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Power of 3

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Paul Freimuth and co-author Feiyue Teng, a scientist in Brookhaven Lab’s Center for Functional Nanomaterials (CFN), at the light microscope used to image bacteria in this study. Photo from BNL

By Daniel Dunaief

Researchers regularly say they go wherever the science takes them. Sometimes, however, the results of their work puts them on a different path, addressing new questions.

So it was for Paul Freimuth, a biologist at Brookhaven National Laboratory. Freimuth was studying plant proteins of unknown function that he thought might play a role in the synthesis or modification of plant cell walls. The goal was to produce these proteins in bacteria or yeast to facilitate an understanding of the protein structures.

When he inserted plant genes into bacteria, however, one of those genes experienced a phase shift, producing a misfolded protein that, when produced in high enough quantities, killed the bacteria.

Working with several interns over the course of five years, as well as a few other principal investigators, Freimuth discovered that this protein had the same effect as antibiotics called aminoglycosides, which are the current treatment for some bacterial infections. He recently published the results of these studies in the journal Plos One.

Aminoglycosides enter the cell and cause ribosomes to create proteins in an error-prone mode, which kill the bacterial cells. The way these proteins kill the cells, however, remains a mystery. Antibiotic-treated cells produce numerous proteins, which makes determining the mechanism of action difficult.

The protein Freimuth studied mirrors the effect of treating cells with aminogylcosides. Researchers now have a protein they can study to determine the mechanism of cell killing.

To be sure, Freimuth said the current research is at an early stage, and is a long way from any application. He hopes this model will advance an understanding of how aberrant proteins kill cells. That information can enable the design of small molecule drugs that mimic the protein’s toxic effect. He believes it’s likely that this protein would be toxic if expressed in other bacteria and in higher cells, but he has not tested it yet.

With antibiotic resistance continuing to spread, including for aminoglycosides, Freimuth said the urgency to find novel ways to kill or inhibit bacterial growth selectively without harmful side effects has increased.

Aminoglycosides cause the ribosome to shift coding phases or to make other errors. The model toxic protein he studied resulted from the bacteria starting to translate amino acids at an internal position, which produced a new, and, as it turns out, toxic sequence of amino acids.

The phase-shifted gene contained a stop codon located just 49 codons from the start site, which means that the toxic protein only contained 48 amino acids, which is much shorter than the average of 250 to 300 amino acids in an E. coli protein.

Since the model toxic protein was gene-encoded rather than produced by an antibiotic-induced error in translation, Freimuth’s team were able to study the sequence basis for toxicity. The acutely toxic effect was dependent on an internal region 10 amino acids in length.

Narrowing down the toxic factor to such a small region could help facilitate future studies of the mechanism of action for this protein’s toxic effect.

Misread signal

Freimuth and his team discovered that the bacteria misread the genetic plant sequence the researchers introduced. The bacteria have a quality control mechanism that searches for these gibberish proteins, breaking them down and eliminating them before they waste resources from the bacteria or damage the cell.

When Freimuth raised the number of such misfolded proteins high enough, he and his colleagues overwhelmed the quality control system, which he believes happened because the misfolded protein affected the permeability of the cell membrane, opening up channels to allow ions to flood in and kill the cell.

He said it’s an open question whether the protein jams open existing channels or becomes directly incorporated into the membrane, compromising membrane stability.

He showed that cells become salt-sensitive, indicating that sodium ion concentration increases. At the same time, it is likely that essential metabolites are leaking out, depriving the cell of compounds it needs to survive.

Now that the bacteria has produced this protein, Freimuth can use various tools and techniques at BNL, including the X-ray beamlines for protein crystallography and the cryo electron microscope, which would provide ways to study the interaction of the protein with cell components. High resolution structures such as the ones he hopes to determine could be used to guide drug design.

Freimuth is in the process of applying for National Institutes of Health funding for additional research, which could help the NIH’s efforts to counter the increasing spread of antibiotic resistance.

Freimuth has worked at BNL since 1991. He and his wife Mia Jacob, who recently retired from her role in graphic design in Stony Brook University’s Office of Marketing and Communication, reside in East Setauket.

The couple’s daughter Erika, who lives in Princeton and recently got married, works at Climate Central as an editor and writer. Their son Andrew works in Port Jefferson at an investment firm called FQS Capital Partners.

When Freimuth is not working at the lab, he enjoys sailing, kayaking and canoeing. During the pandemic, he said he purchased a small sailboat, with which he has been dodging the ferry in Port Jefferson Harbor.

Originally from Middletown, Connecticut, Freimuth was interested in science from an early age. He particularly enjoyed a mycology class as an undergraduate at the University of Connecticut.

As for his unexpected research with this protein, the biologist is pleased with the support he received from Brookhaven National Laboratory.

He said BNL enabled him to address the biofuel problem from protein quality control, which is a new angle. “BNL appreciates that valuable ideas sometimes bubble up unexpectedly and the lab has ways to assist investigators in developing promising ideas,” he said.

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Pallavi Tatapudy with her husband Nishank Mehta.

