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Daniel Dunaief

METRO photo

By Daniel Dunaief

Daniel Dunaief

Once upon a time, a girl named Fiona read the book “The Emperor’s New Clothes.”

She thought it was funny and charming that a child could see what no one else admitted. But then, something strange happened: she thought she could also see things that no one else could.

“That’s sweet, Fiona, but focus on your school work and let your imagination run wild at other times,” her father told her that night.

Fiona did as she was told because she wanted to please her parents and her teachers. It was her teachers that caused problems for her.

It started with Mrs. Butler in her third grade class. A tall, thin woman with white hair and glasses, Mrs. Butler always wore high-heeled shoes. She looked directly in the eyes of every student. One day, her friend Simona fell and hit her head. When Mrs. Butler bent down and checked on her friend, Fiona saw the kind of coat doctors and nurses wear appear around her shoulders. Fiona rubbed her eyes, but the coat was still there. Mrs. Butler calmly told the class to go to their seats, sent Bill to get the nurse and kneeled on the floor near Simona.

When the nurse left with Simona, Mrs. Butler’s white coat disappeared.

The next day, Jeff couldn’t understand a math problem. He wrote numbers all over the paper, but he didn’t have the answer.

Fiona noticed a change again in Mrs. Butler’s clothing. Instead of her powder blue blouse, she had an orange vest and white gloves. With numbers on the smartboard, she directed Jeff away from all the dead ends.

When he got closer to the answer, Jeff smiled. Fiona looked back at Mrs. Butler, whose orange vest and white gloves disappeared.

Later, Doug and Andrew got into an argument near the stack of books at the back of the room. When Doug swung his arm to make a point, he knocked over several books.

Fiona saw Mrs. Butler’s clothing change again, this time into the kind of black and white stripes that referees wear in football games. She could even see a whistle dangling from her teacher’s neck.

The next morning, Jill and Amanda couldn’t agree on how to do a class project. Jill marched to the front of the classroom to complain. Amanda followed closely.

While Fiona couldn’t hear everything, she saw a black robe form around Mrs. Butler.

When the conversation ended, Mrs. Butler said something that made both girls happy. They shook hands and walked back to their desks, where they returned to work on their project.

One day, Fiona arrived early to class. She and her teacher were alone and she felt like she had to say something.

“Mrs. Butler?” Fiona asked.

“Yes?” Her teacher replied.

“I see all the clothing you wear,” Fiona said. “I don’t think anyone else sees it.”

Mrs. Butler narrowed her eyes and looked carefully at her student.

“What do you see?” Mrs. Butler asked.

She described the medical jacket, the orange vest, the referee’s coat and the judge’s robe.

“What do you think of all that?” Mrs. Butler asked.

“Is it real?” Fiona asked.

“Thank you for seeing,” Mrs. Butler grinned. Other students walked into the room and class started.

Just then, Fiona heard an alarm. Mrs. Butler reacted immediately. She held up a shield and directed everyone to the back of the room.

While they waited, Mrs. Butler told everyone to remain quiet. The class waited for the all clear.

“It was a drill,” Mrs. Butler said. “You can return to your desks.”

Fiona was the last to leave the classroom that day.

“Fiona?” Mrs. Butler asked. “Is everything okay?”

“Yes,” she said. “Thanks for … everything.”

Corina Amor ©Len Marks Photography, 2022/CSHL

By Daniel Dunaief

What if scientists could train the immune system to recognize something specific on the outside of unwanted cells?

That’s what new Cold Spring Harbor Laboratory fellow Corina Amor is doing, as she found an antigen on the surface of senescent cells. She hopes to train a patient’s T-cells to search for these cells, much like providing a police dog with the scent of a missing person or escaped convict.

Amor, who joined Cold Spring Harbor Laboratory in January after earning her medical degree in  at Universidad Complutense de Madrid in Spain and her PhD in the lab of CSHL Adjunct Professor Scott Lowe, recently found a surface molecule called uPAR that is upregulated on senescent, or aging, cells.

If senescent cells excessively accumulate, it can lead to tissue decline and disease like lung and liver fibrosis, Lowe, who is the Cancer Biology Chair at Memorial Sloan Kettering Cancer Center, explained in an email. Senescent cells also contribute to tissue decline as people age.

Studies suggest eliminating these senescent cells could provide therapeutic benefit, she added.

Using artificial T-cells, called CAR-T, for Chimeric Antigen Receptor, Amor looks to use specific antigens to find these senescent cells and eliminate them.

“It was sort of a crazy idea, but it worked and, while much more preclinical and clinical work needs to be done, the concept could lead to better treatments for lung and liver fibrosis, and other diseases that increase as we age,” Lowe wrote.

The combination of an inflamed environment and an ineffective immune system can create conditions that favor the growth and development of cancer.

