Power of 3

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Christopher Vakoc in his lab at Cold Spring Harbor Laboratory. Photo courtesy of CSHL

We create buildings that climb into a sky crowded with airplanes and supersonic jets. We harness the energy of the atom, design intricate artwork, compose and perform inspirational music, travel miles below the surface of the ocean and send satellites deep into space. Sometimes, we tap into unlikely sources to learn new ways to improve our lives, even in the fight to understand and attack cancer.

Bacteria have been battling against viruses for so long that they have evolved to disarm these intruders. The bacterial immune system uses a gene-editing system called CRISPR. Researchers have taken some of the CRISPR machinery from bacteria and are using it in human cells. CRISPR was named the American Association for the Advancement of Science’s Breakthrough of the Year for 2015.

Using a bacterial enzyme called Cas9, which isn’t found naturally in humans but can be used in our genetic code, scientists can edit out DNA that contributes to the proliferation of cancer.

Christopher Vakoc, an associate professor at Cold Spring Harbor Laboratory, has used his expertise with CRISPR to study cancer.

Starting in the fall of 2014, he and Charles Keller, the scientific director at Children’s Cancer Therapy Development Institute in Oregon, collaborated to study the disease rhabdomyosarcoma, a rare form of deadly pediatric cancer of the connective tissue that typically involves muscle cells attached to bones. Vakoc’s lab is using CRISPR to discover new vulnerabilities in RMS.

At this point, Keller has found a potential treatment in animal models that shows positive results, while Vakoc has determined how that specific drug is working. They have submitted their work for publication in a scientific journal and are awaiting word back from reviewers.

Starting this fall, Vakoc will add Ph.D. scientist Bryan Lanning, who will try and identify new targets in RMS using CRISPR.

“It’s great to contribute more resources to this effort,” Vakoc said.

In an email, Keller detailed how “we have more insight into how the drug for rhabdomyosarcoma works.” He credits Eric Wang from Vakoc’s lab for contributing “instrumental” results to the early findings. Keller is “grateful for the support of [Vakoc’s] lab and the collaboration it empowers.”

At the same time, Vakoc’s lab continues to work in an area where they have made some breakthroughs with CRISPR, on a site called BRD4. Collaborating with several other labs, Vakoc showed that chemical inhibition of BRD4 provides a therapeutic benefit in mouse models of leukemia, which has led to clinical trials in humans. Using a drug called JQ1, scientists have generated positive results with humans in Phase I of the Food and Drug Administration’s process for therapeutic approval.

Christopher Vakoc/photo courtesy of CSHL
Christopher Vakoc/photo courtesy of CSHL

“Some of the patients at tolerated doses have had complete remission,” he said. He called those early findings “encouraging.”

A major area of focus, Vakoc explained, involves continuing to try to understand on a molecular level how these drugs are working and why BRD4 is a drug target. “It was not clear in the beginning, but we are slowly revealing the special properties of BRD4,” he said.

As the tests move into the next stage, called Phase 2, an important question in order for this therapy to work, Vakoc said, is to anticipate “how we are going to overcome these resistant states.”

While he doesn’t have an answer yet, he said, he hopes a combination of agents can be more active than any one treatment individually. “A lot of what we’ve been doing, while we are waiting for clinical trials to get under way, is to study resistance and therapies in animal and culture models,” Vakoc said.

Vakoc and Johannes Zuber, a group leader at the Research Institute of Molecular Pathology in Vienna, Austria, recently published a paper in which they outlined how some cells become resistant through nongenetic changes. As they described, the cells are rewiring gene expression without introducing new DNA. A cell can evolve to this new state, Vakoc said. In the battle to defeat the disease, this requires a readiness to defeat what he expects will be some level of resistance to this new treatment.

The inhibitors Vakoc and Zuber have worked on have “very broad and desired activity,” but to find a cure “we have to find effective combination therapies,” explained Zuber, who collaborated on BRD4 projects at Cold Spring Harbor when he was a postdoctoral researcher in Scott Lowe’s lab as early as 2008.

“Assuming that cancer drugs can be well-tolerated enough to be combined and administered as chronic therapy, I hold out hope that we can combine numerous agents and apply them upfront, based on information in the lab and real-life information from patients,” Vakoc said. This could mean a cocktail of three, four or five well-tolerated drugs that he hopes won’t increase chemotherapy toxicity.

In an email, Zuber wrote that Vakoc’s CRISPR system will allow systematic CRISPR screens that point toward domains and identify structures for drug development.

Vakoc lives on campus at CSHL with his wife Camila Dos Santos, who studies epigenetic changes that occur after pregnancy. The couple is collaborating in their research. “CRISPR technology is useful for all biologists and my wife is no exception,” he said.

As for his own work, Vakoc expressed an appreciation for the scientific tools bacteria are providing.“Biologists have always been learning from naturally occurring mechanisms used by various organisms” and using them to approach a range of challenges, Vakoc explained.

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Maurizio Del Poeta in his laboratory at Stony Brook University. Photo by Antonella Rella

Like the fictional Steve Austin, Stony Brook University’s Maurizio Del Poeta has become the ““Six Million Dollar Man.”

No, Del Poeta didn’t crash in an experimental spacecraft; and no, he doesn’t have bionic limbs. Instead, work with a potentially deadly fungus in his laboratory helped Del Poeta, a professor in the Department of Molecular Genetics & Microbiology at Stony Brook University, earn two, multiyear $3 million grants from the National Institutes of Health.

Del Poeta is attacking a fungus that can be deadly, particularly for people with weakened immune systems. Recently, his approach yielded an unexpected result that may lead to a vaccine. “We were looking for a gene that would metabolize a fungal sphingolipid on the surface of the fungus,” he said.

The gene he mutated caused a different function than expected, leading mice with exposure to this strain to become resistant to fungal infection, Del Poeta said.

This change may be the key to providing a vaccination against Cryptococcus neoformans, a fungus present in numerous places, including in bird droppings.

Postdoctoroal student Antonella Rella who is working on an antiviral vaccine in Del Poeta’s laboratory at SBU. Photo by Maurizio Del Poeta
Postdoctoroal student Antonella Rella who is working on an antiviral vaccine in Del Poeta’s laboratory at SBU. Photo by Maurizio Del Poeta

“We think that this discovery will open the road to a new vaccination strategy against fungi” including candidiasis caused by Candida albicans or aspergillosis, caused by Aspergillus funigatus, Del Poeta said.