By Daniel Dunaief

Bringing together people from a range of experiences and perspectives, Stony Brook University is preparing to complete the first year of its LEND training program, which is designed to help provide support and services for people with autism and neurodevelopmental disabilities.

Over 100 trainees will complete the course this month, as the leaders of LEND, which stands for Leadership Education in Neurodevelopmental and other related Disabilities, prepare to educate a second year of participants that is expected to exceed 300 people.

Top row: Dr. Matthew Lerner, Dr. Michelle Ballan (co-director and director)
2nd row: Pallavi Tatapudy, Isaac Rodriguez, Morgan McNair
3rd row: Sarah Grosser, Anjolie Nagarwalla, Jenny Andersson
Bottom row: Christopher Rosa, Ava Gurba

Matthew Lerner, LEND Center Co-Director, Research Director of the Autism Initiative, and Associate Professor of Psychology, Psychiatry & Pediatrics, and Michelle Ballan, LEND Program and Center Director, Professor, and Associate Dean for Research in the School of Social Welfare and Professor of Family, Population and Preventive Medicine, run the program, which is the first on Long Island to receive a federal grant that supports training students, families, professionals and self-advocates.

Lerner described three key takeaways for the $2.2 million, five-year grant. 

First, “if we want to be effective in supporting individuals with neurodevelopmental disorders we have to be interdisciplinary,” he said.

Second, the group, which includes trainees at three different levels depending on their time commitment to the program, needs to “listen to the voices of autistic people,” Lerner added. For too long, “they’ve been an afterthought at the table of care.”

Third, the work is a “process and not an outcome,” he said.

Many of the participants in the program appreciated the opportunity to engage in an interdisciplinary effort.

Self-advocate

Ava Gurba, a self-advocate and master’s student at Stony Brook University who has autism and cerebral palsy, said she saw LEND as her chance to “reframe the professional discipline” and inform people in a range of fields about what life is “really like” for her and others.

Many professionals in health care have limited experience working with self-advocates.

“They have only interacted with disabled people as clients in a therapeutic setting or as research subjects,” Gurba said.

Researchers and service providers don’t often know how to incorporate the lived experience for the family and from self- advocates, she added.

Gurba suggested that some professionals need to “unlearn” practices that don’t incorporate the values and needs of people with disabilities.

The medical community is often looking for cures, while Gurba said she and others with disabilities are more often looking for ways to be integrated into the community, through social, employment, or educational opportunities.

Clinical training

For Alan Gerber, a doctoral student in the Department of Psychology at Stony Brook, LEND provided autism-specific clinical training, including planning treatment and reviewing the progress for specific patients.

“It gives me an opportunity to get together with an inter-disciplinary cohort and see things from a different lens,” Gerber said.

Gerber plans to be a clinical researcher and will conduct post doctoral research at the Yale Child Study Center.

LEND “made me think very deeply about what is clinically meaningful research,” Gerber said. When he speaks with families, pediatricians and social workers, he wants to do the kind of research that is “really going to change a family’s life.”

Gerber hopes to remain in contact with other members of the LEND community, where he felt he was part of a team.

Paradigm shift

As a high school bilingual speech language pathologist who works closely with individualized education plans, Jenn Solomon wanted to understand more about the lives and challenges of people with developmental disabilities.

LEND provided a paradigm shift for Solomon in helping her understand disability. “I can listen to what people with disabilities have to say, and I can reflect and learn,” Solomon said.

One of Solomon’s broader goals is to advocate on behalf of students who have obstacles to overcome.

Jenny Andersson, who works for the New York State Department of Education Office of Special Education funded project called the Educational Partnership, suggested that LEND “exceeded what I had imagined.”

Like other trainees, Andersson, who is Director of the Early Childhood Family and Community Engagement Center, appreciated the participation of self-advocates.

“I approach everything in my work now and ask, ‘Did we invite all stakeholders to the discussion?’”

Ripple effects

Andersson is excited to see the ripple effect of the program, where other professionals benefit from what trainees learn and discuss and change their practices.

Indeed, Dr. Pallavi Tatapudy, a second-year psychiatry resident at Stony Brook, said her husband Nishank Mehta, who is a first-year orthopedic surgery resident at Stony Brook, has learned about advocacy from some of the discussions she had through LEND.

“This experience of working together and hearing all of these personal insights, you cannot get from a textbook,” Tatapudy said. 

Tatapudy understands the value of consulting with people who have disabilities and with their families. “The patient is the expert,” she said.

When she worked in the inpatient psychiatric unit on the 12th floor of Stony Brook Hospital, Tatapudy said she spoke to a family who was admitting a child with a neurodevelopmental disability. She asked parents for an idea of ways to comfort their child that de-escalate emotionally charged moments at home. His parents said a particular blanket from home provided comfort, which they brought to the hospital.

Tatapudy is “proud” that Stony Brook is a LEND center, joining 60 others throughout the country.

For Lerner, who was a LEND trainee about a dozen years ago and continues to stay in touch with his LEND cohort, the effort helps experts learn from each other and from self-advocates who can share their perspectives. “None of us has enough expertise to do this alone,” he said.

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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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