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Power of 3

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John Inglis. Photo courtesy of CSHL

By Daniel Dunaief

In the post COVID-19 world, the pace of science and, in particular, scientific publishing has changed, giving researchers a sense of urgency to share information that might lead to preventions, treatments and cures.

Cold Spring Harbor Laboratory has produced two preprint research services, bioRxiv and MedRxiv, that complement the longer peer-reviewed path to publication.

After numerous scientists restructured their labs to contribute to the growing body of knowledge and information about COVID-19, these researchers turned to preprint services to share the results of their work and the evolution of their thoughts on how to defeat the virus.

“It’s absolutely unprecedented for scientists to drop what they are doing and switch their focus to something completely new to aid society and mankind in general,” said John Inglis, the co-founder of bioRxiv and one of the members of joint management group for medRxiv.

MedRxiv, which started in June of 2019, helped provide the scientific community with an outlet for their health science research, with the caveat that the results haven’t received a thorough peer review, as they might in the New England Journal of Medicine, Cell, or other periodicals.

The number of preprint research papers has climbed dramatically this year, as scientists race to get their results from the bench to the server. The number of papers in bioRxiv increased to 88,268 in June from 71,458 in January. The increase at the newer medRxiv is much more dramatic, climbing from 953 in January to 7,541 in June.

The number of pandemic related papers on medRxiv and bioRxiv in total is 6,458, with 5,133 on medRxiv and 1,325 on bioRxiv.

Pandemic-related papers account for close to 70 percent of the new research published on medRxiv since January 1st, while the percentage of virus-related papers on bioRxiv is 6.2%, in large part because bioRxiv includes numerous other subject areas, including ecology, bioinformatics, plant biology and zoology.

The world has taken notice of all these papers, with page views peaking in April for medRxiv to almost 11 million for the month.

While the papers aren’t peer reviewed, the managers of these sites urge readers to remain cautious in their interpretation and use of these findings, while the scientific community continues to duplicate any encouraging or compelling results.

“We remind people all the time that these are preprints,” Inglis said, as the site has numerous reminders about the early nature of the findings. “They are preliminary reports and should not guide clinical practice or be reported as established information. That’s a battle we’re still fighting.”

The peer review process has also picked up some speed, as journals, inundated with potential game-changing material, have been accelerating the process of reading and reviewing papers. The median time between posting an article on bioRxiv and publication in a journal before the pandemic was nine months. Some papers in medRxiv have been published in journal in as few as 35 days.

For medRxiv, the screening process requires an ethics statement, a funding statement, and any potential conflicts of interest. These requirements are “all far more familiar in medical publishing than in scientific publishing,” said Inglis.

At bioRxiv, which recently introduced a competing interest statement as well for authors, freelancers and a group of Principal Investigators look at everything before it posts, to make sure it’s science and that it’s not dangerous. The screeners turn the manuscripts back to the team if they have any concerns.

“We felt, early in the pandemic, that it was necessary to make sure we have people with expertise in outbreak science,” Inglis explained. “We brought on volunteers.”

According to Inglis, the percentage of manuscripts that scientists submit, but that bioRxiv doesn’t publish, is between 5 and 10 percent, while that figure is closer to 20 to 25 percent for medRxiv.

Inglis said numerous scientists have done some modeling based on public data, but that the preprints don’t accept those papers unless they contain additional research.

The preprint management team was “worried about the indiscriminate use of these models to guide public policy,” he said.

Additionally, the team excluded manuscripts that might be dangerous to human health or human-health related behavior. They didn’t want people to rush out and take something that, theoretically, might help, but that hasn’t received sufficient testing. A treatment might block a receptor, but also have significant side effects.

Inglis said the team of people who work at the preprints, which includes five full-time preprint-platform dedicated staff members and seven other CSHL staff with other responsibilities, including the founders, tech developers and production staff, worked seven days a week, with long working days to meet the increased need and demand.

People working on this effort “are not doing it because they are getting rich or handsomely acknowledged.” An arduous job with thousands of papers, the staff are working out of a “sense of purpose and mission,” Inglis explained.

The Chan Zuckerberg Initiative and CSHL provide financial support for these preprints. The research community has shared their appreciation for these preprints and CSHL generously acknowledges the work of the staff.

Inglis and Richard Sever co-founded bioRxiv. MedRxiv is managed by Sever and Inglis in collaboration with Professors Harlan Krumholz and Joe Ross from Yale and Dr. Theo Bloom and Claire Rawlinson from BMJ, which was originally called the British Medical Journal.

Inglis said numerous papers have become game-changers in the battle against the virus, including a study from two weeks ago in the United Kingdom on dexamethasone, a steroid that was proven effective in severe cases of COVID-19. Indeed, just recently, a Bethesda hospital became the first in the nation to use the steroid to combat the virus.

The team working in preprints at CSHL appreciates the opportunity to contribute to the public health crisis.

Inglis is pleased with how the community trusted the preprints with their work, while numerous members of the community helped screen manuscripts and provide advice about how to react to the needs of the pandemic.

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Eric Yee. Photo by Felicia Allard

By Daniel Dunaief

In the second of a two-part series, Times Beacon Record News Media will feature the work of Eric Yee, who, like his wife Felicia Allard who was featured last week, is joining the Pathology Department at Stony Brook University.

Eric Yee

Eric Yee, who started as an Associate Professor and Director of Surgical Pathology at Stony Brook Renaissance School of Medicine on July 1, described the focus of his scientific research as translational.

He consults with and helps science researchers put together ideas for experiments, while he and his wife Felicia Allard focus on bringing that work into the clinical setting.

“We provide expertise mainly in clinical gastrointestinal and hepatobiliary pathology,” Yee explained in an email. “We also give insights and perspectives as practicing pathologists to help [with the] analysis of data and how that data in the lab or in animal models may be relevant to clinical medicine.”

Yee completed a gastrointestinal pathology fellowship, working on collaborative research projects and publishing manuscripts with investigators.