The same gene for sterol glucosidase that Del Poeta and the researchers in his lab mutated is also found in the genome of these other fungal species. “One could potentially make a vaccine containing the three fungal mutants combined and inject them together to protect simultaneously” against all three species, he said. These three infections account for over 1.3 million deaths per year, according to the Centers for Disease Control and Prevention.

This vaccine could prove effective for immunocompetent and immunocompromised individuals. A potential vaccine is particularly important for the latter group.

Del Poeta and his colleagues injected the mutated version of the fungus into an animal model that mirrored the conditions of a patient with the human immunodeficiency virus. The vaccine “protected 100 percent” against an infection, Del Poeta said. “Whatever this mutant is doing, the protection is not determined by the presence of CD4 cells.”

CD4 cells are a type of white blood cell that fights infection. They are at the center of vaccines that train the immune system to recognize and destroy live versions of infections. Without those cells, vaccination becomes more difficult, but, clearly, not impossible.

His results earned him a 1 score, the top mark from reviewers, from the National Institutes of Health, which recently awarded him a $3 million grant to study this mutated fungus. The grant should become active on July 1.

John Perfect, the James B. Duke Professor of Medicine and chief of the Division of Infections Disease at Duke University, brought Del Poeta into his laboratory from Italy. He is proud of his protege, describing Del Poeta in an email as a “major investigator in fungal pathogenesis.”

An important question Del Poeta can’t answer is how this attenuated strain conveys resistance.

Before this promising early work can become a part of preventive treatment, Del Poeta said he and his team will look for a different formulation of this potential vaccine.

“It will be difficult to convince the FDA to administer a live fungus to an immunocompromised patient, even if the fungus will be attenuated,” he explained. “So, we need to make a better vaccine.”

His postdoctoral researcher, Antonella Rella, who is the first author on a paper published in Frontiers in Microbiology describing their results, is making and testing new formulations. She has already found promising results using only certain portions of the cell, Del Poeta said.

Maurizio Del Poeta in front of the brick oven he built in the backyard of his Mount Sinai home. Photo by Chiara Luberto
Maurizio Del Poeta in front of the brick oven he built in the backyard of his Mount Sinai home. Photo by Chiara Luberto

Del Poeta is also working in drug development. He received a $3 million grant this past December from the NIH for his continued work on drugs to treat fungal infections.

Last June, Del Poeta published a study in mBio, the online journal of the American Society for Microbiology, in which he found two compounds, BHBM and its derivative DO, that decreased the level of a lipid fungal cells need to reproduce.

Since then, he has found that some derivatives are more potent and less toxic.

He has teamed up with Iwao Ojima, the director of the Institute of Chemical Biology and Drug Discovery at Stony Brook University, and John Mallamo, who was a director in drug discovery at Cephalon. The scientific team is working with Brian McCarthy, an entrepreneur-in-residence, as a part of a new company called MicroRid Technologies.

The first milestone in the next three to four years is to raise additional funds for FDA filing and to perform a Phase 1 clinical trial some time between 2018 and 2020.

Del Poeta “exudes optimism” and his “scientific rigor and thoughts are simply first rate,” said Perfect.

When he’s not working to stop potentially deadly fungal infections, Del Poeta lives in Mount Sinai with his wife Chiara Luberto, who is studying leukemia at the Cancer Center at Stony Brook, and his sons Matteo, who is 9, and Francesco, who is 6.

Originally from Treia, Italy, which is near Florence on the Adriatic coast, Del Poeta worked in a pizzeria when he was younger. He built a brick oven in his backyard, where he hosts neighbors and the families of his sons’ classmates. His favorite pizza, called Amir Pizza after a former talented postdoctoral student in his lab, is a white pizza with extra-thin-sliced white onions, one thin-sliced hard avocado, a generous portion of pistachios and mozzarella.

While the work Del Poeta does has clinical implications, he has no expectations to move to a biotechnology company. “I love what I do,” he said. “If I can make the life of a patient a little better, if I can bring a new drug to the clinic or even contribute a little bit to improve the survival of a patient, I would be so grateful.”

Readers who would like to know more about the battle against fungal infections can gather information at the Global Action Fund for Fungal Infections web site, www.gaffi.org.

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Alice Cialella during the Muddy Tire Mountain Bike Race in Wading River in 2015/Photo by Mark Wiggins

Researchers at Brookhaven National Laboratory have traveled the world, placed their scientific instruments aboard commercial ships, or gathered information from satellites, aircraft and ground-based facilities to study the atmosphere, the environment and the weather.

Chemist Arthur Sedlacek, whose work was featured last week in the Times Beacon Record, has journeyed in a plane above wildfires in the western United States to collect information about aerosolized particles, while atmospheric scientist Ernie Lewis has gathered data from commercial ships that trek back and forth from Los Angeles to Hawaii to determine how clouds change along the route through the Pacific.

Assistant ecologist Shawn Serbin, meanwhile, has studied the spectroscopic properties of forests to determine how an area responds to different temperature, precipitation and atmospheric conditions.

These are all part of the mission of the Environmental and Climate Sciences Department at BNL, explained Alice Cialella, the interim chair of the department and also the manager of the DOE ARM Climate Research Facility External Data Center.

The Environmental and Climate Sciences Department, which includes over 50 scientific, professional and technical staff, is also engaging in several new efforts, including a collaboration with Stony Brook University. Using several mobile radar systems donated by companies and the military, these two local institutions will gather a wealth of data about the local and regional climate and environment.

“The unprecedented array of radars will help us better understand pre-storm conditions before high impact weather events, provide detailed wind data for modeling energy and pollution flow through cities and better process level understanding of precipitation and cloud formation,” Cialella explained in an email.

To be sure, the initiative is so new that the weather satellites, which can be loaded on a truck and moved to different parts of a city, haven’t arrived yet. “There are many more details to work out,” she said.

This is just one of several initiatives that are all a part of the DOE-funded facility’s efforts to gain a better understanding of the local and global environment and how it might be changing over time.

Recently, Cialella’s department participated in a study to look at how air particles circulate through New York City subway stations for the Department of Homeland Security. Separately, atmospheric scientist Andrew Vogelmann is collaborating with a multi-institution study to connect ARM Climate Research Facility’s observations to climate modeling efforts.

