he and Seung started called Certerra, which provides a rapid analysis of brain activity at different times. The company, located in Farmingdale, has a growing customer base and has a staff of about five people.

As for the recent work, researchers suggested it would help continue to unlock mysteries of the brain. This research is “a basic but important step toward understanding how the brain works,” Zeng added. “This paper provides a new and efficient approach that will be powerful when combined with genetic tools that can label different cell types.”

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Heather Lynch at Spigot Peak in the Antarctic. Photo by Catherine Foley

By Daniel Dunaief

Counting penguins is like riding the highs and lows of Yankees rookie Aaron Judge’s home run streaks, followed by his series of strike outs. He’s not as bad as his strike outs suggest, although he’s also not a sure thing at the plate either.

Similarly, in local populations, the Adélie penguin, which waddles to and fro squawking on land and gliding gracefully through the water, isn’t as clear a barometer of changes in the environment. Also, like Judge, when populations rise and fall, people are eager to offer their explanations for exactly what’s happening, even if the sensational explanations — he’s not that good, no, wait, he’s the greatest ever — may overstate the reality.

Heather Lynch visits Cape Lookout in Antarctica during recent trip that included an NBC TV crew that produced a feature for ‘Sunday Night with Megan Kelly.’ Photo by Jeff Topham

“We have to be careful not to be overreactive,” said Heather Lynch, an associate professor of ecology and evolution at Stony Brook University. “The concern is that, when we see increases or decreases, the implication is that there’s a miraculous recovery or a catastrophic crash.”

That, however, is inconsistent with Lynch’s recent results, which were published in the journal Nature Communications. Examining penguin data from 1982 to 2015, Lynch, Christian Che-Castaldo, who is a postdoctoral researcher in Lynch’s lab, and nine other researchers looked to see if there’s a way to connect the size of the population to changes in the environment. The study involved two teams of researchers, one supported by NASA and the other backed by the National Science Foundation.

“It’s a noisy system,” Lynch concluded. Managers of the populations of krill, small crustaceans that are the mainstay of the Adélie diet, try to use time series of key indicator species to understand what’s going on in the marine realm. In this article, Lynch said, local Adélie penguin populations may not be a clear signal of the health of the krill stocks because penguin abundance fluctuates for reasons she and her team couldn’t pinpoint.

These penguins, which Lynch has counted during her field work in the Antarctic, exhibit changes in population that can run contrary to the health, or stressed condition, of the environment.

“You can’t have your finger on the pulse” with the available data, Lynch said. “Part of our inability to model year-to-year changes is because we can’t measure the right things in the environment.”

The drivers of abundance fluctuations likely involve other animals or aspects of the krill fisheries they couldn’t model, she suggested.

“There’s a lot we don’t know about what penguins do under water, where they spend a large portion of their time and where they feed,” Grant Humphries, who was in Lynch’s lab for a year and now runs his own data science company in Scotland called Black Bawks Data Science Ltd, explained in an email. “The signals that drive year to year changes might actually lie there.”

Tom Hart, a researcher of the Department of Zoology at the University of Oxford who was not involved in this study, explores local scale variation in penguin populations. Locally, Hart said in an interview by Skype, “Things are incredibly noisy. When you aggregate, you get good signals, but with some error.” He suggested that this research drives him on further, showing that “local influences are important” because there’s so much variance left to explain. Lynch’s research is “a really good study and shows very well what’s happening on the regional scale, but leaves open what happens below that,” he said.

Indeed, Lynch suggested that by putting sites together, researchers can look at larger areas, which provide a clearer picture on shorter time scales.

Michael Polito, an assistant professor in the Department of Oceanography and Coastal Sciences at Louisiana State University who was not involved in the study, suggests that this extensive analysis indicates that “you can still look at the relationship between the abundance of penguins and the environment in a robust way. Even though any individual time series may not be the best way to understand these relationships, in the aggregate you can use them.”

Managers who set fishery policies in Antarctic waterways are often concerned about harvesting too much krill, leaving the penguins without enough food to survive and feed their chicks.

The challenge with this result, Lynch acknowledges, is that it makes setting krill boundaries more difficult.

A strategy that involves resetting conservation targets based on annual monitoring appears unrealistic given these results, Lynch said. “From a practical standpoint, we threw in everything we could and could explain only a tiny fraction of the variation,” she said.

Hart added that this is “not an argument to fish away,” he said. “We need to understand what’s going on at a local scale and we’re not there yet.”

To get people involved, Lynch and her team created a science competition, called Random Walk of the Penguins, to see who could predict the overall penguin populations for Adélie, gentoo and chinstrap penguins from the 2014 to 2017 seasons.

The competition, which was a collaborative effort with Oceanites, Black Bawks Data Science and Driven Data included $16,000 in prize money, which was donated by NASA. Entrants could use data from the 1982 through the 2013 seasons. The contest drew competitors from six continents. Of the five winners, all were from different countries.

Humphries, who was the lead on the data science computation, said the results were “somewhat humbling” because competitors were able to make “decent predictions” using only the time series. “With long-term predictions and for determining the tipping points, there is still a lot of work to be done.”

Lynch is relieved that her co-authors supported the direction the article took. “I’m a skeptic by nature and more than happy to throw orthodoxy (or even my own previous work) under the bus,” she wrote in an email. “I do hope that others will use our model as a starting point and we’ll never go back to the old days where everyone looked only at ‘their sites.’”