As one of the newest members of the staff at Stony Brook, he has worked on some studies looking at certain kinds of inflammatory diseases in the liver. He collaborated with senior investigator Zhenghui Gordon Jiang of Beth Israel Deaconess Medical Center to look at mediators of inflammation in the disease steatohepatitis. He has also worked on different cancer research projects, which is part of the appeal of Stony Brook.

Stony Brook has “important pancreatic research,” Yee said, adding that. Pathology Department Chair Ken Shroyer is a “renowned investigator whose research team has done great work that has led to important insights into pancreatic cancer biology.”

Pancreatic cancer is of particular interest to Yee in his clinical work and he hopes to explore the variety of research expertise at Stony Brook, to support ongoing efforts and to develop projects of his own.

Relocating to Stony Brook from the College of Medicine at the University of Arkansas for Medical Sciences, where Allard and Yee both worked in the Pathology Department, took some convincing for both of the scientists.

“We were very happy in Little Rock and purchased a home in Arkansas two years prior and were just starting to set down roots,” Yee described in an email. “We made lifelong friendships and very much enjoyed the camaraderie among our peers and other departments.”

Yee and Allard had no plans to leave as they approached their third year and were hesitant to move.

In his first visit, Yee said he was impressed with the amount of research in the Stony Brook department, which, he said, has more researchers compared to other institutions of similar size.

On the other side, however, Yee said he and Allard had to reconcile the higher cost of living in New York. They also weren’t eager to make too many moves in their career, especially when they were happy in Arkansas.

Even after the first visit, Yee said he was hesitant to make a move, which would require time to settle in, build relationships, find a home, learn a new system, and find new opportunities, among other challenges..

Shroyer was “very understanding of my hesitation,” Yee explained. “He’s been one of my mentors since medical school and knew exactly where I was coming from.

Clinically, the couple also believed in the potential for career growth.

“There’s a lot of energy in the department,” Yee said. He also appreciated the opportunity to be the Director of Surgical Pathology, where he could shape the operations that support the clinical mission. He would like to optimize the department by specialization, creating a sub-specialty model.

“This is something I want to do to increase the efficiency in the department,” Yee explained. “I’m hoping as we sub-specialize that we make our clinical work flow more efficient” which will create more consistency. “Part of what I’d like to do is to help [Shroyer] create a department where it’ll allow the clinical faculty to thrive.”

Yee thinks any work efficiencies will provide researchers with more time to build on their teaching efforts, and to develop new lectures and teaching models.

Yee will measure his success through a comprehensive report that includes an analysis of the efficiency of the response to clinical needs. He hopes to create a system that will enable the success of the entire anatomic pathology division. He will also become actively engaged in the academic mission, which is measured in the number of publications as well as in staff appointments to editorial boards or major national societies.

“The more people we can get into the national arena the better it is for the institution,” Yee said. These contributions bring good public relations and expertise to the institution.

Yee and Allard will also contribute to Stony Brook through their efforts in education.

Yee believes the school has an advantage in telepathology and distance learning. He believes the Department of Bioinformatics led by Dr. Joel Saltz facilitates telepathology and distance learning.

With the uncertainty caused by COVID-19, Yee believes maintaining social distancing and finding innovative ways for communication and education will provide valuable alternatives to communicate and collaborate.  Radiology has had digital methods in place to send MRIs and CAT scans for a longer period of time than pathologists, who still produce glass slides.

“There will always be some challenges and limitations that are unique to pathology,” Yee suggested.

A native of San Francisco, where he and his older brother, who now works in Boston, grew up, Yee was interested in medicine during the middle of his college career.

Yee and Allard met in medical school and, among numerous other parts of their lives they have in common, discovered they were both fans of the Star Wars films. Early on when they were dating, the pathology couple saw Star Wars: Episode III – Revenge of the Sith together.

Yee enjoys tennis, table tennis, riding road bikes and hiking. He has also developed an appreciation for bird watching, which has allowed him to practice amateur photography.

The couple also shares an interest in music, as Yee grew up playing the piano, while Allard played the trumpet.

When he was in medical school, Yee published his first  paper with Shroyer. He has remained in touch with the pathology chair over the years and appreciates the advice Shroyer has offered.

Yee described Shroyer as an “inspirational leader” and appreciates his energy, selflessness and passion, among other qualities.

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Felicia Allard

By Daniel Dunaief

Stony Brook University recently added a wife and husband team to its Pathology Department. Felicia Allard and Eric Yee are joining SBU from the University of Arkansas.

Allard and Yee will “replace an individual who had moved to a leadership position at another institution and to meet increased caseloads in surgical pathology and cytopathology,” Ken Shroyer, the chairman of the Pathology Department, explained in an email.

Times Beacon Record News Media will profile Allard and Yee over the next two weeks.

Felicia Allard

Eric Yee and Felicia Allard. Photo by Joshua Valencia

A self-described “mountain girl” from Colorado, where she attended medical school and met her husband Eric Yee, Felicia Allard had only been to Long Island three times before accepting a job at Stony Brook.

She came once when she was interviewing for a residency and twice during the interview process.

Allard and Yee accepted the jobs in the middle of February and weren’t able to look at potential homes during the height of the lockdown caused by COVID-19.

For now, the couple have moved into temporary housing in Port Jefferson Station, as they look for longer term living options.

Allard, who will be an Associate Professor at SBU, said the move started with Pathology Department Chair Ken Shroyer, who was looking to fill two positions and reached out to Yee.

Shroyer was involved in a type of cancer work that interested her.

“The active pancreatic cancer research group was a big draw for me as I am hoping to expand my research career,” Allard explained in an email.

Allard said she was particularly interested in pancreatic cancer, in large part because of its intractability and the poor prognosis for most patients.

“It was clear to me that this is one of the areas where we had a lot of work to do in terms of being able to offer any type of meaningful treatment to patients,” she said.

Allard said she, like so many others in the medical community, entered the field because she wanted to make a difference. She searched for areas where the “greatest good could be done, and pancreatic cancer is still one of those.”

