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Power of 3

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Jessica Tollkuhn Photo courtesy of CSHL

By Daniel Dunaief

Estrogen plays an important role in the developing mouse brain. By facilitating connections to other brain regions, estrogen turns on genes that affect how the brain of male and female rodents develops and, down the road, how mice behave.

Cold Spring Harbor Laboratory Associate Professor Jessica Tollkuhn this week, along with  graduate student Bruno Gegenhuber who recently earned his PhD, published research in the journal Nature that demonstrates how a specific region of the brain, called the bed nucleus of the stria terminalis, or BNST, responds to estrogen when the hormone receptor binds to DNA.

Male rodents convert a surge in testosterone into estrogen, which then triggers the development of more cells in the BNST than in female rodents. Later on in life, this can affect mating, parenting and aggression.

At this point, there is no data on how the BNST is masculinized in humans, although it is bigger in adult men than in women. Scientists also don’t know what the BNST does in humans. The BNST in humans is not much bigger than it is in mice.

On a broader scale, by understanding how estrogen shapes the developing brain differently in males and females, Tollkuhn hopes to discover the progression of behavioral disorders that are often more prevalent in one gender than the other. Boys have more neurodevelopmental disorders than girls, such as autism, language delays, dyslexia and attention deficit hyperactivity disorder, or ADHD. Girls, on the other hand, particularly after puberty, have twice the incidence of major depression compared to their contemporary male counterparts, Tollkuhn said.

Tollkuhn is part of a collaboration, funded by the Simons Foundation, to study autism. The CSHL researcher doesn’t believe autism originates in any particular brain region, describing it as a complex disorder with many causes.

“I do think that sex differences in brain regions such as the BNST can intersect with other genetic and environmental factors to increase vulnerability to developing certain symptoms in boys,” she explained.

In rodents, estrogen protects against programmed cell death. In the BNST and a few other brain regions, there are sex differences in cell death that are dependent on hormone exposure. A male mouse without exposure to estrogen would not have a larger BNST.

History of her research

Tollkuhn has been looking for estrogen receptor alpha in the brain since she started her post doctoral research at UCSF in 2007. The genome-wide targets of this receptor in breast cancer cells were first described in 2006.

Back then, the technology wasn’t good enough to capture estrogen receptor alpha binding in the small, sparse population of cells. These receptors, after all, aren’t in most brain cells.

The receptors for a hormone that plays such an important developmental role sit in the same place in males and females.

Tollkuhn’s assumption going into this study was that estrogen receptor alpha would have access to different genes in adult males and females, based on the different life histories of when the two sexes had prior estrogen exposure, which was transient in the developing male brain and fluctuated in females after puberty.

That, however, was not the case. Giving females and males the same hormones caused the genome to respond the same way.

“It’s really the differences of which hormones are present in the circulation that determines what genes are active,” she explained in an email.

Future studies

Tollkuhn is interested in the variation of hormones, receptors and gene responses between individuals within a single species and among various species.

She suggested that a spectrum of variability in sexual differentiation likely exists within and across species. The differences in the way these hormones and receptors shape individual development “is advantageous” because the plasticity in behaviors makes a species more resilient to subtle or dramatic changes in the environment, enabling an organism to alter its behaviors depending on internal states such as hunger, time of year, or place in a social hierarchy.

Tollkuhn would also like to know the genomic targets of androgen receptor, within the BNST and elsewhere. She would like to look at where estrogen receptors and androgen receptor are expressed in the developing human brain. She also plans to study estrogen receptor beta, which is “poorly understood even outside the brain.”

Studying these receptors and the genes they alter could enhance an understanding of cognition and mood, as well as measures of stress and anxiety.

Women with estrogen receptor positive breast cancer sometimes take a medication that blocks estrogen in the breast and in the brain. A side effect of this medicine, however, is that it causes women to have menopausal-type symptoms, such as disrupted sleep, thermoregulatory issues like “hot flashes,” and mood disorders.

Tollkuhn and Cassandra Greco, a graduate student at Stony Brook University, will investigate how different breast caner medications that target estrogen receptor alpha differentially affect its recruitment to the genome.

Tollkuhn plans to test the three most commonly prescribed treatments to see how they are affecting the brain and what they are doing to the estrogen receptor regulated genes in the brain.

She hopes one day to help develop a therapy with more specific targets that doesn’t have the same side effects.

Science origin story

When she was young, Tollkuhn liked reading books about biology, but didn’t discover her interest in research until she attended Mills College in Oakland, CA.

She got her first research experience working at biotech companies during her undergraduate studies. At that point, she learned that she was capable of doing challenging experiments.

In addition to continuing to read about a range of other research experiments, Tollkuhn enjoys the challenge of research.

“The joy of this job is that I get paid to ask questions that are interesting,” she said.

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A. Laurie Shroyer Photo by Jeanne Neville/Stony Brook University

By Daniel Dunaief

Publish or perish.

It’s the academic paradigm that defines the importance of getting great research and ideas in front of the public. Not only does publishing enable researchers to share discoveries, but it also provides additional rungs on a career ladder.

Science journals with greater impact can raise the visibility of up-and-coming researchers, helping them win more competitive grants, get papers published in other journals, and receive coveted promotions and tenure.

In a recent study led by A. Laurie Shroyer, Professor of Surgery and Vice Chair for Research at the Renaissance School of Medicine at Stony Brook University, women authors in positions considered significant — first, second or last — appeared at a rate that was below their representation in academic medical school faculty for the three top ranking medical journals.

Published in the journal PLOS ONE of 1,080 author citations from 2002 to 2019 in The Lancet, the Journal of the American Medical Association and the New England Journal of Medicine, a team of researchers determined that women were listed as senior, or last, authors 18.6 percent of the time. Meanwhile, 26.8 percent of women were first authors.

The first and last author rates for women were lower than the 37.2 percent of women full-time academic faculty members, according to Shroyer. “This is truly striking. I never in my wildest dreams thought [the publication rate for women] was this low” particularly for last authors.

Indeed, the percentages varied by journal, with the New England Journal of Medicine coming in the lowest for first authors, at 15.83 percent, and the Journal of the American Medical Association showing the highest rate, at 35.39 percent. Lancet had 29.39 percent.