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Adam Gonzalez. Photo from SBU

By Daniel Dunaief

More than four days after lift off, pioneering astronauts Neil Armstrong and Buzz Aldrin had landed in the Sea of Tranquility on the surface of the moon. The NASA schedule, which included preparing the vehicle for an emergency abort of the mission in the event of a problem, called for a nap of four hours. Once they were there, however, Armstrong and Aldrin couldn’t imagine taking a four-hour respite.

“Both Armstrong and Aldrin were, understandably, excited about where they were and decided to forgo the sleeping and changed history,” Thomas Williams, element scientist in Human Factors and Behavioral Performance at NASA, described in an email.

A future trip to Mars, however, would involve considerably longer delayed gratification, with the round trip estimated to take over 400 days. The stresses and strains, the anxiety about an uncertain future and the increasing distance from family and friends, not to mention the smell of cut grass and the appearance of holiday decorations, could weigh on even the most eager of astronauts.

Determined to prepare for contingencies, NASA is funding research to understand ways to combat the mental health strains that might affect future astronauts who dare to go further than anyone has ever gone.

‘Being in long-duration space missions with other people, we expect the mental health risk will be much more elevated’. — Adam Gonzalez

Gonzalez, an assistant professor of psychiatry at Stony Brook University, received over $1 million in funding from NASA to explore ways to help these future astronauts who might be anxious or depressed when they’re on the way to the red planet.

In a highly competitive process, Gonzalez received the financial support to provide guidance on what NASA considers a low-probability, high-consequence mental health event, according to Williams.

Gonzalez “was funded because of the soundness of his research proposal and the clinical and technological expertise of the research team he assembled to help NASA address this research gap,” Williams explained.

Gonzalez started providing three different types of psychological assistance to 135 people in the middle of September. He is testing ways to provide mental health assistance with a delay that could require over 40 minutes to travel back and forth.

One group of test subjects will use a system called myCompass, which is a mental health self-help program. Another group will use myCompass coupled with a delayed text messaging response from a therapist, and a third will have a myCompass system along with delayed video messaging from a therapist.

“Being in long-duration space missions with other people — in this case, months and potentially years — stuck in extremely close quarters with others, we expect the mental health risk will be much more elevated relative to what they are going to have on the International Space Station,” Gonzalez said.

Williams said astronauts to date have not had any diagnosable disorders, but NASA has seen fluctuations in their mood, which appears linked to workload demands and the phase of the mission, Williams said. For astronauts, NASA does not want a continuing negative trend that, over a longer term, could turn into a problem.

“Part of what we hope to achieve with [Gonzalez’s] research is a validated approach to address any of these concerns,” Williams said, adding that astronauts typically understand that their contributions involve work in “high-demand, extreme environments,” Williams said.

Still, like explorers in earlier centuries, astronauts on a trip to Mars will journey farther and for a longer period of time than anyone up to that point. MyCompass is a “good, efficacious program” that takes a “trans-diagnostic cognitive behavioral therapy approach,” Gonzalez said. He suggested that the program is broad enough to help individuals manage their emotions more generally, as opposed to targeting specific types of health disorders.

Gonzalez emphasized that the choice of using myCompass as a part of this experiment was his and might not be NASA’s. The purpose of this study is to investigate different methods for communicating for mental health purposes when real-time communication isn’t possible.

William suggested that Gonzalez’s work, among others, could lead to individualized procedures for each astronaut. In addition to his work with NASA, Gonzalez also assists people at the front lines after man-made or natural disasters. He has worked with Benjamin Luft, the director of Stony Brook University’s WTC Wellness Program, on a program that offers assistance to first responders after the 9/11 attacks.

Gonzalez’s father, Peter, was a police officer who worked on the World Trade Center cleanup and recovery efforts. The elder Gonzalez has since had 9/11-related health conditions.

Gonzalez and associate professor Anka Vujanovic, the co-director of the Trauma and Anxiety Clinic at the University of Houston, are putting together a research project for the Houston area. Vujanovic did a mental health survey on Houston area firefighters earlier this year. They are inviting these firefighters to complete an online survey and telephone assessment to determine their mental health after Hurricane Harvey.

They are also conducting a three- to four-hour resilience training workshop for Houston area firefighters engaged in Harvey disaster relief efforts. “This resilience program, developed by [Gonzalez] and his colleagues, has shown promising results in reducing various mental health symptoms when tested among first responders in the aftermath of Hurricane Sandy,” Vujanovic explained in an email.

Vujanovic has known Gonzalez for over 10 years and suggested his questions were focused on “how can we better serve others, how can we improve existing interventions and how can we develop culturally sensitive approaches for vulnerable, understudied populations.” Gonzalez, who grew up in Bensonhurst, Brooklyn, and came to Stony Brook in 2012, said he was always interested in helping others.

Williams suggested that this kind of research can help people outside the space program. “We openly share and encourage the sharing of any of our relevant research findings to help address societal needs,” he added. Gonzalez’s research is “a great example of how a NASA focus on delivering personalized interventions in support of long-duration spaceflight could potentially be generalized to more rural settings where mental health providers may be scarce.”

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From left, Zachary Lippman and Dave Jackson, professors at CSHL who are working on ways to alter promoter regions of genes to control traits in tomato and corn. Photo by Ullas Pedmale

By Daniel Dunaief

He works with tomatoes, but what he’s discovered could have applications to food and fuel crops, including corn, rice and wheat.

Using the latest gene editing technique called CRISPR, Zachary Lippman, a professor at Cold Spring Harbor Laboratory, developed ways to fine-tune traits for fruit size, branching architecture and plant shape. Called quantitative variation, these genetic changes act as a dimmer switch, potentially increasing or decreasing specific traits. This could help meet specific agricultural needs. Looking at the so-called promoter region of genes, Lippman was able to “use those genes as proof of principal” for a technique that may enable the fine-tuning of several traits.