In her initial research, she studied the pancreatic neoplasm, exploring how cells went from pre-invasive to invasive to metastatic conditions. She is interested in how the tumor interacts with the patient’s immune system.

While Allard will continue to provide clinical services, she plans to collaborate with Shroyer in his lab. “I’m hoping naturally to be integrating into Dr. Shroyer’s group,” Allard said.

Shroyer welcomed Allard to the department and to his research team.

Allard is “a highly-qualified surgical pathologist with subspecialty expertise in GI tract pathology,” Shroyer wrote in an email. “She has a specific interest in pancreatic cancer, which will also complement our translational research program,” he said.

Shroyer expects that Allard will be integrated into several cancer research programs and he is “looking forward to having her join my team that is focused on the validation of prognostic and predictive biomarkers for pancreatic cancer.”

Shroyer’s lab, which includes Luisa Escobar-Hoyos, who is an Assistant Professor in the Department of Pathology, will work with Allard to advance the translational aspects of keratin 17 research, building on earlier work to understand the mechanisms through which K17 causes tumor aggression, he explained.

As for her clinical work, Allard said she analyzes biopsies and resections from the esophagus, stomach, intestines, liver, and pancreas. She has also used cytopathology to look at pap smears and to analyze salivary tumor aspirations.

The time to consider any of these slides varies broadly. Sometimes, she receives a slide and the diagnosis is unequivocal within 30 seconds. Other times, a biopsy from a six-month old patient with diarrhea, for example, can have an extensive list of differentials. In that case, the diagnosis can take considerably longer, as a baby could be sick because of an autoimmune disorder, inflammatory bowel disease or an infection.

She said she can “perseverate for hours or even days” over the subtle clues that may help with a diagnosis.

Allard likened the diagnostic process to reading a detective novel, in which the reader might figure out the perpetrator on page three, while other times, the culprit isn’t discovered until page 300.

Allard said she and her husband have a similar clinical background.

Yee is “more of a tech geek than I am,” she said. “He understands artificial intelligence, computer science and bioinformatics more than I do. He is also interested in administrative and leadership to a greater degree.”

Allard said she and Yee may have professional overlaps, but they have unique interests, backgrounds and perspectives that they bring to work that give them each different strengths.

Allard said she knew she wanted to go into medicine in her junior year of high school. When Doctors Without Borders won the Nobel Peace Prize in 1999, she recalls being impressed with that distinction.

In medical school, she said the field of pathology appealed to her because she appreciated the marriage of clinical care and basic science in the field.

She and Yee started dating just before medical school started for her. Yee was two years ahead in school. They continued their relationship from a distance while he did his residency at Beth Israel Deaconess Medical Center at Harvard Medical School. While she was a resident, Allard said Yee had the “distinct pleasure of trying to train me.”

She likes to explore the boundaries of diagnosis to understand the nuances and all the data that factor into interpretations, to tease the art from the science.

Outside of her work, Allard enjoys reading and calls her Kindle one of her favorite possessions. She hopes to learn how to sail while a resident of Long Island.

Allard is excited to start working at Stony Brook. Shroyer was “very persistent and once he got us up to New York to interview, he was persuasive with respect to the type of career growth we could both potentially have,” she said.

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Marci Lobel. Photo from SBU

By Daniel Dunaief

Pregnant women with access to the outdoors are less stressed during the pandemic.

In fact, according to an unpublished finding that isn’t yet peer reviewed, pregnant women who had outdoor access were 67 percent less likely to worry about contracting the virus and 63 percent less likely to feel stress about being unprepared for the birth.

Lobel with a recent doctoral student, Jennifer Nicolo-SantaBarbara.

Stony Brook University recently awarded a project led by Dr. Heidi Preis in the Department of Psychology, with co-Principal Investigators Dr. Marci Lobel in the Department of Psychology and Dr. Brittain Mahaffey in the Department of Psychiatry and Behavioral Health that explored the link between stress and pregnancy. The researchers are hoping to identify what helps pregnant women and what may make them more vulnerable to the impacts of stress.

Stony Brook provided a total of $398,200 in seed funding to 17 research projects in response to the pandemic. Researchers at Stony Brook had put together 63 submissions, using a peer review process to choose the projects to fund, including the COVID-19 Pregnancy Experiences (or COPE) Study. The funding, which is for one year, is designed to provide the kind of seed funding that will lead to further research and that other funding agencies will support.

The COPE study tapped into a global network of collaborators that Lobel, who is the Director of the Stress and Reproduction Lab at SBU, established over the past 30 years to compare the different factors that mitigate or exacerbate stress for pregnant women in Spain, Israel, Italy, Germany Poland and Switzerland.

“The biological impact of COVID-19 is getting the lion’s share of attention, as it should,” said Lobel. “We don’t yet know enough about how the psychological impact will affect vulnerable groups, like pregnant women.”

Indeed, Lobel has spent three decades studying the effect of stress and related psychological factors on pregnancy. In other studies, major stressors, such as earthquakes, ice storms, and periods of warfare, confirm the toxic impact of prenatal stress, particularly for preterm births and low birth weight, she said.

Lobel and her colleagues created a self-report instrument called the Pandemic-Related Pregnancy Stress Scale, or PREPS, in which women report their specific concerns or anxieties caused by COVID-19.

Throughout the United States, the team sought responses from about 4,500 women recruited through social media at the end of April and the beginning of May.

Marci Lobel with her family at Yosemite in 2016. The photo credit is: Photo courtesy of Marci Lobel.

Among the women in the study, just over half of them were pregnant with their first child. In many studies that predated the current work, including some from her own research group, Lobel said women pregnant with their first child had higher levels of stress.

In some preliminary findings, 21.7 percent of pregnant women in the study reported severe levels of anxiety. “I think that is higher than what we typically would find in a population study of pregnant women,” Lobel said.

Women with a history of interpersonal violence also reported higher levels of stress and those whose prenatal appointments were canceled or altered were 1.78 times more likely to experience high stress related to a lack of preparedness and 1.49 times more likely to experience high stress related to worries about perinatal infection.