Alice Cialella in her office at Brookhaven National Laboratory/Photo by Roger Stoutenburgh
Alice Cialella in her office at Brookhaven National Laboratory/Photo by Roger Stoutenburgh

Cialella, who has served as the interim chair of the department for six months, said this effort will “create more synergy between weather observational data sets and climate modelers.”

Martin Schoonen, the associate laboratory director for  the Environment, Biology, Nuclear Science and Nonproliferation Directorate at BNL, said he chose her as interim chair because “she has proven to be a very effective group leader, growing her group significantly over the last few years and taking on a leadership role within the DOE-Atmospheric Radiation Measurement and Climate Research Facility.”

Schoonen called her a “consensus builder” who “listens well to people and takes time to get to know all perspectives.” Cialella is “absolutely” in contention for the full-time role in the Environmental and Climate Sciences Department, Schoonen said.

Cialella said she sees opportunities to encourage scientific partnerships. “I look for a high level understanding of the science and try to identify common themes that aren’t being fully utilized or appreciated,” she said. The department is in two buildings and she tries to ensure that she assists with any potential collaborations among researchers in the same department but at different locations.

Serbin said he appreciates how Cialella has encouraged collaborations among researchers who study different elements of the environment.

Hired at first for her software engineering skills and her master’s degree in physical geography, one of her initial jobs was to create maps for the ARM sites using Geographic Information Systems software.

In her work as the manager of the data center, which represents about half her time, Cialella and Laurie Gregory supervise a team of eight. They identify new sources of data that are external to the ARM Climate Research Facility and that augment the ARM facility, such as weather forecast model data. The group has been creating ARM databases and Web data applications for ARM for over 20 years.

While she hasn’t worked on a computer program in a number of years, Cialella’s work allows her to engage in “more broad-thinking and strategic planning.” Over time, the focus of the ARM Climate Research Facility has shifted from gathering information through observations to using that information to inform global climate models. “In the last couple of years, the move has been to provide the data for the modeling component of the program much more directly,” she said.

A resident of Poquott, Cialella lives with her husband John Robinson, who is a professor in integrative neuroscience in the Department of Psychology at Stony Brook. Using mouse models, Robinson hopes to understand the function and dysfunction of the human central nervous system.

The couple has a daughter Zoe, who is a senior at Ward Melville High School and is planning to attend the University of Vermont in the fall.

Cialella said she enjoys anything that gets her moving. She runs, bikes, swims and does triathlons in the summer. Exercise is a great “stress reliever,” she said. She also enjoys being a part of a book group. She recently read “Tinkers” by Paul Harding.

Cialella grew up in Maryland, the fourth of five children. Her late father, Carmen, was a physicist at Aberdeen Proving Grounds.

As for her work, Cialella said she continues to plan for the future. “You always want to be thinking at least three to five years out and what the next area of research might be,” she said. “The next area may well be high-resolution atmospheric modeling for urban and regional studies.”

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An image from the Biomass Burn Observation Project. Photo from Arthur Sedlacek

The search for small particles has taken Arthur Sedlacek to places like thick plumes of smoke above wildfires raging in the western United States to picturesque vistas on Ascension Island, a staging area for the Allies for antisubmarine activities during World War II.

A chemist in the Environmental and Climate Sciences Department at Brookhaven National Laboratory, Sedlacek is studying aerosols, which are tiny particles suspended in the atmosphere. These particles can form the nuclei of clouds. Depending on their color, they can also either heat or cool the atmosphere.

“White” aerosols, as Sedlacek put it, such as sulfate- or nitrate-based particles, reflect solar radiation, while “black” aerosols, such as soot, absorb the sun’s light and help trap that energy in the atmosphere. By absorbing heat, darker aerosols increase the temperature, while lighter particles reflect some of that heat back into space.

“When you talk about climate change, you identify greenhouse gases, most notably carbon dioxide, which is responsible for warming,” Sedlacek said. “When you run through the model calculations, the models overpredict what we should see. Either something is wrong with the models or something else is counterbalancing the warming effect.”

Arthur Sedlacek photo from Sedlacek
Arthur Sedlacek photo from Sedlacek

Indeed, aerosols represent part of that something else. “We need to incorporate them into our models to better understand what we actually observe in the field,” Sedlacek said. He studies the types of particles, how they age, their color, changes in their color and whether they can act as cloud condensation nuclei.

“We want to understand what’s being produced and how it changes as the plume dilutes and gets older,” Sedlacek said. “How this aging alters the microphysical and optical [properties are] very important to quantifying the contribution of aerosol to climate change.”

During the summer and fall of 2013, Sedlacek was a part of a study called the Biomass Burn Observation Project, which included 14 scientists from seven institutions. Other BNL scientists included his co-principal investigator and chemist Larry Kleinman, atmospheric scientist Ernie Lewis, chemist Stephen Springston and tenured scientist Jian Wang.

Sedlacek spent several hours preparing the equipment that would gather data above these raging fires.

The planes flew into the smoke and then moved in the direction of the smoke, measuring the changes in these aerosols an hour, two hours and more away from the fire. These measurements showed how these aerosols changed over time.

While the study was conducted several years ago, Sedlacek and his colleagues are still working to put together the information.

They have learned that the particles in the air change dramatically in the first few hours. Biomass burning events produce aerosols that are considered “brown carbon” because they are not black, like soot, but they aren’t white like a sulfate- or nitrate-containing aerosol.

Brown carbon is known to evolve. They also observed a particle type referred to as “tar balls.” While others have seen these, Sedlacek and his colleagues are the first to show that they behave like secondary organic aerosols.

The description of these tar balls isn’t meant to suggest boulder-sized pieces of tar hiding somewhere in the clouds: They are about 250 nanometers in diameter, which makes them about 240 times smaller than the thickness of a human hair.

The group is trying to understand how these tar balls form. These tar balls may help clarify a sampling mystery. The top-down view, from satellites, suggests something different than the bottom-up view, from collecting data from particles. The satellite views indicate there should be more “stuff” in the air.

The bottom-up view may not take these tar balls into account. Not all wildfires produce tar balls, but the data Sedlacek and his collaborators collected suggest that they could represent 20 to 30 percent of the particulate mass in the plume.

In addition to flying above wildfires, Sedlacek also jets to places around the world including Brazil and Ascension Island.