For decades, plant breeders have been looking for naturally occurring mutations that allow them to breed those desirable traits, such as a larger fruit on a tomato or more branches on a plant. In some cases, genetic mutations have occurred naturally, altering the cell’s directions. At other times, breeders have sought ways to encourage mutations by treating their seeds with a specific mutagenic agent, like a chemical.

In an article in the journal Cell, Lippman said the results reflect a road map that other researchers or agricultural companies can use to create desirable traits. This article provides a way to “create a new, raw material for breeders to have access to tools they never had before,” he said. Lippman has taken a chunk of the DNA in the promoter region, typically on the order of 2,000 to 4,000 base pairs, and let the CRISPR scissors alter this part of the genetic code. Then, he and his scientific team chose which cuts from the scissors and subsequent repairs by the cell’s machinery gave the desired modifications to the traits they were studying.

Invented only five years ago, CRISPR is a genetic editing technique that uses tools bacteria have developed to fight off viral infections. Once a bacteria is attacked by a virus, it inserts a small piece of the viral gene into its own sequence. If a similar virus attacks again, the bacteria immediately recognizes the invader and cuts the sequence away.

Scientists sometimes use these molecular scissors to trim specific gene sequences in a process called a deletion. They are also working toward ways to take another genetic code and insert a replacement. “Replacement technology is only now starting to become efficient,” Lippman said. Clinical researchers are especially excited about the potential for this technique in treating genetic conditions, potentially removing and replacing an ineffective sequence.

In Lippman’s case, he used the scissors to cut in several places in the promoter regions of the tomato plant. Rather than targeting specific genes, he directed those scissors to change the genome at several places. When he planted the new seeds, he explored their phenotype, or the physical manifestation of their genetic instructions. These phenotypes varied along a continuum, depending on the changes in their genes.

By going backward and then comparing the genes of the altered plants to the original, he could then hone in on the precise changes in the genetic code that enabled that variation. This technique allows for a finer manipulation than turning on or off specific genes in which an organism, in this case a plant, would either follow specific instructions or would go on a transcriptional break, halting production until it was turned on again.

At this point, Lippman has worked with each trait individually but hasn’t done quantitative variation for more than one at a time. “The next question,” he said, “is to do this multitargeting.” He will also use the tool to study how genes are instructed to turn on and off during growth, including exploring the levels and location of expression.

Lippman is talking with agricultural and scientific collaborators and hopes to go beyond the tomato to exploring the application of this approach to other crops. He is working with Dave Jackson, who is also a professor at Cold Spring Harbor Laboratory, on applying this model to corn.

The scientific duo has known each other for 20 years. Jackson taught his collaborator when Lippman was a graduate student at Cold Spring Harbor Laboratory and Jackson was chair of his thesis committee.

They have worked together on and off since Lippman became a faculty member about nine years ago. Last year, the two received a National Science Foundation genome grant to work on using CRISPR to study the effect of changes in promoter regions in their respective plant specialties.

“Unfortunately for us, tomato has a faster life cycle than corn, but we hope to have some results in corn this fall,” Jackson explained in an email. Lippman hopes to continue on the path toward understanding how regulatory DNA is controlling complex traits. “We can use this tool to dissect critical regulatory regions,” he said. “When we create this variation, we can look at how that translates to a phenotypic variation.”

Lippman said he is especially excited about the fundamental biological questions related to plant growth and development. When other scientists or agricultural companies attempt to use this approach, they may run into some challenges, he said. Some plants are “not transformable [genetically] easily.” These plants can be recalcitrant to plant transformation, a step sometimes needed for CRISPR gene editing. Still, it is “likely that CRISPR will work in all organisms,” he said.

Lippman hopes others discuss this technique and see the potential for a system that could help to customize plants. “My hope and my anticipation is that people all over the world will look at this paper and say, ‘Let’s start to try this out in our own systems.’ Hopefully, there will be a grass roots effort to import this tool.”

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Anne Churchland. Photo from CSHL

By Daniel Dunaief

Someone is hungry and is walking through a familiar town. She smells pizza coming from the hot brick oven on her left, she watches someone leaving her favorite Chinese restaurant with the familiar takeout boxes, and she thinks about the fish restaurant with special catches of the day that she usually enjoys around this time of year. How does she make her decision?

While this scenario is a simplified one, it’s a window into the decision-making process people go through when their neurons work together. A team of 21 neuroscientists in Europe and the United States recently created a new collaboration called the International Brain Laboratory to explore how networks of brain cells support learning and decision-making.

“We understand the simple motor reflex,” such as when a doctor taps a knee and a foot kicks out, said Anne Churchland, an associate professor at Cold Spring Harbor Laboratory and the American spokesperson for this new effort. Scientists, however, have only a limited understanding of the cognitive processes that weigh sensory details and a recollection of the outcomes from various courses of action that lead to decision-making, Churchland said.

Scientists likened the structure of the new multilaboratory effort to the circuitry involved in the brain itself. The brain is “massively parallel,” said Alexandre Pouget, a professor at the University of Geneva and the spokesperson for the IBL. “We know it’s working on consensus building across areas so, in that respect, the IBL is similar.”

A greater awareness of the decision-making process could provide a step into understanding the brain network problems involved in mental health disorders.

Churchland’s lab is one of three facilities that will house a new behavioral apparatus to study decision-making in mice. The other sites will be in the United Kingdom and in Portugal. Eventually, other labs will use this same technique and house the same apparatus.