Some women in the study have found ways to reduce the accumulating stress about the health care crisis. The techniques that work for some women, Lobel said, may not work for others, suggesting that stress relief is specific to the individual and is usually determined by the situation itself.

“I don’t recommend any particular way of coping,” Lobel said. “What works for one may not work for another. It’s good to have a tool kit with lots of ways of coping.”

Indeed, some of the techniques pregnant women have found helpful include meditation, prayer, and faith-based practices. Pregnant women have also benefited from social support, which is particularly important during the pandemic when some women may feel “literally and figuratively isolated from others,” Lobel said.

Of all the research Lobel has done, the one that has received the most attention and landed her in the bible for pregnant women, “What to Expect When You’re Expecting,” was a study on optimism. She found that women who were more optimistic had better birth outcomes due in part to the better are they took of their health during pregnancy.

Coping with stress by avoidance predicts increases in emotional distress, Lobel explained. This corroborates much research which shows that avoidance is usually an ineffective way to cope with stress, except in limited cases such as when a stressful situation is brief and uncontrollable.

When people avoid the things that bother them, they can do it cognitively or through alcohol, which is especially dangerous for pregnant women and their developing fetuses. Avoidance can also involve excessive sleeping, as pregnant women may decide they don’t want to deal with life and stay in bed all day.

The scientists plan to collect a second set of data from these women, who were recruited through social media and who represent a diverse socioeconomic background, race and ethnicity, sexual orientation, and other factors, on July 15th.

Lobel said she already has some preliminary, unpublished findings from Poland, which are showing the same kinds of stressors and distress among pregnant women. Polish women have expressed stress related to worries about lack of preparation for birth during the pandemic and stress related to worries about infection.

Lobel said the researchers hope to explore a host of questions as they collect more information. They hope to look at obsessions and compulsions and would like to measure anger. They also will measure levels of depression and anxiety and will compare that to the norms for non-pregnant women.

On the other side of the stress meter, the group will study how being pregnant during the pandemic may help some women appreciate their pregnancy more. For some women, the pregnancy may give them strength to deal with the pandemic, as they focus on having a baby.

The researchers will also explore the level of control women feel over the outcome of their pregnancy and the health of their baby. Feeling in control can create a positive response associated with lower distress.

While Lobel and her colleagues won’t answer all these questions in a year, they hope their initial studies will lead to more funding and research. “Hopefully, we’ll get a [National Institutes of Health] grant to follow up these women for a couple of years to study them and their children to see if there are any developmental or mental or physical health effects” of the pandemic.

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Kevin Reed. Photo from SBU

By Daniel Dunaief

At the beginning of this month, the North Atlantic started its annual hurricane season that will extend through the end of November.

Each year, the National Oceanic and Atmospheric Administration offers a forecast in May for the coming season. This year, NOAA’s Climate Prediction Center anticipates a 60 percent chance of an above-normal season. The Center anticipates 13 to 19 storms, although that number doesn’t indicate how many storms will make landfall.

These predictions have become the crystal ball through which forecasters and city planners prepare for a season that involves tracking disturbances that typically begin off the West coast of Africa and pick up energy and size as they travel west across the Atlantic towards Central America. While some storms travel back out to sea, others threaten landfall by moving up the Gulf Coast or along Atlantic Seaboard of the United States.

Kevin Reed, an Associate Professor at Stony Brook University’s School of Marine and Atmospheric Sciences, and Alyssa Stansfield, a graduate student in his lab, recently predicted the likely amount of rainfall from tropical cyclones.

Alyssa Stansfield at the 33rd Conference on Hurricanes and Tropical Meteorology in 2018. Photo by Arianna Varuolo-Clarke

 

Using climate change projection simulations, Reed and Stansfield came up with a good-news, bad-news scenario for the years 2070 through 2100. The good news in research they published in Geophysical Research Letters is they anticipate fewer hurricanes.

The bad news? The storms will likely have higher amounts of rain, with increased rain per hour.

“If you focus on storms that make landfall over the Eastern United States, they are more impactful from a rainfall standpoint,” Reed said. “The amount of rainfall per hour and the rainfall impact per year is expected to increase significantly in the future.”

In total, the amount of rainfall will be less because of the lower number of storms, although the intensity and overall precipitation will be sufficient to cause damaging rains and flooding.

Warmer oceans and the air above them will drive the increased rainfall, as these storms pass over higher sea surface temperatures where they can gain energy. Warmer, moist air gives the hurricanes more moisture to work with and therefore more potential rainfall.

“As the air gets warmer, it can hold more water in it,” Stansfield said. “There’s more potential rain in the air for the hurricanes before they make landfall.”

Stansfield said the predictions are consistent with what climatologists would expect, reflecting how the models line up with the theory behind them. She explored how climate change affects the size of storms in this paper, but she wants to do more research looking at hurricane size in the future.

“If hurricanes are larger, they will drop rainfall over a larger area,” which could increase the range of area over which policy makers might need to prepare for potential damage from flooding and high winds, Stansfield said.

While her models suggest that storms will be larger, she cautioned that the field hasn’t reached a consensus about the size of future storms. As for areas where there is greater consensus, such as the increased rainfall their models predict for storms at the end of the century, Stansfield suggested that the confidence in the community about their forecasts, which use different climate models, is becoming “more apparent as more modeling groups reach the same conclusion.”

Alyssa Stansfield at Sequoia National Park in 2018. Photo by Jess Stansfield

In explaining the expectations for higher rainfall in future storms, Reed said that even storms that had the same intensity as current hurricanes would have an increase in precipitation because of the availability of more moisture at the surface.

While storms in recent years, such as Hurricanes Harvey, Florence and Dorian dumped considerable rain in their path because they moved more slowly, effectively dumping rain over a longer period of time in any one area, it’s “unclear” whether future storms would move more slowly or stall over land.