In response to emailed questions about the study, officials at the New England Journal of Medicine indicated that the journal does not ask authors to self-identify.

“With a group of publishers lead by the Royal Society of Chemistry, we’re developing best practices for encouraging diversity among authors,” said Eric Rubin, M.D., PhD and Editor-in-Chief of the NEJM. “Diversity in medicine is important, and we are taking steps where we can to encourage change or highlight inequities.”

In September 2021, the NEJM published an editorial that said having more diversity among researchers is one way to help make trials more representative. Additionally, in April 2021, the NEJM published a Special Report about the diversity of the medical student body.

“We believe we must diversify our own ranks and encourage diversity at all stages of medical training,” Dr. Rubin added.

The Lancet, meanwhile, indicated that the data they collected on gender representation among their authors, peer reviewers and Editorial Advisory Board members led them to develop new strategies to improve gender representation in the editorial process, including a diversity pledge and no all-male panel policy, according to a public relations statement. All Lancet International Advisory Boards are now 50 percent women. This past March, the Lancet hosted a webinar on gender equity.

Shroyer lauded The Lancet for providing a public disclosure of their author gender profiles. The Lancet’s “positive actions are admirable,” she said..

A request for comment from the Journal of the American Medical Association was not returned by press time.

While the JAMA women first author rate did not demonstrate a statistically significant difference from the Association of American Medical Colleges, it was different, at 20.8 percent for last authors and for any significant author role, at 32.8 percent compared to 37.2 percent overall.

To be sure, Shroyer and co-author Henry Tannous, chief of Cardiothoracic Surgery Division and co-director of the Stony Brook Heart Institute, didn’t receive the kind of information that would help shed greater light on the publishing process.

Shroyer explained that it would be helpful to have journal-specific editorial office data on author specific and publication specific details for manuscripts received, reviewed and accepted.

Without access to editorial office databases, “it will not be possible to discern the potential reasons behind the lower women author publication rates,” Shroyer explained, adding that with the unknown rate of gender-based submissions, it is possible that the relative proportion of submitted articles published might not be different between men and women.

“My hope is that this publication may inspire all of these top medical journals to publish their own summary reports and to share their own editorial office databases to facilitate future research in this field,” she said.

An ongoing pattern

Shroyer began investigating the author and publication characteristics associated with multiple successful publications in top medical research journals in late 2017.

To determine if the pattern had changed over time, Shroyer and Tannous divided the publication rates into early, 2002 to 2008; mid, 2009 to 2014; and late, 2015 to 2019. Using samples from these years, Shroyer concluded that there were no differences over time.

Among other conclusions, Shroyer said women first authors less commonly published clinical trials as compared with observational study designs. Their projects were also more frequently focused on infectious disease topics. Men, on the other hand, published more work focused on cardiovascular topics.

Shroyer added that the sampling of three journals’ records does not prove a gender bias. She could only show a discrepancy in the author publication rates.

She’s an advocate for individual investigator-based identifiers that are just numbers, which would allow for a more thorough and detailed analysis of any trends in publication rates.

This research provides a call for “greater transparency and accountability” Shroyer said.

As a potential optimistic sign, Shroyer found that first/ last authors with the same gender more often published clinical trials and had higher Web of Science citation counts, compared with first authors with different genders. First authors who were the same gender as last authors also had higher multiple top medical research journal publications.

While this doesn’t necessarily point to a clear mentor benefit, Shroyer suggests this connection between women principal investigators and their research staff may create greater publishing opportunities and advancement for women in science.

“My hope is that we can find ways to help each other,” she said. “Preliminary analysis shows potential promise.”

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Kevin Reed. Photo courtesy of Stony Brook University

By Daniel Dunaief

Rain, rain go away, come again some other day.

The days of wishing rain away have long since passed, amid the reality of a wetter world, particularly during hurricanes in the North Atlantic.

In a recent study published in the journal Nature Communications, Kevin Reed, Associate Professor and Associate Dean of Research at the School of Marine and Atmospheric Sciences at Stony Brook University, compared how wet the hurricanes that tore through the North Atlantic in 2020 would have been prior to the Industrial Revolution and global warming.

Reed determined that these storms had 10 percent more rain than they would have if they occurred in 1850, before the release of fossil fuels and greenhouse gases that have increased the average temperature on the planet by one degree Celsius.

The study is a “wake up call to the fact that hurricane seasons have changed and will continue to change,” said Reed. More warming means more rainfall. That, he added, is important when planners consider making improvements to infrastructure and providing natural barriers to flooding.

While 10 percent may not seem like an enormous amount of rain on a day of light drizzle and small puddles, it represents significant rain amid torrential downpours. That much additional rain can be half an inch or more of rain, said Reed. Much of the year, Long Island may not get half an inch a day, on top of an already extreme event, he added.

“It could be the difference between certain infrastructure failing, a basement flooding” and other water-generated problems, he said. The range of increased rain during hurricanes in 2020 due to global warming were as low as 5 percent and as high as 15 percent.

While policy makers have been urging countries to reach the Paris Climate Accord’s goal of limiting global warming to 2 degrees Celsius above the temperature from 1850, the pre-Industrial Revolution, studies like this suggest that the world such as it is today has already experienced the effects of warming.

“This is another data point for understanding that climate change is a not only a challenge for the future,” Reed said. It’s not this “end of the century problem that we have time to figure out. The Earth has already warmed by over 1 degrees” which is changing the hurricane season and is also impacting other severe weather events, like the heatwave in the Pacific Northwest in 2021. That heatwave killed over 100 people in the state of Washington.

Even being successful in limiting the increase to 2 degrees will create further increases in rainfall from hurricanes, Reed added. As with any global warming research, this study may also get pushback from groups skeptical of the impact of fossil fuel use and more carbon dioxide in the atmosphere.

Reed contends that this research is one of numerous studies that have come to similar conclusions about the impact of climate change on weather patterns, including hurricanes.

“Researchers from around the world are finding similar signals,” Reed said. “This is one example that is consistent with dozens of other work that has found similar results.”

Amid more warming, hurricane seasons have already changed, which is a trend that will continue, he predicted.