An ongoing challenge in this field of research, Churchland said, is that scientists sometimes create their own models to test the neurological basis of behavior. While these approaches may work in their own labs, they have created a reproducibility problem, making it difficult for others who don’t have expertise in their methods to duplicate the results.

Creating this behavioral apparatus will help ensure that the collaborators are approaching the research with a reliable model that they can repeat, with similar results, in other facilities.

While the scientists will all be exploring the brain, they will each be responsible for studying the activity of circuits in different parts. The researchers will collect a wealth of information and will share it through a developing computer system that allows them to maneuver through the mountains of data.

To address this challenge, the IBL is creating a data architecture working group. Kenneth Harris, a professor of quantitative neuroscience at the University College London, is the chair of the effort. He is currently looking to hire additional outside staff to help develop this process.

Harris suggested that the process of sharing data in neurophysiology has been challenging because of the complex and diverse data these scientists share. “In neuroscience, we have lots of different types of measurements, made simultaneously with lots of different experimental methods, that all have to be integrated together,” he explained in an email.

The IBL collaboration will make his job slightly easier than the generic problem of neurophysiology data sharing because “all the labs will be studying how the brain solves the same decision-making task,” he continued.

Harris is looking to hire a data coordinator, a senior scientific programmer and a scientific MATLAB programmer. He has a data management system already running with his lab that he plans to extend to the IBL.

Pouget said there are two milestones built into the funding from the Wellcome Trust and the Simons Foundation for this new collaboration. After two years, the researchers have to have a data sharing platform in place, which will allow them to share data live as they collect it.

Second, they plan to develop standardized behaviors in all 11 of the experimental labs, where the behavior has to be as indistinguishable from one lab to another as possible.

In addition to the experimentalists involved in this initiative, several theoretical neurobiologists will also contribute and will be critical to unraveling the enormous amounts of data, Pouget suggested. “If you’re going to tackle really hard computational problems, you better have people trained in that area,” he said, adding that he estimates that only about 5 percent of neuroscientists are involved in the theoretical side, which is considerably lower than the percent in an area like physics.

Researchers involved in this project will have the opportunity to move from one lab to another, conducting experiments and gaining expertise and insights. The principal investigators are also in the process of hiring 21 postdoctoral students.

Churchland said each scientist will continue to conduct his or her own research while also contributing to this effort. The IBL is consuming between a quarter and a third of her time.

Pouget suggested that Churchland was “instrumental in representing the International Brain Laboratory to the Simons Foundation,” where she is the principal investigator on that grant. “Her role has been critical to the organization,” he said.

Churchland said the effort is progressing rapidly. “It’s moving way faster” than expected. “This is the right moment, with an incredible team of people, to be working together. Everyone is dedicated to the science.”

Harris indicated that he believes this effort could be transformative for the field. “Neuroscience has lagged behind many other scientific domains” in creating large-scale collaborations, he explained. “If we can show it works, we will change the entire field for good.”

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From left, Lisa Miller with her research team Andrew McGregor, Alvin Acerbo, Tiffany Victor, Randy Smith, Ruth Pietri, Ryan Tappero, Nadia Hameed, Tunisia Solomon, Paul Panica and Adam Lowery. Photo by Roger Stoutenburgh, BNL

By Daniel Dunaief

Most of the people at the building that cost near a billion dollars are pulled in different directions, often, seemingly, at the same time. They help others who, like them, have numerous questions about the world far smaller than the eye can see. They also have their own questions, partnering up with other researchers to divide the work.

Lisa Miller, a senior biophysical chemist at Brookhaven National Laboratory, lives just such a multidirectional and multidimensional life. The manager for user services, communications, education and outreach at the National Synchrotron Light Source II, Miller recently joined forces with other scientists to explore the potential impact of copper on a neurodegenerative disease called cerebral amyloid angiopathy (CAA).

Miller is collaborating with Steve Smith, the director of structural biology in the Department of Biochemistry and Cell Biology at Stony Brook University and William Van Nostrand, a professor in the Department of Neurosurgery at SBU who will be moving to the University of Rhode Island. The trio is in the second year of a five-year grant from the National Institutes of Health.

Miller’s role is to image the content, distribution and oxidation state of copper in the mouse brain and vessels. Van Nostrand, whom Smith described as the “glue” that holds the group together, does the cognitive studies and Smith explores the amyloid structure.

In an email, Smith explained that Van Nostrand’s primary area of research is in CAA, while he and Miller were originally focused elsewhere.

Potentially toxic on its own, copper is transported in the body attached to a protein. When copper is in a particular ionic state — when it has two extra protons and is looking for electrons with which to reduce its positive charge — it reacts with water and oxygen, producing hydrogen peroxide, which is toxic.

Miller and her colleagues are working on a technique that will enable them to freeze the tissue and image it. Seeing the oxidation state of the metal requires that it be hydrated, or wet. The X-rays, however, react with water, causing radiation damage to the tissue.

To minimize this damage, the researchers freeze the tissue. At NSLS-II, a team of scientists are working to develop X-ray-compatible cryostages that will allow them to freeze and image the tissue.

Miller is trying to figure out where and why the copper is binding to an amyloid beta protein. This is the same protein that’s involved in plaques prevalent in the brains of people with Alzheimer’s disease.

In Alzheimer’s patients, the plaques are found in the parenchyma, or the extracellular space around the brain cells. In CAA, the deposits are attached to the surface of the blood vessels on the brain side.