Several factors might contribute to a decrease in the number of storms. For starters, an increase in wind sheer could disrupt the formation of some storms. Vertical wind sheer is caused when wind speed and direction changes with increasing altitude. Pre-hurricane conditions may also change due to internal variability and the randomness of the atmosphere, according to Reed.

Reed said the team chose to use climate models to make predictions for the end of the century because it is common in climate science for comparison to the recent historical record. They also used a 30 year period to limit some of the uncertainty due to internal variability of weather systems.

Stansfield, who is in her third year of graduate school and anticipates spending another two years at Stony Brook University before defending her graduate thesis, said she became interested in studying hurricanes in part because of the effects of Superstorm Sandy in 2012.

Alyssa Stansfield at Yosemite in 2019. Photo by Kathy Stansfield

When she was younger, she and her father Greg used to go to the beach when a hurricane passed hundreds of miles off the coast, where she would see the impact of the storm in larger waves. At some point, she would like to fly in a hurricane hunter plane, traveling directly into a storm to track its speed and direction.

Stansfield said one of the more common misconceptions about hurricanes is that the category somehow determines their destructive power. Indeed, Superstorm Sandy was a Category 1 hurricane when it hit New York and yet it caused $65 billion in damage, making it the 4th costliest hurricane in the United States, according to the NOAA.

After Stansfield earns her PhD, she said she wants to continue studying hurricanes. One question that she’d like to address at some point is why there are between 80 to 90 hurricanes around the world each year. This has been the case for about 50 years, since satellite records began.

“That’s consistent every year,” she said. “We don’t know why that’s the number. There’s no theory behind it.” She suggested that was a “central question” that is unanswered in her field. 

Understanding what controls the number of hurricanes will inform predictions about how that number will change in response to climate change.

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Saket Navlakha. Photo from CSHL

By Daniel Dunaief

When people walk into their own home, they immediately ignore sensory cues around them. They may not notice the picture of their children on the wall, the lush leaves of the ficus plant, or the constant smell of soup that greets them when they return from work.

Similarly, animals and even flies become accustomed to cues in their environment, habituating to them so they can focus on more important signals, like the smell of nearby food or the appearance of a fly swatter.

Cold Spring Harbor Laboratory Associate Professor Saket Navlakha and his post doctoral researcher Yang Shen recently studied the way flies subtract smells from the environment, giving them the opportunity to focus instead on odors that might be more important to their lives.

In a paper last month in the Proceedings of the National Academy of Sciences, Navlakha and Shen converted the way flies use a signal filtering process to create a computer algorithm.

Navlakha explained that the tandem were using computer science to understand better a basic biological phenomenon of habituation and how it happens. “We’ve been studying background subtraction,” he said in a recent interview.

One of the applications for their work is in electronic noses. Hotels and even military departments may in the not too distant future use these systems to process odors to determine what’s in the environment.

These electronic noses detect faint signals within noisy backgrounds. Habituation enables them to remove from consideration those scents that would otherwise distract from the goal of scanning the environment for new information.

Navlakha suggested that humans, who are often a visually dominant species, are not always the best species at using a sense of smell to perceive the environment.

Saket Navlaka with his wife Sejal Morjaria, during a run in Port Washington in mid-May. Photo by Lawrence Lau

“Many other species rely on their noses as much as we rely on vision,” he said. “We don’t always have an intuitive sense of what is possible in the olfactory space. Sometimes, that limits our imagination.”

While Navlakha is not crafting sensors that can detect compounds, he is working on the computer science analogs to odor recognition and discrimination. He is exploring the kind of data analysis that would have applications in a range of fields. 

In one example, he said a sensor in an airport might be surrounded by a symphony of smells, including new pungent or even subtle toppings on pizza or even a new cologne from someone working in a watch repair store. 

The sensor might need to sift through all that data to find someone who is transferring a toxic chemical through an airport, the scent of which might be faint and almost insignificant compared with the other odors spreading through the terminal.

In a more everyday example, a sensor in the refrigerator might detect the subtle changes in odors emitted by foods that are starting to become inedible, such as an onion or cream cheese.

“You want to detect” when food is starting to turn so you can “eat it and use it” before it becomes inedible, Navlakha said. “These are the kind of problems we are exploring on the data analysis side.”

Navlakha specifically looked at the activity of Kenyon cells, which are special odor neurons. When a fly receives a new scent, about five percent of these cells turn on, developing a unique activity tag.

Once the fly becomes habituated to a smell that isn’t relevant for its survival — either to indicate the presence of food or to announce the arrival of a predator — Navlakha believes the number of Kenyon cells that make up the tag for the odor declines. While this is his theory, he said more work needs to be done to confirm these predictions.

A new odor repeats the process, bringing the fly’s attention to a new smell. The fly brain in principal can reverse the subtraction process for habituated odors if the odor becomes more rare or important for the fly’s survival. Researchers need to conduct more work to confirm this as well.

Navlakha hopes to frame the fluid process of recognizing, habituating and bolstering the signal for odors to understand how the brain is functioning.

He said the fly brain responds to smells based on two mechanisms. In the first, the fly has an innate, evolutionary behavior. In the second, the fly learns through experience. Navlakha studied the learned behaviors.

The next steps involve pushing more on the experimental front, determining the limits of odor discrimination and looking at the role of habituation.

He hopes to extend an experiment that others have done with people. Experimenters took three odors that were all relatively similar that come from three flowers. Most people could not discriminate between two out of the three odors. In an experimental group, they allowed people to habituate to one of three smells and then they had to discriminate between the other two. By subtracting out the common part of all three smells, they were more successful at decoding the difference between the others.

“We want to see if we can do this in fruit flies” while recording from a region of the fly brain called the mushroom body.

Navlakha also bought an electronic nose. Using this artificial system, he wants to test odor discrimination algorithms.

“One thing this would allow us to do is to test and validate these algorithms to see how well they perform,” he explained. “There are all kinds of tests to see what kind of power these sensors have.”

In the PNAS paper, Navlakha mostly used the literature for their biological inspiration. They discussed numerous parts of the paper with biological collaborators and including biological experiments. They did not introduce any new biological data.