He is also a mentor for two instruments, which means he is responsible for making sure they are functioning. He works with single-particle soot photometers, which measure the amount of black carbon in the air, and the aethalometer, which uses light transmission to determine the concentration of black carbon particles collected on a filter.

With the single-particle soot photometer, Sedlacek looked “at the data in a new way and from that gained insight into the morphology — the shape — of the individual particles, something that nobody had thought to do previously,” Lewis explained in an email. Lewis, who has known Sedlacek for over 10 years and has collaborated on numerous projects, said that Sedlacek is “wonderful to work with” and is a “very careful scientist with keen insight and great attention to detail.”

On Ascension Island, Sedlacek was a mentor in support of another scientist’s field campaign. That effort is exploring how biomass burning aerosols produced in Africa interact with marine clouds as the air mass moves from the west coast of Africa in the general direction of the island.

A photographer and bicyclist, Sedlacek takes numerous pictures of his work.

Sedlacek describes himself as an experimentalist and an observationist. He does not do any of the climate models. His data, however, informs those models and enables other scientists to include more details about the climate and atmosphere.

“Those of us who love to fly get to fly into these plumes,” where they are in an unpressurized cabin, so the outside air makes its way into the plane, he said. They experience considerable turbulence above these fires.

“When we see our instruments and our senses respond at the same time,” he said, “it makes for an unforgettable experience.”

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Above, Johanna Jarcho holds a model of a brain in her lab at SBU. Photo from Jarcho

Ever stare at the head of an anxious adolescent — wait, is that a redundant phrase? — and wonder, “What’s going on inside that head?” While Johanna Jarcho can’t read their minds, she can see areas of the brain that are active during different simulated social situations using a functional-MRI brain scan.

Through her work, she found some areas of the brain are more active, or light up, with children who are isolated or feel socially withdrawn, compared with the same areas of children who are more socially comfortable.

“The goal is to identify what is it about certain kids that are at risk that makes them resilient and what it is about those that develop the symptoms” of anxiety disorders, said Jarcho, who is an assistant professor of psychology at Stony Brook University, with joint appointments in the clinical area as well as the social and health areas. “If we can identify those kids who might be at risk, we can specifically target treatments for them,” she said.

Jarcho, who was part of a study that followed the same group of children from the time they were 2 until they were 11, published her research in the journal Psychological Science. She participated in this ongoing effort for the last four years. “One of the amazing thing about having this long-term data is that we’re still following these kids,” she said. “They are being evaluated now.” The children participating in the study are now 14.

While they are being monitered, Johanna Jarcho asks children to create their own avatar, a cartoon version of themselves. Photo from Jarcho
While they are being monitered, Johanna Jarcho asks children to create their own avatar, a cartoon version of themselves. Photo from Jarcho

Understanding any signature activity in the brain could help with diagnosis, treatment or prevention of anxiety disorders, Jarcho said.

Adolescence is rife with the kind of stresses that can create long-term anxieties. “Social anxiety disorder in particular has a very specific developmental trajectory,” Jarcho said. “If you don’t develop it by the time you’re in your early 20s, your probability of developing it is low.” She said 80 to 90 percent of those who experience social anxiety disorder develop it when they’re adolescents.

Typical clinical measures, including self-reports from adolescents, aren’t good predictors for the development of anxiety disorders said Jarcho, who along with a host of scientists are using other biological measures, like MRI scans, in connection with clinical observations.

Collaborators applauded Jarcho’s efforts and see clinical potential down the road from this type of study. “These findings definitely contribute to our understanding of the etiology of anxiety disorders,” Amanda Guyer, an associate professor in the Department of Human Ecology at the University of California, Davis, explained in an email. “This type of longitudinal work is critical to moving the field forward in understanding the etiology of disorders as they unfold over time” for some adolescents.

Gathering information about anxiety and social interactions while children are in MRI machines required some creativity. The children are on their backs, laying perfectly still in a dark, metal tube, which aren’t conditions conducive to social interactions.

Tapping into the next generation’s comfort with modern technology, Jarcho and her colleagues asked the children to create their own avatar, a cartoon version of themselves. While they are in the machine that monitors their minds, their avatars go through a range of social interactions.

“This is one of the first studies where we were able to utilize a lot of different social nuances that we experience,” Jarcho said. “Using this, we are able to bring a good slice of the social world into this constrained environment.”

These kinds of studies are in the early stages of development, said Jarcho, who made an avatar of herself. Researchers are using the latest technology to gather new insights about what patterns might lead to a range of longer-term emotional outcomes.

Numerous factors contribute to the mental health of developing children, Jarcho said, which could make the interpretation or predictive value of any biological information difficult.“You have to collect a huge amount of data to identify complex patterns to make these meaningful clinical classifications,” she said, including the type of parenting a child receives.

In the bigger picture, Jarcho is interested in understanding the mechanisms associated with having positive social interactions. She said she would like to know how neurobiology of normal social competence develops and what contributes to deficits in social competence.

Johanna Jarcho with her husband, Charles Best, and their rescue dog Tosh. Photo by Best
Johanna Jarcho with her husband, Charles Best, and their rescue dog Tosh. Photo by Best

Jarcho, who joined Stony Brook last August, is also interested in pursuing other research goals, including determining what other people are picking up from someone who has a clinical disorder. She wants to find the subtle signals that people use to interpret someone else’s behavior. She has tracked the eye movements of people observing others with clinical diagnoses to determine if there was something the socially anxious person was doing that signals an anxiety.

Jarcho has added a few undergraduates to her lab and plans to start working with her first graduate student in August.

Guyer, who has known Jarcho for five years and collaborated with her on writing research papers and grants, highlighted Jarcho’s dedication.

“She cares deeply about conducting rigorous research that can have a positive impact on youth,” Guyer said.

Jarcho and her husband Charles Best live in Port Jefferson with their rescue dog Tosh. A mathematician and software developer who was a researcher at Apple, Best is working with Jarcho on a startup effort called RSRCHR, which will provide neuroimaging researchers with a cloud-based platform to help maintain an infrastructure for fMRI data storage, management and analysis.

They have a prototype Jarcho uses and are seeking funding to support their work.

Starting in September, Jarcho plans to collaborate with Stony Brook Psychology Professor Greg Hajcak to look for a neural signature on how children react to their own errors. These signatures may suggest an increased risk for anxiety.