Even on a shorter-term scale, Hurricane Sandy, which devastated the Northeast with heavy rain, wind and flooding, would likely have had more rainfall if the same conditions existed just eight years later, Reed added.

Reed was pleased that Nature Communications shared the paper with its diverse scientific and public policy audience.

“The general community feels like this type of research is important enough to a broad set of [society]” to appear in a high-profile journal, he said. “This shows, to some extent, the fact that the community and society at large [appreciates] that trying to understand the impact of climate change on our weather is important well beyond the domain of scientists like myself, who focus on hurricanes.”

Indeed, this kind of analysis and modeling could and should inform public policy that affects planning for the growth and resilience of infrastructure.

Study origins

The researchers involved in this study decided to compare how the 2020 season would have looked during cooler temperatures fairly quickly after the season ended.

The 2020 season was the most active on record, with 30 named storms generating heavy rains, storm surges and winds. The total damage from those storms was estimated at about $40 billion.

While the global surface temperature has increased 1 degree Celsius since 1850, sea surface temperatures in the North Atlantic basin have risen 0.4 to 0.9 degrees Celsius during the 2020 season.

Reed and his co-authors took some time to discuss the best analysis to use. It took them about four months to put the data together and run over 2,500 model simulations.

“This is a much more computationally intensive project than previous work,” Reed said. The most important variables that the scientists altered were temperature and moisture.

As for the next steps, Reed said he would continue to refine the methodology to explore other impacts of climate change on the intensity of storms, their trajectory, and their speed.

Reed suggested considering the 10 percent increase in rain caused by global warming during hurricanes through another perspective. “If you walked into your boss’s office tomorrow and your boss said, ‘I want to give you a 10 percent raise,’ you’d be ecstatic,” he said. “That’s a significant amount.”

Ecstatic, however, isn’t how commuters, homeowners, and business leaders feel when more even more rain comes amid a soaking storm.

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Mehdi Damaghi. Photo from Stony Brook Hospital

By Daniel Dunaief

Do the birds on the Galapagos Islands, with their unique coloration, differently shaped beaks and specific nesting places, have anything to do with the cancer cells that alter the course of human lives?

For Mehdi Damaghi, Assistant Professor in the Department of Pathology at the Renaissance School of Medicine at Stony Brook University, the answer is a resounding, “Yes.”

Damaghi uses the same principles of evolutionary biology to understand how cancer, which resides within human genes, works to adapt, as it tries to win the battle to survive.

“What we try to understand is the Darwinian principals of cancer,” said Damaghi. Cancer “adapts and reprograms themselves” to their environment to survive.

Damaghi, who arrived at Stony Brook four months ago from Moffitt Cancer Center, plans to address numerous questions related to cancer. He recently received a $4 million grant from the Physical Science in Oncology program (PSON) through the National Institutes of Health/ National Cancer Institute. Working with cancer biologists, clinicians, and computational scientists, he plans to define and understand cancer’s fitness.

“We are trying to study the core evolution of cancer cells and the normal stroma around them,” said Damaghi. “We are looking at the evolution of the tumor and some of the host cells.”

Cancer biologists are trying to build mathematical and theoretical models to explore the playbook cancer uses when confronted with threats, either in the form of a body’s natural defenses against it or from therapies against which it can, and often does, develop resistance.

Treating cancer could involve using adaptive therapy, which could enable people to control and live with cancer longer, Damaghi suggested.

In studying cancer’s phenotype, or the way the disease is expressed and survives, he hopes to understand factors in the microenvironment. Many cancers, he reasons, become more problematic as people age. Indeed, centuries ago, cancer wasn’t as prevalent as it is today in part because life expectancy was shorter.

Damaghi also has an evolutionary model to explore metastasis, in which cancer spreads from one organ or system to other parts of the body. He is looking at the earliest stages of breast cancer, to see what factors some of these cancers need or take from the environment that enables them not only to develop into breast cancer, but also to spread to other systems.

Through the microenvironment, he is looking for biomarkers that might signal a potential tumor development and metastasis long before a person shows signs of an aggressive form of the disease.

“We look at the tumor as a part of a whole ecosystem that can have different niches and habitats,” he said. “Some can be hypoxic and oxidative, and others can be like a desert on Earth, where not much grows and then cancer evolves.”

Damaghi challenges cells in a culture or organoids, which are miniature, three-dimensional live models of human cells, with different microenvironmental conditions to see how they respond. He exposes them to hormones, immune cells, and hypoxic conditions.

“We try to understand what is the adaptation mechanism of cancer to this new microenvironment and how can we push them back to the normal phenotype,” he said.

Like other scientists, Damaghi has demonstrated that many of these cancer cells use sugar. Removing sugar caused some of the cancer to die.

Increasing the survival for patients could involve knowing what kinds of micro-environments cancer uses and in what order. Deprived of sugars, some cancers might turn to amino acids, dairy or other sources of food and energy.

Damaghi thinks researchers and, eventually, doctors, will have to approach cancer as a system, which might have a patient-specific fingerprint that can indicate the resources the disease is using and the progression through its various diseased stages.

Choosing Stony Brook

Damaghi appreciates the depth of talent in cancer sciences at Stony Brook University. He cited the work of Laufer Center Director Ken Dill and Cancer Center Director Yusuf Hannun. He also suggested that the Pathology Department, headed by Ken Shroyer, was “very strong.”

For their part, leaders at Stony Brook were pleased to welcome, and collaborate with, Damaghi. Hannun suggested Stony Brook recruited Damaghi because his research “bridges what we do in breast cancer and informatics.”

Shroyer, meanwhile, has already started collaborating with Damaghi and wrote that his new colleague’s focus on breast cancer “overlaps with my focus on pancreatic cancer.”

To conduct his research, Damaghi plans to look at cells in combination by using digital pathology, which can help reveal tumor ecosystems and niches.

He also appreciated the work of Joel Saltz, the Founding Chair in the Department of Biomedical Informatics. “In the fight against cancer, we all need to unite against this nasty disease,” Damaghi said. “From looking at it at different angles, we can understand it first and then design a plan to defeat it.”