He came across this literature about 18 months ago.

“We thought it was interesting because we could understand the whole series of transformations when a fly smells,” he said. He worked on how to understand the process from input to output.

During the COVID-19 lockdown, he has been spending considerably more time doing theoretical work and modeling. He and his wife Sejal Morjaria have also gotten out of the house to do some running.

As for his work, Navlakha is hoping to build on what he’s done so far and expects he will, if you’ll pardon the pun, follow his nose as the research progresses.

 

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Nancy Reich. Photo from SBU

By Daniel Dunaief

Even as pharmaceutical companies are working furiously to produce a vaccine for COVID-19, scientists are taking other approaches that might lead to treatment for this disease or for other viruses that might threaten public health.

Nancy Reich, a Professor in the Department of Microbiology and Immunology at the Renaissance School of Medicine at Stony Brook University, and several colleagues at SBU recently received a $450,000 grant from the G. Harold and Leila Y. Mathers Foundation to pursue the laboratory study of two possible interventions.

Reich and her colleagues plan to investigate the use of interferon-lambda, which is in clinical trials for Hepatitis D virus, and an inhibitor for bradykinin called icatibant, which is approved for angioedema.

“Although we are very hopeful for a vaccine in the near future, vaccines can take months or years” to develop and use, Reich said. “The likelihood is that there will be more emerging diseases” which increases the need for broad spectrum first line defense therapeutics that might provide relief and save lives.

A few months ago, several faculty in microbiology and immunology got together on a Zoom call to discuss what they could do to combat COVID-19. The group was “very enthusiastic” about interferon, which is a natural hormone and is the only cytokine that’s antiviral. It has the ability to prevent the spread of the virus by reducing replication.

Reich will work with Patrick Hearing and Erich Mackow, who are both professors in the Department of Microbiology and Immunology, on the molecular aspects of COVID-19. Associate Professor Janet Hearing and Assistant Professor Hwan Kim are certified to work in high containment biosafety laboratories.

COVID-19 seems to have figured out how to block the action or production of interferon, Reich said, although the lower levels of the hormone haven’t been confirmed yet.

Other researchers are testing how the virus that has caused the pandemic has blocked the production of this defense mechanism. The Reich-led group is also planning to test this process.

To get protection from interferon, people would likely need an increased amount of the antiviral molecule early in the infection process, Reich said. She and her team are focusing on interferon lambda, which is a specific type that primarily affect epithelial cells, which are the type of cells that line the respiratory and digestive systems.

Interferon alpha and beta cause systemic problems, which can trigger an overactive immune system to cause a cytokine storm. This can lead to severe symptoms, if the body’s reaction is strong enough.

“Because interferon lambda is more specialized in the targets it hits, it doesn’t cause this crazy, global effect in your body,” Reich said.

At this point, Reich is looking to use a pre-clinical animal model of COVID-19 to understand the processes involved with the virus and its reaction to different concentrations of this hormone at different times after infection.

Reich has reached out to a company called EIGR Pharmaceuticals, which is the only company that produces a pegylated version of interferon lambda. By adding polyethlylene glycol, or PEG, EIGR can extend the time that the drug remains in the body, reducing the need for new doses.

The interferon lambda receptors are prevalent in hepatocytes, or liver cells. The liver is particularly important in capturing bacteria, viruses and macromolecules that might otherwise cause harm in the human body. The interest in the liver and interferon is mainly because of hepatitis viruses.

Interferon lambda’s higher specificity reduces potential side effects that other interferons trigger in the blood or in the central nervous system. EIGR has created this interferon to treat Hepatitis D.

“I have contacted [EIGR] to do some COVID work and now they are,” Reich said. “They have some clinical trials going on in the United States, Israel and Australia.” In addition to their research work with interferon lambda, the group will also study the effects of bradykinin, which is a small peptide hormone that the angiotensin-converting enzyme 2 (or ACE2) receptor inactivates.

The group is exploring the use of inhibitors for bradykinin, hoping to reduce a molecular trigger that exacerbates symptoms of the disease.

“We are taking two approaches; one is more about the symptoms, through bradykinin inhibition, and the other is trying to block virus replication,” said Reich.

In their research with interferon and inhibitors to bradykinin, Reich is hoping to generate data that will be ready within several months.

If both of the approaches proves effective independently, Reich said the next steps could involve combining them.

If the combination works better than either of the treatments alone, the researchers, and, down the road, the doctors, who might use this approach could use a lower dose of both drugs, which could reduce any potential side effects.

Reich said this research is possible at Stony Brook because it has a Biosafety Level 3.“We are able to do these experiments that others may not be able to do,” she said.

The animal facility that will house the mice for her studies is still not accepting new animals. Reich hopes they start to accept them in June.

Reich appreciated the speed at which the Mathers Charitable Foundation reacted to their request for funds.

The Foundation, which was created by a Santa Barbara, California couple who donated their wealth to research in 1983, made a decision within weeks, reflecting the urgency that the public health crisis triggered by COVID-19 has created.

Many foundations typically take six to eight months to decide on funding.

Reich appreciates that she and her colleagues will have a chance to contribute to a growing body of research about a virus that has caused close to 100,000 deaths in the United States and has disrupted billions of lives around the world.

“Everybody realizes the urgency,” Reich said.

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Jennifer Keluskar. Photo from SBU

By Daniel Dunaief

In the second of a two-part series, Times Beacon Record News Media describes the clinical and research work of Jennifer Keluskar, a Clinical Professor in the Department of Psychiatry at Stony Brook University.

Keluskar and Matthew Lerner, an Associate Professor of Psychology, Psychiatry & Pediatrics (see last week’s paper), recently received a grant from the Office of the Vice President for Research & the Institute for Engineering-Driven Medicine to study the effects of COVID-19-induced social isolation on people with Autism Spectrum Disorder. 

Keluskar spends half her time working at the Outpatient Department of Psychiatry, Child and Adolescent Services, where she provides cognitive behavioral intervention and ASD diagnostic evaluations for youth with autism, and the other half working on the SB Autism Initiative.