Lisa Miller and her dog Dora on a recent 100-mile trek from Hiawassee, Georgia, to Fontana Dam in North Carolina Photo from Lisa Miller

The current hypothesis about how copper becomes reactive in the brain originates from work Van Nostrand and Smith published recently. They suggested that the amyloid fibrils in CAA adopt an anti-parallel orientation and the fibrils in the plaques in Alzheimer’s are in a parallel orientation. The anti-parallel structure predicts that there is a binding site for copper that, if occupied, would stabilize the structure.

“We are currently working to establish if this idea is correct,” Smith explained in an email, suggesting that the NSLS-II provides a “unique resource for addressing the role of copper in CAA. The data [Miller] is collecting are essential, key components of the puzzle.”

The NSLS-II will provide the kind of spatial resolution that allows Miller to measure how much copper is in the deposits. Ideally, she’d like to see the oxidation state of the copper to see if a reaction that’s producing hydrogen peroxide is occurring.

A challenge with peroxide is that it’s hard to find in a living tissue. It is highly reactive, which means it does its damage and then reverts to water and oxygen.

As someone with considerable responsibilities outside her own scientific pursuits, Miller said she spends about a quarter of her time on her own research. One of Miller’s jobs during the summer is to host the open house for NSLS-II, which allows members of the community to visit the facility. This year, at the end of July, she “was thrilled” to host about 1,600 members of the community.

“Most of them wanted to go on the floor and meet the scientists and walk” around the three quarters of a mile circle, she said. While they are interested in the research, the surprising mode of transportation strikes their fancy when they trek around the site.

“The thing that fascinates them when they walk in the door is the tricycles,” she said. The NSLS-II can’t take credit for being the first facility to use these adult-sized tricycles, which number over 100 at the facility. “It’s a synchrotron thing.”

The previous NSLS at BNL was too compact and had too many turns, which made the three-wheeled vehicles, which, like a truck, need a wider turning radius to maneuver on a road, impractical.

Miller, who is a part of the trike-share program, is an avid hiker. This summer, she completed a 100-mile trek from Hiawassee, Georgia, to Fontana Dam in North Carolina. This section was located in the area of totality for the solar eclipse and Miller was able to witness the astronomical phenomenon at Siler Bald in North Carolina.

A resident of Wading River, Miller, who grew up in the similarly flat terrain of Cleveland, spends considerable time walking and running with her rescue mutt Dora, who accompanied her on her recent hike.

While Miller finds the research she does with copper rewarding, she said she also appreciates the opportunities NSLS-II affords her. “Every day is different and we never know what project will show up next,” she said.

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Laurie Shroyer, center, with Gerald McDonald, left, who was chief of surgery survive at the VA Central Office and is now retired, and Fred Grover, right, a professor of cardiothoracic surgery in the Department of Surgery at the University of Colorado. Photo from Laurie Shroyer

By Daniel Dunaief

To use the pump or not to use the pump? That is the question heart surgeons face when they’re preparing to perform a surgery that occurs about 145,000 times a year in the United States.

Laurie Shroyer. Photo from SBU

Called coronary artery bypass graft, surgeons perform this procedure to improve blood flow to a heart that is often obstructed by plaque. Patients with severe coronary heart disease benefit from a technique in which an artery or vein from another part of the body is inserted into the heart, bypassing the blockage.

Doctors can perform the surgery with a heart-lung machine, which is called on pump, or without it, which is called off pump.

Recently, a team of researchers led by Laurie Shroyer, who is a professor of surgery and the vice chair for research at the Stony Brook University School of Medicine, published a study in the New England Journal of Medicine that compared the survival and health of 2,203 veterans five years after surgery, with or without the pump.

Contradicting some earlier research that showed no difference in the health and outcomes after the surgery, the study revealed that using the pump increased the survival rate and reduced the rate of other health problems.

Along with the other research articles in this area, this study “should help in deciding the relative value and risks of each technique,” Frederick Grover, a professor of cardiothoracic surgery in the Department of Surgery at the University of Colorado, explained in an email.

The study Shroyer led, which is known as the Rooby trial, showed that on-pump patients had a five-year mortality of 11.9 percent, compared with 15.2 percent for the off-pump patients, Shroyer explained.

The five-year rate of medical complications, including death, nonfatal heart attacks and revascularization procedures was also lower for the on-pump group than the off-pump group, at 27.1 percent compared to 31 percent, respectively.

Consistent with these findings, the overall use of off-pump procedures has declined, from a peak of 23 percent in 2002 to 17 percent in 2012, down to 13.1 percent in 2016, according to data from the Society of Thoracic Surgeons Adult Cardiac Surgery Database Committee.

At one point, surgeons had considered an off-pump approach to be safer, but when other trials didn’t show a benefit and when the current Rooby trial demonstrated on pump had better outcomes, it “likely influenced many surgeons to use the off pump less often for specific reasons, considering it is a somewhat more difficult technique except in the most experienced hands,” Grover wrote.

The explanation for the difference five years after surgery are “not clear,” Shroyer explained in an email. The article suggests that the off-pump patients had less complete revascularization, which is known to decrease long-term survival.

Grover explained that the outcomes may have been better for the on-pump procedures in the Rooby trial for several reasons, including that the surgeons in the different trials had different levels of experience.

Leaders of the study suggested that patients and their surgeons needed to consider how to use the information to inform their medical decisions. Participants in the study were men who were veterans of the armed services.

“The data can likely be extrapolated to the general population since it is not an extremely high-risk population, but it is all male so would primarily extrapolate to males,” Grover suggested. Additionally, patients with specific conditions might still have better outcomes without the use of a pump.