Originally from Tehran, Iran, Damaghi is the oldest of five brothers. He said his parents encouraged them to explore their curiosity.

Damaghi, whose wife Narges and two daughters Elissa and Emilia are still in Tampa and hope to join him before long, has hit the ground running at Stony Brook, where he has hired three postdoctoral researchers, a lab manager, four PhD students, two master’s candidates, and three undergraduates.

Damaghi is inspired to conduct cancer research in part because of losses in his family. Two grandparents died from cancer, his aunt has breast cancer, and his cousin, who had cancer when he was 16, fought through the disease and is a survivor for 20 years.

Damaghi bicycles and plays sports including soccer. He also enjoys cooking and said his guests appreciate his Persian kebobs.

As for his arrival in Stony Brook, he said it was “the best option for me. It’s a great package and has everything I need.”

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Heather Lynch Photo courtesy of Rolf Sjogren/ National Geographic

By Daniel Dunaief

To borrow from the Pink song in the movie Happy Feet, the Pew Trusts for Marine Conservation recently delivered “something good” to Stony Brook University’s Heather Lynch. 

Endowed chair for ecology and evolution at Stony Brook University’s Institute for Advanced Computational Science, Lynch was selected as one of six Pew Fellows in Marine Conservation.

Lynch, who uses a host of tools including physics and satellite imagery to study penguin populations in Antarctica and associated island groups including in South Georgia and the South Sandwich Islands, is one of six international recipients of the 2022 fellowship, which includes $150,000 over three years, and is a mid-career prize.

Lynch plans to use the funds to chronicle species health in the macaroni and king penguin and forecast risks to Antarctica’s penguin populations.

Lynch’s work is “really important,” said Claire Christian, Executive Director of the Antarctic and Southern Ocean Coalition (ASOC), who nominated Lynch for the fellowship. Lynch provides the kind of information “we need to make effective decisions about protecting Antarctica.”

Christian, who has known Lynch for about five years, said Lynch’s consistent commitment helps “provide a broader picture of what’s happening down there over a longer time frame.”

Christian is particularly pleased that Lynch’s work in the Antarctic brings necessary attention to the region, even though “it’s far away at the end of the world,” she said. “People understand that [the Antarctic] is worth investing time and resources into studying.”

The Pew Fellows Program in Marine Conservation provides recipients with an opportunity to interact with other winners and alumni. This year, the Pew Trust received over 50 nominees.

Past honorees at Stony Brook University include Endowed Professor of Ocean Conservation Sciences at the School of Marine and Atmospheric Science Ellen Pikitch and Endowed Research Chair for Nature and Humanity Carl Safina.

Jane Lubchenco, who won a Pew Fellowship in marine conservation in the 1992, was the first woman to lead the National Oceanographic and Atmospheric Administration and is the current Deputy Director for Climate and Environment in the White House.

Rebecca Goldburg, Director of Environmental Sciences at the Pew Charitable Trusts, appreciates the mixture of high-level research Lynch produces and the application of her discoveries to conservation and added that Lynch has “outstanding scientific achievement that is well-integrated into decision making.”

Climate change

While researchers haven’t broadly chronicled the movement of macaroni penguins into the Antarctic, Lynch anticipates that climate change would draw them into the Antarctic.

“My hope is that a focus on macaroni penguin census data will illuminate their trends,” she explained in an email.

King penguins, meanwhile, have recently arrived in the Antarctic. The presence of king penguins would represent a turning point for Lynch, as they would suggest that the Antarctic is starting to show ecological similarities with the sub-Antarctic.

King penguins have attempted to breed on Elephant Island, which is about 800 miles from their typical habitat in South Georgia. While this species of penguin has traveled this distance in prior years, their decision to settle and try to raise chicks, which they haven’t successfully done, is “new and ecologically interesting,” Lynch explained.

Lynch suggested such a geographic expansion is rare because these birds are long-lived and an established pair will breed in the same location for years. Even in young individuals traveling to new territories, the rate of range shift is slow and hard to track.

“The movement of king penguins into Antarctica is exactly what would have been predicted and so it is an exciting (if, from a climate perspective, disturbing) time to be watching this all unfold,” she said.

King penguins can form large colonies, which could, over the course of a longer period of time, create competition for space with chinstraps. Lynch suggested that the region could be in the early days of an ecologically important event.

Where’s Waldo?

As for macaroni penguins, whose stories about how they got their name include one involving a sailor slang for men who dressed in bright colors, they have frequently been the “Where’s Waldo?” of what Lynch does, she said, as she encounters them by chance in a colony of another species.

She is pulling together several decades of offhand notes about her findings on macaronis to track them systematically. She believes collecting information about populations of macaroni and king penguins in Antarctica is going to be informative.

In analyzing penguin populations across species, Lynch plans to take the kind of approach portfolio managers apply when they consider where to focus their attention.

A mutual fund manager with a large percentage of the value of the fund linked to changes in the stock price of Apple would likely track the earnings of the company and its share price more closely than stocks in which she has smaller holdings or whose values don’t fluctuate much.

For penguins, Lynch suggested that scientists and conservationists may “need to understand those colonies, and there may not be that many, that contain a large percentage of the world’s population,” she said.

For a long time, researchers have focused on colonies that were easier to study because they were small and close by. “I don’t think we can justify that approach anymore,” Lynch said.

Picking penguin spots

Goldburg appreciates Lynch’s framework for penguin conservation.

Lynch will address the “key penguin colonies,” some of which are contributing disproportionately to the risk of penguin declines, Goldburg said. This approach will enable conservationists to monitor important sites because they “can’t do everything.” 

Understanding penguin populations goes beyond a simple rule that more of any population is necessarily better. Major increases or decreases should be cause for concern because they reflect shifts in the functioning of the ecosystem, she explained.

Christian is confident the work Lynch does will provide policy makers with key information.

“Her work is really important and it deserves to have a lot of visibility and funding,” Christian said. “Without understanding what’s happening to species that are living down there, we can’t” design effective strategies to protect them and their ecosystems.

Lynch provides the kind of information necessary to “make effective decisions about protecting Antarctica,” Christian added.