The pandemic has challenged young people with autism, as they manage through social isolation and worry about an uncertain future. Many of Jennifer Keluskar’s patients are struggling, with some dreading the return to school in the fall and others grappling with the removal or change in a routine or structure.

Some of her clients have felt increased pressure to organize their time and be productive amid a lack of peer support and without the opportunities to model their performance based on interacting with other students at school.

Through modeling, some students take notes when they notice their classmates writing down concepts or ideas a teacher is sharing or gaining some measure of reassurance when they see that everyone is struggling with the work load.

“This latter point is particularly relevant given the novelty of this situation for teachers as well as the consequent likelihood that they will have trouble knowing how much work to give, especially given the wide variety” of circumstances at home, Keluskar explained in an email.

For some students with autism who have a measure of social-anxiety disorder, the remote learning environment has provided some measure of relief, reducing the difficulty in reading nonverbal cues from their classmates and teachers.

Now that these students are learning remotely, these “social stressors have been lifted,” Keluskar said.

Nonetheless, even the patients who have felt relieved about fewer anxiety-inducing social interactions are starting to develop concerns about a potential resumption of classes in the fall.

Keluskar has already seen some patients who are perseverating on that future upcoming transition. “We are going to see more of it in my clientele as we get closer to reopening schools,” she said, adding that she has some patients who are afraid of not being able to advance in life, to college or to jobs, but who, at the same time, are afraid of taking the next step after getting used to quarantine.

Jennifer Keluskar with her husband Raja, 5-year-old daughter Skylar and three-year-old son Colby.

Working with Alan Gerber, a graduate student in Matthew Lerner’s lab at SBU, Keluskar will assess responses to COVID-19. They have sent out two questionnaires. One, which was released by other researchers, examines how the pandemic has affected circumstances and behaviors, from employment changes to junk food consumption. The other is an evidence-based measure of parental stress that is not specific to the virus. She is going to measure anxiety and depression to see how they change during quarantine. 

Keluskar appreciates how the Initiative offers programs such as a homework club, which students can attend virtually for an hour each day. “I have connected some of my clients in the clinic to undergraduate mentors and so far this has been quite successful” although the scale of these connections has been small so far.

The Initiative currently has a mentoring program geared towards older adolescents. She is planning to offer this program to younger individuals.

Deborah Gross, the Initiative’s coordinator, runs a program called the Sidekicks Squad, which is for older adolescents and young adults with special needs.

“Some of my patients would benefit from pairing with a mentor,” Keluskar said. “Through these mentoring sessions, people with autism hang out with their mentors.”

Child-directed interpersonal time is “so important for people’s well being and development,” Keluskar explained, referring to both the mentor and the mentee.

She appreciates that this mentoring program is laid back and fun and believes that mentors benefit just as much from it as mentees.

Through the Initiative, the group has also done eight weekly, Facebook livestream events. The organizers discuss a topic and add three tips at the end. The tips have provided suggestions, including: using creativity to engage children by adding special interests into activities; taking a collaborative problem solving approach when running into difficulties getting a child to cooperate; and understanding emotional underpinnings to children’s behavioral difficulties.

Keluskar recognizes the challenge that come from having self-directed resources available to children and their parents. Even when people have access to many resources, they do not always know where to begin or what to prioritize, she said.

She advises a parents to try to get enough rest for themselves. “You need to take care of yourself so you can model [appropriate behavior] to your children,” she said.

Through the pandemic challenges, Keluskar also urges parents to be creative in their responses to the stressors that are affecting them and their children. She suggests people to take chances in how they approach their interactions with anxious children.

“You can’t be creative if you’re afraid of being wrong,” she said. “Being able to move past little mistakes shows flexible control. Set limits and be structured, but also be flexible at the same time.”

A resident of Commack, Keluskar lives with her husband Raja Keluskar, who is an engineer, their five-year old daughter Skylar and their three-year old son Colby.

Keluskar said she has been anxious about public speaking since she was young and can empathize with others who struggle with this. Through Facebook groups and other efforts, she said she can “personally attest to the value of multiple exposures and say that it can even become enjoyable with time and practice.”

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On Zoom screen, clockwise from top left, Committee member Hoi-Chung Leung; Committee Member Matthew Lerner; Eve Rosen; Committee Member Nicholas Eaton; Tamara Rosen; graduate student Cara Keifer; and Shira Yudkoff.

By Daniel Dunaief

On April 17, Tamara Rosen did something she had been anticipating for six years: she defended her graduate thesis.

Working in the lab of Matthew Lerner, who is an Associate Professor of Psychology, Psychiatry & Pediatrics in the Department of Psychology at Stony Brook University, Rosen had focused her efforts on the symptoms people with autism exhibit when they are anxious or depressed.

While the questions in her graduate thesis defense followed a pattern she anticipated, with professors asking her about the way she compiled her data and the conclusions she drew, the format wasn’t what she had expected.

Like so many other gatherings that had formerly been public events, Rosen’s thesis defense was broadcast by Zoom. The downside was that she wasn’t in the room with everyone, where she could have a discussion one on one. The upside was that her friends and family could tune in as easily as they do to work calls or other family gatherings. Indeed, Rosen’s mother, Marna; her step-mother Eve; and her father Dennis, all of whom share an appreciation for the work Tammy did for her thesis, watched the defense from start to finish, exulting in a landmark achievement.

“This was a really important day in our family’s history,” Dennis Rosen told his daughter, sharing the pride he felt for her.

“I always knew you were smart, but now I know you are brilliant,” her mother beamed.

After the call, Rosen saw her mother and stepmother overwhelmed with emotions, shedding tears for an achievement she sometimes needs to reassure herself really happened.

Rosen’s work focused on how anxiety and depression, two conditions that mental health professionals are concerned are becoming more prevalent amid the viral pandemic, have different symptoms in the population of people with autism spectrum disorder than they do for those who are not on the spectrum.