“Our manuscript identifies an example for ‘patients with an extensively calcified aorta, in whom the off-pump technique may result in less manipulation of the aorta, potentially decreasing the risk of aortic emboli or stroke,’” Shroyer wrote in an email. Grover also suggested people with severe liver failure also might want to avoid the pump to prevent additional harm to the liver.

Shroyer and her team have already submitted a proposal to the VA Central Office Cooperative Studies Program. “Pending approval and funding, 10-year follow-ups will be coordinated appropriately,” Shroyer said.

Grover described Shroyer as a “spectacular investigator with a very high level of knowledge of clinical research” and, he added, a “perfectionist.” When he met Shroyer, Grover said he was “blown away by her intelligence, experience, background and energy.” He interviewed her many years ago to direct a major VA Cooperative Study. After the interview and before the next meeting, he called another interviewer and asked if he, too, agreed to hire her on the spot.

Grover recalled a trip back from Washington to Denver 15 years ago after they had been in a 10-hour meeting with no scheduled breaks. She took out her laptop on the airplane and asked him to write up results for a new grant.

“I was beat and finally said if she didn’t let up, I was going to jump out of the airplane just to get away from her,” he recalled. She shut her computer, ordered drinks and they enjoyed a peaceful flight back.

A resident of Setauket, Shroyer lives with her husband Ken, who is the chair of the Department of Pathology at Stony Brook School of Medicine. The professor said she loves the Staller Center, which she considers one of the greatest kept local secrets. She appreciates the opportunity to hear classical music performances by the Emerson String Quartet and by cellist Colin Carr.

When she entered biomedical research in 1992, it was unusual for women to rise to the level of full professor at an academic medical center. She strives to be an outstanding mentor to her trainees, including women and under-represented minorities, so that they can achieve their potential, too. As for her work, Shroyer’s hope is that the Rooby research “will provide useful information to guide future changes in clinical care practices” and, in the longer term “to improve the quality and outcomes for cardiac surgical care.”

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Above, Ken Dill shows how molecules fold and bind together. Photo from SBU

By Daniel Dunaief

The raw materials were here. Somehow, billions of years ago, these materials followed patterns and repeated and revised the process, turning the parts into something more than a primordial soup.

Ken Dill, who is a distinguished professor and the director of the Laufer Center for Physical and Quantitative Biology at Stony Brook University, took a methodical approach to this fundamental development. He wanted to understand the early statistical mechanics that would allow molecules to form long chains, called polymers, which contained information worthy of being passed along. The process of forming these chains had to be self-sustaining.

After all, Dill said, many activities reach an end point. Putting salt in water, for example, creates a mixture, until it stops. Dill, however, was looking for a way to understand auto-catalytic or runaway events. Lighting a forest fire, for example, is much more self sustaining, although even it eventually stops. Life has continued for over four billion years.

On Aug. 22, Dill, Elizaveta Guseva and Ronald Zuckermann, the facility director in biological nanostructures at the Lawrence Berkeley National Laboratory, published a paper in the journal Proceedings of the National Academy of Sciences (PNAS).

The researchers developed a fold and catalyze computational model that would explain how these long chains developed in a self-sustaining way, in which hydrophilic and hydrophobic polymers fold and bind together.

Random sequence chains of each type can collapse and fold into structures that expose their hydrophobic parts. Like a conga line at a wedding reception, the parts can then couple together to form longer chains.

These random chemical processes could lead to pre-proteins. Today’s proteins, Dill said, mostly fold into a very particular shape. Pre-proteins would have been looser, with more shape shifting.

The workhorses of the body, proteins perform thousands of biochemical reactions. Dill suggested that this model “rates high on the list” in terms of the findings he’s made over the course of his career.

Zuckermann described this work as significant because it lays out predictions that can be tested. It highlights the importance of chemical sequence information in polymer chains and “how certain sequences are more likely to fold into enzyme-like shapes and act as catalysts than others,” he explained in an email.

Zuckermann works with substances he figured out how to make in a lab that are called peptoids, which are non-natural polymers. These peptoids are a “good system to test the universality of [Dill’s] predictions,” he said.

The “beauty” of Dill’s work, Zuckermann suggested, is that “it should apply to most any kind of polymer system” where researchers control the monomer sequence and include hydrophobic and hydrophilic monomers in a particular order, putting Dill’s predictions to the test.

For her part, Guseva worked in Dill’s lab for her PhD thesis. She had started her research on something that was “more standard physical biology” Dill said, but it “was not turning out to be particularly interesting.”

The scientists had a discussion about trying to develop a chemical model related to the origins of life. While exciting for the scope of the question, the research could have come up empty.

“There was so much potential to fail,” Dill said. “I feel pretty uncomfortable in general about asking a graduate student to go in that direction, but she was fearless.”

Dill and Zuckermann, who have collaborated for over 25 years, are trying to move forward to the next set of questions.

Zuckermann’s efforts will focus on finding catalytic peptoid sequences, which are nonbiological polymers. He will synthesize tens of thousands of peptoid sequences and rank them on how enzyme-like they are. This, he explained, will lead to a better understanding of which monomer sequences encode for protein-like structure and function.

Zuckermann suggested that the process in this research could have the effect of transforming a soup of monomers into a soup of functional polymers. This, he said, might set the stage for the evolution of DNA and RNA.

Proteins could have been a first step towards a genetic code, although life, as currently defined, would not have blossomed until a genetic code occurred, too, Dill suggested.