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Famotidine molecule Image courtesy of Wikipedia

By Daniel Dunaief

An over-the-counter stomach-soothing medication may also relieve some of the symptoms of mild to moderate COVID-19.

Tobias Janowitz Photo courtesy of CSHL

In a study recently published in the journal Gut, Cold Spring Harbor Laboratory Assistant Professor Tobias Janowitz and a team of collaborators at CSHL and The Feinstein Institutes for Medical Research at Northwell Health demonstrated that Famotidine, the active ingredient in Pepcid, shortened the duration of symptoms for a diverse patient group of adults soon after developing COVID-19 symptoms.

In a placebo-controlled study, people taking 80 milligrams of Famotidine three times a day reported that symptoms such as headaches declined after 8.2 days, compared with 11.4 days for patients who were taking the placebo.

“We think that the results are preliminary, but encouraging,” Janowitz explained in an email. 

The research, which included 55 volunteers, may offer health care providers another tool to help treat mild to moderate cases of COVID-19. In the clinical study, the use of Famotidine helped reduce a potentially overactive inflammatory response without suppressing the immune system’s efforts to ward off the virus.

Participants in the study received Famotidine or placebo pills along with a host of instruments they could use at home to gather clinical data about themselves, including a cellular activated Apple iPad, a scale, thermometer, fitness tracker, spirometer to measure air flow in and out of the lungs and a pulse oximeter, which measured oxygen levels by taking a reading over a person’s fingernails.

The protocol for the study allowed volunteers to stay home, where they gathered results from the instruments and reported on their health and any symptoms they felt. Technicians came to the home of each volunteer on the first, seventh, 15th, and 28th days after entering the clinical trial.

Researchers and doctors involved in the analysis of the effectiveness of COVID believe this remote approach to participating in clinical trials could prove a safe and effective way to conduct research for other diseases.

“In today’s virtual world, our clinical trial strategy has significant implications for how to study new drugs in patients at home,” Dr. Kevin Tracey, president and CEO of the Feinstein Institutes, explained in a Cold Spring Harbor Laboratory news brief.

Janowitz added that other studies could also use testing protocols at home, including for other diseases. “We are looking forward to employing it to help develop better treatments for people with cancer,” which is the disease at the center of his research, he explained.

The CSHL Assistant Professor focuses on the whole body response to cancer, although many of the biological considerations are transferable to other diseases.

Pivot to COVID

According to Janowitz, “It was relatively easy for us to pivot to COVID research when it was a global area of unmet need.” 

The researchers chose Famotidine because of encouraging studies and from a case series, Janowitz explained. They also found a potential mechanism of action where Famotidine blocked the H2 receptor, which encouraged them to move to a phase 2 randomized clinical trial.

The researchers were pleased that the participants in this small trial included people from a range of ages and ethnic groups. Nearly two thirds of patients, who were 18 years and older, were from black, mixed-race or Hispanic communities.

“Patients with different ancestry may have different responses to this disease,” Janowitz explained. “It helps to learn about the generalizability of the results.”

In a CSHL news brief, Nicole Jordan-Martin, executive director for New York City Health + Hospitals, added that “accessible, safe and low-cost outpatient treatment options are a priority in our global efforts to combat COVID-19.” Northwell and New York City Health + Hospitals provided care for the communities most in need of support for New York City, she added.

The collaborators were also encouraged by their teamwork.

“Our institutions worked extremely well together to face challenges the pandemic posed, like offering digital solutions and reaching populations who struggled for access to care,” Dr. Christina Brennan, vice president of clinical research at the Feinstein Institute and co-investigator of the trial, said in the news brief. 

“From screening patients to organizing home delivery of the equipment and medication, this sets a new model for future trials and convenience for participants.”

Janowitz described the safety profile of Famotidine as “excellent” and said it “appears to have few interactions with other drugs and very few side effects in general.”

To be sure, Janowitz cautioned doctors and patients not to stock up on Famotidine before researchers conduct additional studies.

“Our trial is not conclusive and an early phase clinical trial (phase 1 or 2) is not sufficient to inform clinical practice,” he wrote.

Additionally without further study, researchers don’t know the best potential dose and dosing interval for this possible treatment. At this point, they know how long the drug stays in the blood and the strength of its binding to its receptor.

A dose of 20 milligrams per day or less may be too little to achieve an effect, but “we do not know this for certain,” Janowitz explained.

While researchers agreed that further studies were necessary to answer key questions, they believed that the results from this research could provide fodder for studies outside of the COVID world.

“It is possible that sustained inflammation contributes to illness in other contexts and changing this inflammation would be beneficial,” Janowitz wrote. “This will have to be explored separately. Importantly, the methods used in this trial are also transferrable, so we have learned a lot of important information” from this research.

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Jose M. Adrover and Mikala Egeblad. Photo by Lijuan Sun

By Daniel Dunaief

Cold Spring Harbor Laboratory Professor Mikala Egeblad thought she saw something familiar at the beginning of the pandemic.

Mikala Egeblad. Photo from CSHL

Egeblad has focused on the way the immune system’s defenses can exacerbate cancer and other diseases. Specifically, she studies the way a type of white blood cell produces an abundance of neutrophil extracellular traps or NETs that can break down diseased and healthy cells indiscriminately. She thought potentially high concentrations of these NETs could have been playing a role in the worst cases of COVID.

“We got the idea that NETs were involved in COVID-19 from the early reports from China and Italy” that described how the sickest patients had severe lung damage, clotting events and damage to their kidneys, which was what she’d expect from overactive NETs, Egeblad explained in an email.

Recently, she, her post doctoral researcher Jose M. Adrover and collaborators at Weill Cornell Medical College and the Icahn School of Medicine at Mt. Sinai proved that this hypothesis had merit. They showed in hamsters infected with COVID and in mice with acute lung injuries that disabling these NETs improved the health of these rodents, which strongly suggested that NETs are playing a role in COVID-19.

“It was very exciting to go from forming a hypothesis to showing it was correct in the context of a complete new disease and within a relatively short time period,” Egeblad wrote.

Egeblad, Andover and their collaborators recently published their work in the Journal of Clinical Investigation Insight.

Importantly, reducing the NETs did not alter how much virus was in the lungs of the hamsters, which suggests that reducing NETs didn’t weaken the immune system’s response to the virus.