Jarcho said she feels comfortable at Stony Brook. “The longer I’m at Stony Brook, the more I realize what a truly unique place it is,” she said. “The faculty in the Psychology Department has a tremendous interest and willingness to collaborate.”

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Above, from left, Lorna Role, Li Jiang and David Talmage, members of a Stony Brook University research team that has developed a method to control memory in mice. Photo from Stony Brook University

Not all memories are created equal. Some moments, like the time we first hold our child tower in the memory landscape over the moments we clip our toenails.

Focused on how we hold onto some of these more important memories, Lorna Role, SUNY distinguished professor and chair of the Department of Neurobiology and Behavior who is also a professor at the Neurosciences Institute at Stony Brook Medicine, used an animal model to test the way a neurotransmitter she’s studied for years, called acetylcholine, might affect memories of a recent, fear-inducing event.

Collaborating with several other scientists, including her husband David Talmage, a professor of pharmacological sciences at Stony Brook University, Role found that stimulating the axons of nerves in the amygdala region of the brain to release acetylcholine during a traumatic event affected the mouse’s behavior for a longer period of time.

On the other hand, reducing acetylcholine in that region during a traumatic event reduced the response. They recently published their work in the journal Neuron.

This research may have applications for conditions such as post traumatic stress disorder. In PTSD, memories of a traumatic event may be significant and painful enough to reduce the quality of life.

To be sure, Role recognizes that there’s a long way to go between what she’s discovered and any potential human therapy. “There are a lot of steps between the basic science set of observations and the applications,” she said. “I don’t have an answer for how it will be done.”

Still, she hopes this type of information could lead to an approach to treating PTSD with nonpharmacological therapies. It also might provide a better target for drug therapies. The results are also consistent with prior work suggesting that cigarette smoking can worsen PTSD. Nicotine is a drug form of acetylcholine.

Role targeted the release of acetylcholine by the cholinergic neurons. Along with Talmage and several other collaborators, Role used the relatively new molecular biology technique of optogenetics. With light, they can activate a select class of neurons without affecting other neurons nearby.

The group went to the axons, which extend far from the cell body, and activated them. “We wanted to go into a particular region associated with a kind of memory and activate the cholinergic terminals,” said Role. They were only releasing acetylcholine in the amygdala.

The group played a tone at the same time the mouse had an unpleasant experience. If the animal had a higher level of acetylcholine for a brief time during that experience, the mouse continued to react in fear in response to the tone even when the sound didn’t occur at the same time as something unpleasant.

“It made the memory essentially indelible. It was much harder to eradicate the memory,” Role said.

When the animal’s acetylcholine levels were lower during the combination of a negative event and the tone, the animal didn’t exhibit fear in response to the sound. “We didn’t expect we could block the recollection of this pairing” of the tone and the unpleasant experience, she said.

One of the next experiments will involve exploring how to decrease the effect of these traumatic experiences after they’ve already occurred.

Talmage, who has a shared lab with Role, said the idea for this set of experiments originated during a meeting in Chicago. The concept was a compelling idea, but “everybody has ideas. It’s what you do with having a crazy idea” that matters. He credits Role with “putting together the team that’s willing to take a risk” to do work that may not pan out as they had hoped. He suggested she spearheaded the research “exceedingly well.”

Role’s broader research interest is in slowing down or reversing memory loss. She is aware of the difficulties families endure when a member has a cognitive decline where that person can’t recognize a loved one.

“It is my hope that not only will we be able to use some of these techniques to strengthen memories that have been diminished, but also to strengthen positive emotionally salient memories,” she said.

Role can envision increasing acetylcholine in these key areas that are important for memory recollection. Cognitive declines can affect the quality of life for people with diseases including Alzheimer’s and Parkinson’s.

Memories that are critical to Role include moments with her daughters, Lindsay Standeven, who is a psychiatrist and resident at Johns Hopkins, and Masha Role, who is receiving her training as a clinical psychologist.

Role and Talmage, whose descendants include the founding families in Southampton and Bridgehampton and members of the Setauket spy ring during the American Revolution, live in Port Jefferson.

To continue with her research and serve as the chairman of her department, Role wakes up at 4 in the morning and is most productive between 4 a.m. and 9 a.m. She recognizes that collaborating with her doesn’t involve producing numerous papers with incremental results. She’s looking for a broad understanding of what she has discovered before publishing the results and said she discusses the results all the time, because the more feedback she can get, the better.

“Everything I’ve published has been a labor of love over a long time course,” Role said. Her collaborators recognize her need to put all the pieces together before publishing. “I’ve been at this neuroscience research for more than 35 years. I prefer to work to publish as complete a story as possible.”

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Molly Frame photo by Otto Schultejans

It’s the ultimate supply truck. It starts out full of products necessary through the system, travels to the equivalent of cities, towns and villages, and returns for another round trip.

Unlike the trucks on the Long Island Expressway, however, these delivery vehicles are considerably smaller. In fact, they are in each of us, traveling through the heart and lungs and visiting everything in our bodies.

A key part of the cardiovascular system, red blood cells pass through a maze of arteries, arterioles, veins and capillaries. When they carry oxygen to their destination and ferry away carbon dioxide, their journey keeps the human body healthy.

When something obstructs blood flow or alters the various pathways, inflammation, diseases  and localized stress can build up.

Molly Frame, a SUNY distinguished service professor in biomedical engineering at Stony Brook University has been intrigued by how the blood flows through her body ever since she read her mother’s nursing anatomy and physiology textbooks in seventh grade. In her research, which she has conducted at Stony Brook since 2002, Frame is seeking to understand the localized signals that can open or close an arteriole.

“How does a red blood cell get from the lung, where it’s filled with oxygen, to the toes, where it empties oxygen, and what route does it take?” Frame asked, describing the route the red blood cells take through the body. “The flow path is altered in identical ways for any inflammatory processes” studied to date.

Frame said the ideal flow of blood through the system is homogeneous, without any misdirection or interruption. When people get sick, the flow appears to be more irregular and heterogeneous and can be more like areas of desert next to areas of flood. The correct amount of blood flow is nearby but is not uniformly spread out, she suggested.

Frame would like to know how blood vessels respond amid competing signals and what strength or concentration of a signal is necessary for a particular type of reaction.

Clinton Rubin, the chair of the Department of Biomedical Engineering at Stony Brook, applauded Frame for her work in her lab on behalf of the school.