Based on prior research, Rosen wanted to account for the different symptoms in her follow-up analysis.

Prior studies have found that the traditional models of anxiety and depression do not adequately fit youth with autism. Others had suggested, but not tested, the notion that the Diagnostic and Statistical Manual model of these symptoms provides an ineffective model of anxiety and/or depression symptoms because of the influence of autism symptoms.

That is why Rosen specifically examined the influence of autism on these conditions in one of her analyses.

Among other findings, Rosen said that autism influences anxiety and depression. The prevalence of anxiety and depression is higher compared to the general population.

There are a range of clinical implications for her work, Rosen said.

Her work validates what clinicians are doing, which is to take the profile of autism into account when they treat anxiety.

Rosen moved to Colorado last July to start her internship year at JFK Partners at the University of Colorado School of Medicine, where she is also starting her post-doctoral clinical fellowship. She is treating clients with autism and anxiety and depression, which she said is in her “wheel house” of expertise.

Rosen is grateful for the support she received from Lerner and the program at Stony Brook. “It was great training,” she said.

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Matthew Lerner. Photo from SBU

By Daniel Dunaief

Though hampered by the pandemic in their direct contact with people who have autism, the founder of The Autism Initiative and research director Matthew Lerner along with the Head of Autism Clinical Education Jennifer Keluskar at Stony Brook University are managing to continue to reach out to members of the community through remote efforts. In a two-part series, Times Beacon Record News Media will feature Lerner’s efforts this week and Keluskar’s work next week.

Through several approaches, including improvisational theater, Matthew Lerner works with people who are on and off the autism spectrum on ways to improve social competence, including by being flexible in their approach to life.

In the midst of the ongoing pandemic, he has had to apply the same approach to his own work.

Lerner, who is an Associate Professor of Psychology, Psychiatry & Pediatrics in the Department of Psychology at Stony Brook University, recognizes that it’s difficult to continue a project called SENSE ® Theatre (for Social Emotional NeuroScience Endocrinology), where the whole function of the process is to provide in-person social intervention.

The SENSE Theater study is a multisite National Institute of Mental Health-funded project focused on assessing and improving interventions to improve social competence among adolescents with autism. The core involves in person intervention through group social interaction.

Matthew Lerner with his sons Everett,6, and Sawyer,2. Photo by Chelsea Finn

That, however, is not where the effort ends.“There are arms of that study that are more educational and didactic,” Lerner said. “We’re starting to think about how we could capitalize on that.”

In the ongoing SENSE effort, Lerner is coordinating with Vanderbilt University, which is the lead site for the study, and the University of Alabama.

Stony Brook is in active contact with the families who are participating in that effort, making sure they know “we are doing our best to get things up and running as quickly as possible,” Lerner said.

The staff is reaching out to local school districts as well, including the Three Village School District, with whom Lerner is collaborating on the project, to ensure that people know the effort will restart as soon as it’s “safe to be together again.”

Lerner is also the founder and Research Director of The Autism Initiative at SBU, which launched last year before the pandemic altered the possibilities for in-person contact and forced many people to remain at or close to home for much of the time. The initiative provides programs and services for the community to support research, social and recreational activities and other therapeutic efforts.

The Stony Brook effort initially involved video game nights, adult socials and book clubs. The organizers and participants in the initiative, however, have “stepped up in a huge way and have created, in a couple of weeks, an entirely new set of programming,” Lerner said.

This includes a homework support club, guidance, webinars and support from clinicians for parents, which address fundamental questions about how to support and adapt programs for people with autism. The group is keeping the book club active. The initiative at least doubled if not tripled the number of offerings, Lerner suggested.

Additionally, SBU has two grants to study a single session intervention adapted for teens with autism. The project has been running for about nine months. Lerner said they are looking to adapt it for online applications. For many families, such remote therapy would be a “real boon to have access to free treatment remotely,” he said.

Lerner had been preparing to conduct a study of social connections versus loneliness in teens or young adults with autism. Since COVID-19 hit, “we have reformulated that and are just about to launch” a longitudinal a study that explores the effects of the lockdown on well-being and stress for people who have autism and their families.

Lerner is looking at how the pandemic has enhanced the importance of resilience. He said these kinds of studies can perhaps “give us some insight when we return to something like normalcy about how to best help and support” people in the autism community. “We can learn” from the stresses for the community of people with autism during the pandemic.

To be sure, the pandemic and the lockdown through New York Pause that followed hasn’t affected the entire community of people with autism the same way. Indeed, for some people, the new norms are more consistent with their behavioral patterns.  “Some autistic teens and young adults have said things to me like, ‘I was social distancing before it was cool,’” Lerner said.

Another teenager Lerner interacted with regularly went to the bathroom several times to wash his hands. When Lerner checked in on him to see how he was doing amid the pandemic, he said, “I was made for this.”

Lerner also said people who aren’t on the spectrum may also gain greater empathy through the changes and challenges of their new routines. People find the zoom calls that involve looking at boxes of people on a full screen exhausting. After hours of shifting our attention from one box to another, some people develop “zoom fatigue.”

Lerner said someone with autism noted that this experience “may be giving the rest of us a taste of what it’s like for folks on the spectrum,” which could provide insights “we might not otherwise have.”

Even though some people with autism may feel like the rest of the world is mirroring their behavioral patterns, many people in and outside the autism community have struggled with the stresses of the public health crisis and with the interruption in the familiar structure of life.

The loss of that structure for many with autism is “really profound,” which is the much more frequent response, Lerner said. “More kids are telling us they are stressed out, while parents are saying the same thing.” In some sense, the crisis has revealed the urgency of work in the mental health field for people who are on and off the spectrum, Lerner said.

The studies in autism and other mental health fields that come out of an analysis of the challenges people face and the possible mental health solutions will likely include the equivalent of an asterisk, to capture a modern reality that differs so markedly from conditions prior to the pandemic. There may be a new reporting requirement in which researchers break down their studies by gender, age, race, ethnicity, income and “another variable we put in there: recruited during social isolation.”

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