Additional experiments would be necessary to prove this is true for people battling the worst symptoms of COVID-19, Egeblad added.

While the research is in the early stages, it advances the understanding of the importance of NETs and offers a potential approach to treating COVID-19.

An unexpected direction

Jose Adrover. Photo from CSHL

When Adrover arrived from Spain, where he had earned his PhD from the Universidad Complutense de Madrid and had conducted research as a post doctoral fellow at the Spanish Center for Cardiovascular Research in March of 2020, he expected to do immune-related cancer research.

Within weeks, however, the world changed. Like other researchers at CSHL and around the world, Egeblad and Adrover redirected their efforts towards combating COVID.

Egeblad and Andover “were thinking about the virus and what was going on and we thought about trying to do something,” Adrover said. 

Egeblad and Adrover weren’t trying to fight the virus but rather the danger from overactive NETs in the immune system.

Finding an approved drug

Even though they were searching for a way to calm an immune system responding to a new threat, Egeblad and Adrover hoped to find a drug that was already approved.

After all, the process of developing a drug, testing its safety, and getting Food and Drug Administration approval is costly and time-consuming. 

That’s where Juliane Daßler-Plenker, also a postdoctoral fellow in Egeblad’s lab, came in. Daßler-Plenker conducted a literature search and found disulfiram, a drug approved in the 1950’s to treat alcohol use disorder. Specifically, she found a preprint reporting that disulfuram can target a key molecule in macrophages, which are another immune cell. Since the researchers knew this was important for the formation of NETs, Daßler-Plenker proposed that the lab test it.

Working with Weill Cornell Medical College and the Icahn School of Medicine at Mt. Sinai, Adrover explored the effect of disulfiram, among several other possible treatments, on NET production.

Using purified neutrophils from mice and from humans, Adrover discovered that disulfiram was the most effective treatment to block the formation of NETs.

He, Assistant Professor Robert Schwartz’s staff at Weill Cornell and Professor Benjamin tenOever at Mt. Sinai tried disulfiram on hamsters infected with SARS-Cov-2. The drug blocked net production and reduced lung injury.

The two experiments were “useful in my opinion as it strengthens our results, since we blocked NETs and injury in two independent models, one of infection and the other of sterile injury,” Adrover said. “Disulfuram worked in both models.”

More work needed

While encouraged by the results, Egeblad cautioned that this work started before the availability of vaccines. The lab is currently investigating how neutrophils in vaccinated people respond to COVID-19.

Still, this research offered potential promise for additional work on NETs with some COVID patients and with people whose battles with other diseases could involve some of the same immune-triggered damage.

“Beyond COVID, we are thinking about whether it would be possible to use disulfiram for acute respiratory distress syndrome,” Egeblad said. She thinks the research community has focused more attention on NETs.

“A lot more clinicians are aware of NETs and NETs’ role in diseases, COVID-19 and beyond,” she said. Researchers have developed an “appreciation that they are an important part of the immune response and inflammatory response.”

While researchers currently have methods to test the concentration of NETs in the blood, these tests are not standardized yet for routine clinical use. Egeblad is “sensing that there is more interest in figuring out how and when to target NETs” among companies hoping to discover treatments for COVID and other diseases.

The CSHL researcher said the initial race to gather information has proven that NETs are a potentially important target. Down the road, additional research will address a wide range of questions, including what causes some patients to develop different levels of NETs in response to infections.

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Christopher Vakoc. Photo from CSHL

By Daniel Dunaief

Diseases like cancer take the normal raw materials of a cell and make them a part of a pernicious process that often threatens a person’s health.

Ideally, when researchers find the raw materials cancers need to survive, they discover specific proteins that are necessary for cancer, but aren’t critical for healthy cells.

That appears to have happened recently in the lab of Cold Spring Harbor Laboratory Professor Chris Vakoc in the study of the blood disease Acute Myeloid Leukemia, or AML.

Vakoc’s former graduate student Sofya Polyanskaya, who now works in a pharmaceutical company in Germany, discovered the importance of an understudied protein called SCP4, which removes phosphate groups from other proteins, in some forms of AML. This protein acts as an enzyme, which makes it a particularly appealing target.

In his lab, Vakoc said he and his researchers take “genes and the proteins they encode and [try to] publish the first paper linking them to cancer,” Vakoc said.

Polyanskaya and Vakoc recently published their findings in the journal Cell Reports.

These scientists disabled proteins in a host of diverse cancer types, looking for dependencies that were unique to each cancer. After determining that SCP4 was only needed in leukemia and not other cancers, they inactivated the protein in normal, healthy blood cells and found that it wasn’t needed.

“Leukemia cells are super sensitive to the loss of this enzyme,” Vakoc said.

Vakoc praised the work of Polyanskaya, who he said conducted the “inspiring work” that led to this conclusion. “It’s not easy for a brand new scientist entering the field to write the first cancer paper on a target.”

Polyanskaya surveyed hundreds of these enzymes to find a potential new protein that cancer, specifically, might need. The CRISPR technology, which didn’t exist nine years ago, provides a way of altering a large number of potential enzymes to find the ones that are critical for cancer’s survival.

Ideally, this kind of analysis enables researchers like Polyanskaya and Vakoc to focus in on the ones that are critical to cancer, but that don’t perform any important function in normal cells.

One of the other benefits of this work is that it validates the importance of targets that have become the focus of other research projects.

“Part of what we’re doing is making sure that our processes more broadly in the field are robust,” Vakoc said. “We are more confident in other targets we didn’t discover” but that play a role in the progression of leukemia.

To be sure, the discovery of the SCP4 target is the first step in a series of questions that may require considerable time and resources to ensure a reliable and safe clinical benefit.

As with many cancers, leukemia may have the equivalent of a back up plan, in case this seemingly important enzyme is unavailable. Indeed, the battle against cancer and other diseases involves moves and counter moves by pharmaceutical and biotechnology companies and the diseases they battle.

Additionally, researchers like Vakoc need to discover the reason cells produce this enzyme in the first place. Mice lacking SCP4 are born, but develop metabolic stress after birth.