Frame does “cutting edge research that helps us understand how red blood cells move through the microenvironment, which is critical for understanding everything from diabetes to wound repair, and she makes major contributions to the educational mission of the university.”

In addition to her research, Frame is the undergraduate program director in the Department of Biomedical Engineering.

“She didn’t inherit something and add icing on the cake to it,” Rubin said. “She built it out.”

Rubin said Frame goes “above and beyond the call of duty” and suggested she was a “visionary” and an “implementor.”

Frame has recently dedicated time and effort to understanding how nanoparticles that can enter the body through the skin, lungs or food can affect blood flow. “We have figured out that some particles look like they’re getting through the skin,” she said.

Regulations haven’t caught up with technology, Frame suggests. “This is part of the system” and not the fault of the Food and Drug Administration.

To be sure, Frame isn’t suggesting the immediate cessation of activities involving nanofabrication. Indeed, production using these tiny particles takes place in secure areas where water and air is filtered and waste is contained, as workers are covered from head to toe, she described.

The hazard from nanoparticles is generally presumed to be identical to micron-sized equivalents, which are considerably larger and have less surface area. That, however, may not be the case.

Collaborating with scientists at SUNY Polytechnic Institute and George Washington University School of Medicine, Frame helped develop a way to find nanoparticles in tissues.

The Stony Brook biomedical engineering lab developed a low-volume Franz chamber for exposure to oxides. Franz chambers require large volumes of the material. The biomedical engineering design team, which included undergraduates at Stony Brook, developed a smaller, more economical version of the chamber.

“The biomedical team created something amazing,” Frame said “They took an idea we had on paper and made it into something smaller” and more practical.

Nanoparticles can be in everything from shiny sports drinks, which doesn’t include Gatorade, to toothpaste whiteners. Frame referred readers interested in learning more about nanoparticles to the following website: www.nanotechproject.org/cpi.

Toxic elements are not included in these materials because the FDA has prohibited them. This, however, is a case where the size of the particle might affect their local chemistry in the body.

Frame is married to John McMahon III, a retired police officer. The couple lives in Sag Harbor. They have what she describes as a blenderized family, with 14 children. Many of them have served or are serving in the military, with several also acting as volunteer firefighters or police officers. Their children also include an engineer, a restaurant manager and a manager with a global agency.

The daughter of a mechanical engineer and a nurse, Frame said she and her siblings were encouraged to excel. She said she recalls holding a flashlight for her father, Wilbert Schultejans, while he was working on something. Schultejans, who died in 1998, would call out numbers of dimensions that he used to calculate how many more nails or screws were needed.

Her mother, Nancy Schultejans, demonstrated to her children how to figure out in their heads how much of something was needed, from dosages for her patients, to yardage for fabric, to flour for bigger batches of cookies.

As for her work, Frame said she will continue to focus on nanoparticles.

“More studies are needed to keep up with the technology,” she said.

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Gena Sbelia stands with her guide Elahavelo at Beza Mahafaly Special Reserve in southwestern Madagascar. Photo by Erik Patel

For the last 25 years, Patricia Wright has traveled back and forth from Stony Brook to Madagascar, studying the island nation’s lemurs. Along the way, she has worn numerous hats.

Within a day of returning recently to Madagascar, a country that honored her with three Legion of Honor medals, Wright received a letter from a mayor who made an unusual request. He wrote to her explaining that “You’ve been talking about trash for a long time,” related Wright, who is a distinguished service professor in the Department of Anthropology at Stony Brook University and the director of the Institute for the Conservation of Tropical Environments.

He promised to help arrange for its pick up and removal “if you buy us three wheelbarrows.” She wrote back indicating that she’d purchase two wheelbarrows if he bought the last one.

Living and conducting research in Madagascar, other countries around the world or in the United States requires a vast array of skill sets, including negotiation, Wright said.

Indeed, Wright spoke with a scientific colleague she’s known from her work with spiders in Madagascar, Sarah Kariko, recently about a one-day training session Wright’s graduate students could attend at Harvard, so they could learn to work with people with different agendas.

Katherine Kling holds a Verreaux’s sifaka, a type of lemur, at Kirindy Mitea National Park in Madagascar. Photo by Rebecca Lewis
Katherine Kling holds a Verreaux’s sifaka, a type of lemur, at Kirindy Mitea National Park in Madagascar. Photo by Rebecca Lewis

“Having to learn the negotiation fields on your feet is very difficult,” Wright said via Skype from Madagascar. “If you have a skill set you can draw on, you could deal with many of these situations so much easier.”

Kariko, who is a research director at Gossamer Labs and an associate in the Department of Organismic and Evolutionary Biology at Harvard University, and Gillien Todd, a lecturer on law at Harvard helped lead the training.

The goal of the seminar, Kariko explained, was to teach negotiation skills through role playing, games, lectures, discussion and case studies that participants, which included undergraduates and graduate students from Harvard, among others, could apply to their own life and work.

Wright’s graduate students appreciated the opportunity to hear and consider different scenarios that might require negotiation.

Katherine Kling recently started her Ph.D. in Wright’s lab. She studies lemurs that live in nontraditional environments including rice paddies and farms. “Crossover disciplinary training is important,” Kling said. “We’re not just doing science. We need to consider negotiating techniques.”

Kling is developing a conservation radio program in Madagascar. Every episode will focus on one of the lemur species in the country. To build interest in the stories, she hopes to involve music and musicians and stories from children and researchers.

“Who doesn’t want to listen to the radio?” Kling asked. “We’re hoping to make programs about lemurs, conservation and the environment that are interesting and fun.”

Kling “hopes to inspire people to care and know they can” achieve conservation goals on their own, she suggested.

In her research, Kling hopes to gain a better understanding of why lemurs are moving into these so-called matrix environments. She would like to see how humans altering a landscape affect lemur behavior.

Kling graduated from college in 2013 and took two years off before starting her Ph.D. The anthropologist developed and honed several important skills outside the realm of scientific research, as she worked at Disney World’s Animal Kingdom Theme Park in Florida.

Kling described the experience as “awesome” and explained that she “wanted to learn how people respond to conservation.” She appreciated the chance to work with children and help them forge a connection with animals at the theme park and carried over the skills and approach she used at work into everyday parts of her life.

“We were trained to talk to anyone we saw in the park,” she recalled. She’d go to the grocery store and would “talk to everyone there. You can’t turn yourself off.”