The origins of DNA, however, remains an unanswered question. “We’re trying to think about where the genetic code comes from,” Dill said. “It’s not built into our model per se. Why would biology want to do a two polymer solution, which is messy and complicated and why are proteins the functional molecules? This paper doesn’t answer that question.”

Dill and Zuckermann are in the early stage of exploring that question and Dill is hopeful he can get to a new model, although he doesn’t have it yet.

Dill moved from the University of California at San Francisco to join the Laufer Center about seven years ago. He appreciates the freedom to ask “blue sky questions” that he couldn’t address as much in his previous work.

Wearing a hat from his native Oklahoma, Dill, in a photo from around 1997, tinkers with a toy boat he made with sons Tyler and Ryan. Photo by Jolanda Schreurs

A resident of Port Jefferson, Dill lives with his wife Jolanda Schreurs, who has a PhD in pharmacology. The couple has two sons, Tyler and Ryan.

Tyler graduated with a PhD from the University of California at San Diego and now works for Illumina, a company which which makes DNA sequencers. Ryan, meanwhile, is earning his PhD in chemistry from the University of Colorado and is working on lasers.

“We didn’t try to drag our sons into science,” Dill said. “With both kids, however, we had a workshop in the basement” where they often took anything that was within arm’s reach and nailed it to a board. One of the finished products was a remote-controlled and motorized boat.

As for his lab work, Dill is thrilled to have this model that he, Guseva and Zuckermann provided, while he recognizes the questions ahead. Scientists “see something puzzling and, rather than saying, ‘I need to avoid this, I don’t have an answer,’ we find it intriguing and these things lead from one step to the next. There tends to remain a huge number of super fascinating problems.”

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Alex Orlov on the campus of the University of Cambridge. Photo by Nathan Pitt, University of Cambridge

By Daniel Dunaief

The Ukranian-born Alex Orlov, who is an associate professor of materials science and chemical engineering at Stony Brook University, helps officials in a delicate balancing act.

Orlov, who is a member of the US-EU working group on Risk Assessment of Nanomaterials, helps measure, monitor and understand the hazards associated with nanoparticles, which regulatory bodies then compare to the benefit these particles have in consumer products.

“My research, which is highlighted by the European Union Commission, demonstrated that under certain conditions, [specific] nanoparticles might not be safe,” Orlov said via Skype from Cambridge, England, where he has been a visiting professor for the past four summers. For carbon nanotubes, which are used in products ranging from sports equipment to vehicles and batteries, those conditions include exposure to humidity and sunlight.

“Instead of banning and restricting their production” they can be reformulated to make them safer, he said.

Orlov described how chemical companies are conducting research to enhance the safety of their products. Globally, nanotechnology has become a growing industry, as electronics and drug companies search for ways to benefit from different physical properties that exist on a small scale. Long Island has become a focal point for research in this arena, particularly at the Center for Functional Nanomaterials and the National Synchrotron Light Source II at Brookhaven National Laboratory.

Alex Orlov on the campus of the University of Cambridge. Photo by Nathan Pitt, University of Cambridge

Indeed, Orlov is working at the University of Cambridge to facilitate partnerships between researchers in the chemistry departments of the two universities, while benefiting from the facilities at BNL. “We exchange some new materials between Cambridge and Stony Brook,” he said. “We use BNL to test those materials.”

BNL is an “essential facility,” Orlov said, and is where the postdoctoral student in his lab and the five graduate students spend 30 to 60 percent of their time. The data he and his team collect can help reduce risks related to the release of nanomaterials and create safer products, he suggested.

“Most hazardous materials on Earth can be handled in a safe way,” Orlov said. “Most scientific progress and environmental protection can be merged together. Understanding the environmental impact of new technologies and reducing their risks to the environment should be at the core of scientific and technological progress.”

According to Orlov, the European Union spends more money on technological safety than the United States. European regulations, however, affect American companies, especially those that export products to companies in the European Union.

Orlov has studied how quickly toxic materials might be released in the environment under different conditions.

“What we do in our lab is put numbers” on the amount of a substance released, he said, which informs a more quantitative understanding of the risks posed by a product. Regulators seek a balance between scientific progress and industrial development in the face of uncertainty related to new technologies.

As policy makers consider the economics of regulations, they weigh the estimated cost against that value. For example, if the cost of implementing a water treatment measure is $3 million and the cost of a human life is $7 million, it’s more economical to create a water treatment plan.

Orlov teaches a course in environmental engineering. “These are the types of things I discuss with students,” he said. “For them, it’s eye opening. They are engineers. They don’t deal with economics.”

In his own research, Orlov recently published an article in which he analyzed the potential use of concrete to remove pollutants like sulfur dioxide from the air. While concrete is the biggest material people produce by weight and volume, most of it is wasted when a building gets demolished. “What we discovered,” said Orlov, who published his work in the Journal of Chemical Engineering, “is that if you take this concrete and expose new surfaces, it takes in pollutants again.”

Fotis Sotiropoulos, the dean of the College of Engineering and Applied Sciences at SBU, said Orlov has added to the understanding of the potential benefits of using concrete to remove pollutants.

Other researchers have worked only with carbon dioxide, and there is “incomplete and/or even nonexistent data for other pollutants,” Sotiropoulos explained in an email. Orlov’s research could be helpful for city planners especially for end-of-life building demolition, Sotiropoulous continued. Manufacturers could take concrete from an old, crushed building and pass waste through this concrete in smokestacks.

To be sure, the production of concrete itself is energy intensive and generates pollutants like carbon dioxide and nitrogen dioxide. “It’s not the case that concrete would take as much [pollutants] out of the air as was emitted during production,” Orlov said. On balance, however, recycled concrete could prove useful not only in reducing waste but also in removing pollutants from the air.