“The important experiment in the future will be to determine what the consequences of targeting SCP4 are in normal tissue much later after birth,” Vakoc explained in an email.

Like other cancers, leukemia is a heterogeneous disease, which is another way of saying that not everyone with the disease has the same symptoms and prognosis and not everyone would respond to the same treatment in the same way.

Vakoc would like to figure out for “which subset of patients with leukemia is this protein the most important. Down the road, that could help determine who might benefit from an SCP4 inhibitor.

“We want to personalize therapy as much as possible,” he said.

In his follow up research, Vakoc hopes to learn more about the three-dimensional structure of the protein complex.

Vakoc’s interest in leukemia stems from his interest in studying blood. When he conducted his PhD training at the University of Pennsylvania, he studied normal blood development.

He was particularly interested in pediatric cancer. While AML is on of the cancers that children can develop, it is far more common in elderly people.

The lab has a strong focus on leukemia.

Vakoc, whose lab is next door to CSHL Cancer Center Director David Tuveson, has also starting searching for potential therapeutic targets in pancreatic cancer.

He is excited about the potential to bring attention to a possible candidate that may provide a therapeutic benefit for patients at some point.

“It feels good to put a new target on the map,” he said.

The CSHL scientist recognizes that cancer can and often does develop resistance to a treatment that tackles any one enzyme or protein. Still, he said treating cancer with any new and effective therapy could extend life by several months, which are often “very valuable to patients.”

Vakoc suggested that any potential new treatment for leukemia would likely involve several drugs working together to stay ahead of cancer.

“The real hope and optimism is that, if you had a copule of targets like this that are not needed in healthy cells, you could add 10 or 20 years of high quality life. You could keep the disease in a chronic, latent state.”

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Abhay Deshpande with a group of students at Stony Brook University. Photo from SBU

By Daniel Dunaief

The American Association for the Advancement of Science recently named physicist Abhay Deshpande a Fellow.

Abhay Deshpande. Photo from SBU

Deshpande, who thinks big about small matter, has distinguished himself with his discoveries, ideas, leadership, innovation, and mentorship. The Director of Electron Ion Collider Science at Brookhaven National Laboratory (BNL) and SUNY Distinguished Professor at Stony Brook University will become a fellow as part of an online ceremony on Feb. 19.

“I was really pleasantly honored” to be a part of a group that includes so many leaders in science, including actor and science advocate Alan Alda, who founded the eponymous Alan Alda Center for Communicating Science at Stony Brook, said Deshpande.

Deshpande’s collaborators and scientific colleagues said Deshpande deserved the AAAS honor, which the society has given since 1874.

“Everything [Deshpande] has been doing is advancing science,” said Haiyan Gao, Associate Laboratory Director in Nuclear and Particle Physics at BNL.

Fundamental questions

A physicist who earned his bachelor’s degree from the University of Bombay, which is now called the University of Mumbai, his Master’s degree from the Indian Institute of Technology, Kanpur and his PhD at Yale University, Deshpande has put his academic and intellectual talents to work answering fundamental questions about atoms.

In his research, Deshpande studies protons in the nucleus.

Inside protons and neutrons are quarks and gluons, which are fundamental particles. Gluons have no mass and bind the quarks together, which suggests that the mass of protons must come from quarks — except that it doesn’t.

“The surprise is that all quarks together only account for about one percent of the proton’s mass,” Deshpande explained in an email.

Researchers don’t know how the components of quarks and gluons and their energies contribute to the proton’s mass. At the same time, Deshpande wants to know about the origin of a proton’s spin. 

Quarks constitute about a quarter of a proton’s spin and gluon’s another quarter, which suggests that the remaining spin should come from their orbital angular momentum.

Deshpande never thought about the mass deficit until a few years ago because of his focus on a proton’s spin. “The same rotational motion of the quarks and gluons could not only explain the spin, but hopefully explain the mass,” Deshpande said. Such a solution to both unanswered questions would be “elegant,” he said.

EIC champion

A $2 billion Electron Ion Collider, which the Department of Energy awarded BNL in 2020, will take measurements that will study the origin of the remaining spin and mass. BNL will start building the EIC, which will take eight years to construct, in 2024.

Dmitri Kharzeev, Distinguished Professor and Director in the Center for Nuclear Theory at Stony Brook University, helped nominate Deshpande to become a AAAS fellow in part because of his work developing BNL’s EIC bid.

Deshpande “really played a major role in bringing this project to Long Island,” Kharzeev said. “It means a lot for BNL, and it also means a lot for Long Island as a whole. A lot of people will be hired to work on it.”

Kharzeev said Deshpande is the leader of the science effort at the EIC “precisely because of his status in the scientific community.”

Kharzeev said some of Deshpande’s papers are “among the highest-cited papers in experimental nuclear physics,” which is considered a reflection of the importance of the work.

Gao credited Deshpande and other key leaders in the community for preparing a “white paper which laid out the science in a very convincing and powerful way,” which helped make the EIC a reality.

In addition to Deshpande’s accomplishments as a scientist, Kharzeev lauded his colleague’s leadership. Deshpande brought together researchers from BNL and Thomas Jefferson National Accelerator Facility in Virginia, which were originally competing for the rights to build the EIC. He helps researchers “put science first and scientific politics second,” which is a “spectacular achievement,” Kharzeev said.

Throughout his career, Deshpande has sought to find complementary strengths among his colleagues.

He is the founding director of the Center for Frontiers in Nuclear Science, which is a joint operation between BNL and SBU and is passionate about sharing the excitement of research with people who work outside science.

“The science we do, the excitement we feel, needs to be talked about to high school students, to college students, to their parents” and to others, Deshpande added. 

Decision-makers in the government need to understand the benefit of the research, as well as the general public, whose taxes ultimately fund future discoveries, he said, and believes communicating science requires connecting with a range of audiences.

Science communicator

Deshpande’s colleagues gave him high marks for encouraging productive collaborations. He is “able to make very good, easy connections with people,” Gao said and is “approachable and easy to work with.”