From left to right, Katherine Kling, Elise Lauterbur (a graduate student in Patricia Wright’s lab) and Gena Sbeglia pose in lemur suits during World Lemur Day last October. Photo from Patricia Wright
From left to right, Katherine Kling, Elise Lauterbur (a graduate student in Patricia Wright’s lab) and Gena Sbeglia pose in lemur suits during World Lemur Day last October. Photo from Patricia Wright

Gena Sbeglia, another Ph.D. student in Wright’s lab who is studying how social behavioral patterns affect disease transmission, suggested that people often feel negotiation starts with conflicts, which isn’t always the case.“There can be a mutual movement towards a good,” Sbeglia said.

Negotiations are a part of the research and life experience for scientists that extend well beyond the realm of their scientific mission.

Sbeglia said she was preparing to do field work in the Tsaranoro Valley and wanted to put identifying colors on ring-tailed lemurs. Any research needs the approval of the local kings. She had already received approval for her work in the forest, but no researcher had put collars on the lemurs before.

She understood that it would be difficult to get permission because the animals are considered sacred. With her guide as an intermediary, she explained how she would bring an experienced darting team that included a vet and that she intended to study these lemurs for a year. Other scientists would also be able to conduct their own field work if they could track and monitor individual animals.

Sbeglia received permission, although she didn’t put collars on the lemurs because the logistics of the site were inappropriate for her research.

Wright suggested that discussions in the conservation world can lead to creative solutions. When she was working to establish Ranomafana National Park, Wright hired Professor Beth Middleton, an expert on cattle damage in rainforests, to determine the effect of the cows on the park. Her work showed that for the population of cattle in the park at the time, the negative impact on the forest was minimal. The village elders had kept the cattle there to protect them from cattle rustlers.

“The elders agreed not to put more cattle in the park,” which was a satisfying solution for the scientists, Wright recounted. “By allowing the cattle to stay inside the forest, it showed that negotiation works both ways, so that both sides can win.”

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From left to right, Jan Argentine, Linda Sussman, Ted Roeder, Richard Sever, John Inglis and Inez Sialiano meet to discuss upcoming publications. Photo by Denise Weiss

In 1933, a gathering of scientists took place at Cold Spring Harbor Laboratory. The symposium, which started a tradition that continues today, resulted in the publication of a book.

With that book, CSHL started a publishing arm that now includes eight journals and over 200 books. One of the newer efforts is open to a scientific and worldwide audience for free. Created in 2013, bioRxiv (pronounced “bio-archive”) is a preprint service designed to share cutting edge and unedited biological and scientific information by posting manuscripts on its website.

The service, which has been growing rapidly and is supported by the Lourie Foundation and CSHL, had approximately 400,000 page views and 185,000 downloads in March.

“BioRxiv offers scientists the chance to share their work with colleagues who can make their own, often expert assessment of the work that’s been done without waiting for the often lengthy process of peer review,” said John Inglis, executive director and publisher at CSHL Press and one of the co-founders of bioRxiv, along with Richard Sever, who is the assistant director at CSHL Press.

Indeed, in September 2015, two prominent cardiologists made a public argument, through the New York Times Op-Ed pages, that information in clinical trials, particularly those that may alter the course of treatment for patients, should be made available as soon as possible.

The traditional publication process, which involves preparing data, presenting graphics and sending information to journals for peer review, can take months or more. Eric Topol, a cardiologist at the Scripps Clinic and Harlan Krumholz, a cardiologist at Yale-New Haven Hospital, suggested that this data should be on a National Institute of Health website or published on a preprint platform, such as bioRxiv.

“A very large number of clinical trials are open and then closed for various reasons,” said Inglis. “They thought it was a good idea and we now have that category.”

John Inglis, photo at left, is the executive director, and publisher at CSHL Press  and one of the co-founders of  BioRxiv. Photo by Gina Motisi / Cold Spring Harbor Laboratory
John Inglis, photo at left, is the executive director, and publisher at CSHL Press
and one of the co-founders of BioRxiv. Photo by Gina Motisi / Cold Spring Harbor Laboratory

BioRxiv, which provides a preprint service for scientists in categories ranging from animal behavior and cognition to biochemistry, biophysics, neuroscience and zoology, also recently developed a section for epidemiology. That, Inglis said, is as far as the CSHL preprint service is prepared to go into clinical medicine at this point.

Modeled after a similar preprinting effort called arXiv that is hosted by Cornell University for physics, math, computer science and related disciplines,  not only can bioRxiv provide scientists with a way to share information more rapidly, but it can also serve as a forum to share incremental pieces of information or a negative result.

In Gholson Lyon’s case, the preprint service, which is housed in the same building where he works, helped him find doctors around the world.

An assistant professor, Lyon had worked with two boys with intellectual disability and who had unusual facial characteristics. After screening their genes, he searched for others who might have the same undiagnosed condition.

Preprinting on bioRxiv helped him find doctors in Colombia, Mexico, France, Germany and the United Kingdom who had patients with similar symptoms. BioRxiv expedited the pace of scientific discovery, Lyon said.

Steven Shea, an associate professor at CSHL, used bioRxiv because of the slow pace of the review process.

“We wanted [the work] to see the light of day,” Shea said. Shea believes more scientists can and should share their results on the website.

While bioRxiv offers a preprinting service, it doesn’t aim to replace peer-reviewed journals, Inglis said. Rather, it is a quicker step between the bench and the scientific community.

BioRxiv has been growing rapidly, particularly in the last few months. According to Inglis, between May and December of 2015, the rate of submissions doubled. The pace of submissions picked up even before a high profile Accelerating Science and Publication in Biology (ASAPbio) meeting in February.

To be sure, the site still posts a small percentage of the scientific information published in its fields.

Early on, Inglis said some journals resisted preprints. Not only has that number dwindled, but eight scientific publications have become a part of a pilot process that allows scientists to submit manuscripts directly through bioRxiv. He expects that number to climb to 20 by the end of April.

Unlike with peer-reviewed journals like Lancet, where Inglis started his scientific publishing career, bioRxiv does not provide editing or content review services. Each post includes a mention at the top that it is a preprint and has not been peer-reviewed.

CSHL makes sure the posts aren’t spam. Before they share the manuscripts with the public, they put them in a queue, where a group of 40 scientists make sure they really are science.