Orlov urged an increase in the recycling of concrete, which varies in the amount that’s recycled. He has collaborated on other projects, such as using small amounts of gold to separate water, producing hydrogen that could be used in fuel cells.

“The research showed a promising way to produce clean hydrogen from water,” Sotiropoulos said.

As for his work at Cambridge, Orlov appreciates the value the scientists in the United Kingdom place on their collaboration with their Long Island partners.

“Cambridge faculty from disciplines ranging from archeology to chemistry are aware of the SBU/BNL faculty members and their research,” Orlov said. A resident of Smithtown, Orlov has been on Long Island for eight years. In his spare time, he enjoys hiking and exploring new areas. As for his work, Orlov hopes his work helps regulators make informed decisions that protect consumers while making scientific and technological advances possible.

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From left, scientist Lin Yang at the LiX beamline demonstrates how the beam hits the sample to high school teachers James Ripka, Mary Kroll, Fred Feraco, Janet Kaczmarek and Jocelyn Handley-Pendleton. Photo from BNL

By Daniel Dunaief

He helped build it and now a range of researchers are coming.

Lin Yang helped create the LiX beamline at the National Synchrotron Light Source II at Brookhaven National Laboratory, which is attracting researchers eager to study the fine structure and function of everything from proteins to steel.

The lead scientist for the LiX beamline at the NSLS-II at BNL, Yang was the control account manager for the construction of the beamline and was the spokesperson for a team that wrote the original beamline development proposal.

“In our case, the scattering from the sample is sensitive to the underlying structure” of materials, Yang said. “That’s why people want to use scattering to study their samples.”

Like the other beamlines at the NSLS-II, the LiX enables scientists to use sophisticated equipment to search for links between structures and function. Each beamline has a three-letter acronym. In the case of LiX, the “Li” stands for life sciences, while the “X” represents X-ray scattering.

When they designed the beamline, LiX researchers were seeking optics that were capable of producing a beam to conform to the specifications required for different types of measurements. They then designed an experimental station that is suitable for handling biological samples. Specifically, that involved developing an automated sample handler for measurements on protein molecules in solution.

“With atomic resolution structures and functional assays, we do get new insights [about] important ions such as calcium,” which are involved in signaling and physiology, Qun Liu, a principal investigator in the Biology Department at BNL, described in an email. “LiX will be essential to allow us [to see] the transport process in real time and space.” Liu wrote that Yang is an “outstanding X-ray beamline scientist” who is also well known for his pioneering work on membrane diffraction.

The ability to perform measurements using a beam of a few microns is “pretty unique right now,” which also attracted researchers working with steel samples, Yang said. “When we designed the instrument, our focus [was] on the biological structure” but the beamline is “versatile enough” that it has found other uses, Yang said.

Researchers working with steel realized that the same diffraction-based approach to finding underlying structures in living tissue could also shed light on the structures of their samples.

In everyday life, diffraction is visible from the wavelengths of light that form the hologram on a credit card. Scientists working with steel have been applying for time on the LiX beamline, too, creating a competitive environment for researchers working in both fields.

Lynne Ecker, the deputy department chair in the Nuclear Science and Technology Department at Brookhaven National Laboratory, has used the beamline to study the effect of neutrons and ions on steel.

“Ions will only damage steel so far,” Ecker said. The LiX is “perfect” to study the degree of the damage. Ecker said she’s tried this kind of analysis in other places, but the LiX provides better spatial resolution. The LiX scientists are working on improving the degree of automation for sample handling and data processing.

“We are about to install a six-axis robot, which is typically seen in industrial automation, to help realize unattended overnight measurements on protein solution samples,” Yang said. The robot is already at the facility and Yang and his team will be installing the support structure to mount the robot in the experimental station this month. “The more challenging task is to put the software in place so that the beamline can control the robot,” he explained in an email.

The LiX beamline uses lenses made from beryllium, which are transparent to X-rays. For X-rays at the wavelength of about one angstrom, about 93 percent can pass through about a millimeter of beryllium. That compares favorably to aluminum, which allows about 2 percent to pass through at the same thickness.

The LiX beamline can run at 500 frames per second, which produces a wealth of data. In practice, it may take up to a second for the detector to accumulate enough signal from the sample. Still, the beamline can generate enough data that the experimenter may not be able to examine it frame by frame, which makes automated data processing more important.

Scientists have used the beamline to explore the structure of plants. These researchers mainly want to understand how materials like cellulose are organized within different parts of the plant and in different plants.

In bones, researchers can differentiate between organic matter like collagen and inorganic matter. Not only can they determine where they are, but they can also explore their orientation in a sample. Bones are easy samples since collagen and minerals in bone have distinctive scattering and diffraction patterns, Yang said. Researchers “like to look at how biological molecules change their shape as they interact with their functional partners,” Yang said.

A resident of East Setauket, Yang lives with his wife Mian Wang, who is an architect in Farmingdale, and their two daughters. A fan of tennis, Yang plays as often as he can during the summer at the Three Village Tennis Club.

Yang grew up in Yunnan province in the southwest of China. Trained as a physicist, Yang picked up knowledge of molecular biology from his years of working with other scientists. In his work, he gets to combine his talents in engineering, programming and molecular biology.

“We learn new things when we interact with our users/guest researchers since we first need to learn about their problems before we can help solve them,” he described in an email. Yang hopes the research he and the team at the LiX support will result in high-impact publications. “As more researchers know about us and our capabilities, I expect more people will want to perform experiments at our beamline,” he said.

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