Ciprian Gal, Assistant Research Professor at Mississippi State and Visiting Scholar at the Center for Frontiers in Nuclear Science, was a graduate student in Deshpande’s lab from 2010 to 2014

While he appreciated Deshpande’s intellectual acumen and knowledge of physics, Gal admired his mentor’s accessibility and eagerness to share his passion for science.

“He’s always very open” to everyone, Gal said, including students of any age. During Summer Sunday events at BNL, Deshpande spoke at length with middle school students and their parents.

“He instills a desire to communicate in all of us,” said Gal, who also appreciated how Deshpande made himself available to the graduate students in his lab during off hours and on weekends.

Engaging audiences

While he was interested in science during his formative years in high school in Mumbai, India, Deshpande also participated in several dramatic productions that were in Marathi, his native language. Typically, the plays tried to convey messages such as the importance of literacy and education or against blind faith and misinformation. Deshpande sees a benefit to using the techniques of drama to engage the audience.

He believes the EIC will provide precise knowledge of properties of the proton and the nuclei. “I promise that we will learn lots of new things,” he said.

Kindergarten connection

The celebrated physicist is married to Arati Deshpande, who works at American Health Pharmaceuticals. The couple, who met when they were in kindergarten and now live in Miller Place, have a daughter, Pooja, who is a graduate student at the Gillings School of Public Health in Chapel Hill, N.C. and a son, Ameesh, who is in high school.

As for his advice to students, Deshpande urges them to “identify a good scientific problem and pursue it no matter the cost or time.”

 

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Jason Trelewicz Photo from SBU

By Daniel Dunaief

One day, ships in the Navy may not only last longer in the harsh environment of salt water, but some of their more complicated parts may also be easier and quicker to fix.

That’s thanks to the mechanical engineering efforts of researchers at Stony Brook University and Brookhaven National Laboratory, who have been teaming up to understand the microstructural origins of corrosion behavior of parts they produce through laser additive manufacturing into shapes with complex geometries.

The Navy is funding research at the two institutions.

Eric Dooryhee. Photo from BNL

“As you would expect you’d need near any marine environment with salt water, [the Navy] is interested in laser additive manufacturing to enable the production of parts at lower cost that have challenging geometries,” said Jason Trelewicz, Associate Professor of Materials Science and Engineering at Stony Brook University. Additionally, the Navy is hoping that such efforts can enable the production of parts with specific properties such as corrosion resistance on demand.

“If you’re out at sea and something breaks, can you make something there to replace it?” asked Trelewicz. Ideally, the Navy would like to make it possible to produce parts on demand with the same properties as those that come off a manufacturing line.

While companies are currently adopting laser additive manufacturing, which involves creating three-dimensional structures by melting and resolidfying metal powders one layer at a time with the equivalent of a laser printer, numerous challenges remain for developing properties in printed materials that align with those produced through established routes.

Additive materials, however, offer opportunities to structure products in a way that isn’t accessible through traditional techniques that create more complex geometry components, such as complex heat exchangers with internal cooling channels.

In addition to the science remaining for exploration, which is extensive, the process is driving new discoveries in novel materials containing unique microstructure-chemistry relationships and functionally graded microstructures, Trelewicz explained.

“These materials are enabling new engineering components through expanded design envelopes,” he wrote in an email.

With colleagues from BNL including Research Associate Ajith Pattammattell and Program Manager for the Hard X-ray Scattering and Spectroscopy Program Eric Dooryhee, Trelewicz published a paper recently in the journal Additive Manufacturing that explored the link between the structure of the material and its corrosive behavior for 316L stainless steel, which is a corrosion resistant metal already in wide use in the Navy.

The research looked at the atomic and microstructure of the material built in the lab of Professor Guha Manogharan at Penn State University. Working with Associate Professor Gary Halada in the Department of Material Science and Chemical Engineering, Trelewicz studied the corrosive behavior of these materials.

Often, the surface of the material went through a process called pitting, which is common in steels exposed to corrosive environments, which occurs in cars driven for years across roads salted when it snows.

The researchers wanted to understand “the connection between how the materials are laser printed, what their micro structure is and what it means for its properties,” Trelewicz said, with a specific focus on how fast the materials were printed.

While the research provided some structural and atomic clues about optimizing anti corrosive behavior, the scientists expect that further work will be necessary to build more effective material.

In his view, the next major step is understanding how these defects impact the quality of this protective film, because surface chemical processes govern corrosive behavior.

Based on their research, the rate at which the surface corrodes through laser additive manufacturing is comparable to conventional manufacturing.

Printed materials, however, are more susceptible to attack from localized corrosion, or pitting. 

At the hard x-ray nanoprobe, Pattammattel explored the structure of the material at a resolution far below the microscopic level, by looking at nonstructural details.

“It’s the only functional beamline that is below 10 nanometers,” he said. “We can also get an idea about the electronic structures by using x-ray absorption spectroscopy,” which reveals the chemical state.

Pattammattel, who joined BNL in 2018, also uses the beamline to study how lung cells in mice interact with air pollutants. He described “the excitement of contributing to science a little more” as the best part of each day.

Meanwhile, Dooryhee as involved in writing the seed grant proposal. By using the x-rays deflected by the variety of crystalline domains or grains that compose the materials, HE can interpret the material’s atomic structure by observing the diffraction angles. The discrete list of diffraction angles is a unique fingerprint of the material that relates to its long-range atomic ordering or stacking.

In this study, researchers could easily recognize the series of diffraction peaks associated with the 316L stainless steel.

Dooryhee was able to gather insight into the grain size and the grain size distribution, which enabled him to identify defects in the material. He explained that the primary variable they explored was the sweeping rate of the laser beam, which included 550, 650 and 700 millimeters per second. The faster the printing, the lower the deposited energy density.

Ultimately, Dooryhee hopes to conduct so-called in situ studies, in which he examines laser additive manufacturing as it’s occurring.

“The strength of this study was to combine several synchrotron techniques to build a complete picture of the microstructure of the [additively manufactured] material, that can then be related to its corrosion response,” he explained in an email.

Dooryhee grew up in Burgundy France, where his grandfather used to grow wine. He worked in the vineyards during the fall harvest to help pay for his university studies. Dooryhee has worked at BNL for over 12 years and appreciates the opportunity to collaborate with researchers at Stony Brook University.

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