BioRxiv declines submissions that are out of the scope of its publishing interests or that are term papers, theses or unsubstantiated hypotheses, which is fewer than 5 percent of the submissions, Inglis said.

Authors can revise their manuscripts on the site, which has occurred about 30 percent of the time, Inglis said.

A native of Aberdeen, Scotland, Inglis met with CSHL’s former CEO James Watson, who approached him about joining the institution. A few months before Inglis arrived, CSHL had launched its first journal.

When Inglis arrived in 1987, he and his wife Lesley, who has been teaching English as a second language at CSHL for nine years, said they expected to have “an adventure for a few years” and then return to the United Kingdom with their sons, who were in middle school. Adam now lives in Arlington, Massachusetts, with his wife Lizzie and their two sons and Tony and his wife Louise live in Brooklyn.

As for bioRxiv, Inglis sees the preprint offering as an approach consistent with the current cultural environment.

The research community includes numerous “young people who have grown up with the internet and all its possibilities,” Inglis said. “They are very comfortable with sharing in general but also with the embrace of technologies that create community across the boundaries of geography, culture, age and status.”

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From left, Bruce Stillman with Anthony Mazurek, a former research investigator who is now with Pfizer, and Marlies Rossmann, a postdoctoral student. Photo from CSHL

When he was 11, Bruce Stillman read about spina bifida and wanted to know what was happening and how he might help. By the time he got to college, genetic discoveries moved him away from medicine and toward scientific discovery.

In 1979, he came to Cold Spring Harbor Laboratory from his native Glen Waverley through Sydney, Australia, for what he expected would be just two years. At the time, the lab was led by Nobel-prize-winning scientist James Watson, who discovered the structure of DNA the year Stillman was born.

By the time he was 38, Stillman’s research success led Watson to pick him as his successor to lead an institution with an international reputation.

Now in his 36th year at Cold Spring Harbor Laboratory and with children and a grandchild born in the United States, Stillman has trained a generation of scientific leaders while maintaining two time- and energy-consuming jobs.

“I spend 80 percent of my time” on being the president and chief executive officer of CSHL and “the other 80 percent running the lab,” he jokes.

Former members of Stillman’s lab and collaborators have marveled at Stillman’s ability to continue to remain so active in his scientific pursuits while raising funds, hiring researchers and overseeing a lab with an endowment of $450 million, up from $32 million in 1994.

Stillman, his colleagues say, has a passion for discovery and a dedication to science that informs both sides of a schedule that often includes discussions, meetings and interactions during what many would consider off hours.

Bruce Stillman with Manzar Hossain, a graduate student. Photo from CSHL
Bruce Stillman with Manzar Hossain, a graduate student. Photo from CSHL

Leemor Joshua-Tor, a professor at CSHL who has collaborated with Stillman for about nine years, has interacted with Stillman as an administrator and as a scientist. She says it’s clear which role wins out.

When Joshua-Tor was the dean of the Watson School of Biological Sciences, she would email him in his capacity as president. She would often get a time slot three or four weeks from her request.

“If I called/emailed and said I would like to speak with him regarding the science, the reply would often be, ‘How’s 4 p.m.?’” Joshua-Tor recounted.

Stillman said that continuing in his role as a scientist helps him make better decisions for CSHL. He has a “connection with what’s going on” scientifically that informs his pursuit of scientific expertise and new technology, he said.

Stillman has also forged numerous connections with the people who work at CSHL. Joshua-Tor said he knows most people by name, from the grounds keepers to the graduate students to the postdoctoral researchers, a skill she said also follows Watson’s legacy.

In his long, storied and award-winning career, Stillman has worked with viruses, yeast and human DNA, making landmark discoveries that include using the Simian Virus 40 to discover human cell DNA replication proteins.

Stillman “covered many areas during his career that make him special,” said Christian Speck, a nonclinical lecturer in the Faculty of Medicine at the Institute of Clinical Sciences at the Imperial College in London who earned his Ph.D. in Stillman’s lab in 2006 and who collaborates with Stillman.

Huilin Li, a biophysicist at Brookhaven National Laboratory and a professor of biochemistry and cell biology at Stony Brook University, said Stillman’s discovery of the Origin Recognition Complex, abbreviated ORC, “set off an entire research field of eukaryotic DNA replication initiation.”

Indeed, Stillman, Li, Speck, Joshua-Tor and others continue to devote considerable energy to understanding the protein, signals and processes that are a key part of DNA replication, which allows cells to make genetic copies of themselves.

Replication makes it possible for the body to produce red and white blood cells at the rate of 500 million per minute. Spreading the spectacularly thin, tightly wrapped genetic material out over that minute would produce a million kilometers of base pairs, which could wrap around the equator 25 times.

Replication isn’t just important for passing along information, but, as Stillman recognized when he was 11, biological processes don’t always follow the typical code.

Stillman and his collaborators have explored numerous ORCs, which occur once every 50,000 to 100,000 base pairs along the chromosome. His recent studies suggest the ORC is involved in the fundamental decision of whether or not a cell divides.

His recent unpublished findings also show that ORC controls the expression of genes that are overexpressed in cancer by interacting with tumor suppressor genes, he said.

Understanding how DNA replication is regulated has already produced drugs that are in the clinic or are heading that way, Stillman said.

Through his years at CSHL, Stillman has worked with talented scientists. His lab was near that of Barbara McClintoch, who won a Nobel Prize for her work on jumping genes in corn. While Stillman said he enjoyed most of his interactions with her, he did struggle on occasion to return to his own research, which could often take 12 to 14 hours a day, after a long discussion with her.

Avoiding McClintoch during those long research days was no easy task for the six-foot, four-inch scientist, whose tall, trim figure is easy to spot down a hallway or in the picturesque CSHL laboratory setting.

Stillman met his wife Grace, a co-founder of Operation Hearts and Homes, a charity dedicated to improving the lives of orphans around the world, in Huntington. Their son Keith is a commercial real estate appraiser and their daughter Jessica is a fifth-grade teacher specializing in literacy.

Stillman, who has no plans to step away from either role in the near future, suggested that the scientific process, though demanding, has given him numerous rewarding experiences. In the 1980s, he made a hand drawing of how he thought histones, the fundamental building block of chromatin, might get together. About a decade later, X-ray crystallography showed that the drawing was close to accurate.

“It was how I imagined it to be,” he recalled. These discoveries provide “excitement and then with the new insight, [a desire to] get to a full answer quickly.”