Amor, who currently has one technician and is planning to add a graduate student this summer at her lab at CSHL, is building on her PhD research.

“My doctoral work was the development of the first CAR-T cells that are able to target senescent cells,” she said. “We were the first in the world to do this.”

Amor, who was recently named to the 2022 Forbes 30 under 30 Europe list, describes this approach as a new frontier for treating senescent cells and one in which researchers would need to clear numerous hurdles before developing clinical therapies.

She is searching for other antigens on the surface of cancerous and fibrous cells that would increase the specificity of these synthetic immune cells.

Combining antigens could be the key to avoiding off target effects that might cause the immune system to attack healthy cells.

Amor plans to tap into CSHL’s affiliation with Northwell Health to analyze clinical samples that might provide a better understanding of various potential markers.

Fellowship route

Cold Spring Harbor Laboratory is one of several programs in the country that provides talented researchers with the opportunity to go directly from finishing their PhD to leading their own lab.

Amor is following in the footsteps of her MSKCC mentor Lowe, who also had been an independent fellow at CSHL.

Lowe saw some similarities in their career paths, as they both made “unexpected discoveries during our Ph.D. research that were not only important, but clearly set a path for future research,” he explained in an email.

Lowe describes Amor as an “intense and driven scientist” who has an “extraordinary bandwidth to get things done, and a mental organization that allows her to execute science efficiently.” He believes her work is game changing at many levels and opens up numerous new directions for scientific study.

Lowe is “extraordinarily proud of [Amor] for becoming a CSHL fellow – and I hope she both contributes and benefits from the lab as I did,” he wrote in an email.

Amor said CSHL provided an ideal balance between finding collaborators who worked in similar areas, without competing for the same resources and conducting similar research.

“The last thing you want is to go somewhere and be completely isolated,” she said. “You also don’t want to be at a place where there’s three other people doing the same thing and you’re not adding anything.”

She feels like she had a “nice synergy” with CSHL, which is trying to expand its immunology research. 

As the first person to bring cellular therapy to CSHL, she has already started collaborating with several groups. 

Amor recognizes the challenges ahead in training scientists who often have their own ideas about the questions they’d like to ask.

“The science is the easy part” and it comes naturally, but there is a “learning curve in how to manage people,” she said.

She appreciates the opportunity to talk with senior researchers at Cold Spring Harbor Laboratory and plans to attend courses and seminars for principal investigators who are starting out.

When she was in graduate school, Amor said she rotated through different labs. When everything didn’t work as she might have hoped during those rotations, she said she had the opportunity to learn from those experiences.

“When training people in the lab, I try to be really specific about what I want to do” while also ensuring that the researchers understand and appreciate the bigger picture and context for individual experiments, she said.

Originally from Madrid, Amor felt comfortable during her five years in Manhattan and is enjoying the open space and fresh air of Long Island in her role at CSHL. She also appreciates the chance to kayak in the waters around Long Island.

When she was around seven years old, Amor said her mother Esperanza Vegas was diagnosed with breast cancer. By participating in a clinical trial for a new drug, her mother fought off the disease.

“That made me realize how important science and research is,” Amor said.

During her educational training, Amor went directly from high school into a six-year program in which she earned a bachelor’s degree and a medical degree.

By the time she finished her PhD, she was hooked on research.

She appreciates the advice she received from Lowe, who encouraged her to conduct experiments despite the risks.

“Don’t get paralyzed at the beginning by fear,” she said. “Do the experiment and see what happens.”

METRO photo

By Daniel Dunaief

Daniel Dunaief

Empty nest? Seriously? I almost want to laugh maniacally when people ask about our empty nest.

For starters, we have a dog and two cats, which means that our nest, such as it is, has plenty of creatures with ongoing needs. One of our neighbors even asks regularly about our “little one.” It still takes me a second to realize she’s not inquiring about our children, who are anything but little, but our dog, who is also over 80 pounds.

The pandemic and the weather have disrupted so much over the last few years that we half expect to see one or both of our children at the airport or on our doorstep at any given moment.

Sure, we’ve had a few weeks where we’ve been on our own (with our pets), but in between, we’ve entertained visitors thrilled to travel again. We, ourselves, have also traveled back and forth to visit family, which means that the whole us-time has morphed into a collection of pet feedings and short trips.

Like so many other parents of college kids, we welcomed our children back to our home recently. It’s a wonderful chance to see them face to face, when they pick their heads up from their phones, and to connect the dots on snippets of their lives that they’ve shared from a distance.

The dog, who loves both of our children something fierce and whose tail threatens to detach from his hindquarters and float to the ceiling each time they return, is completely exhausted. After a few late nights with the kids and their friends, the dog reaches the sidewalk in front of the house, stands stock still, and stares at me, as if to say, “you want me to walk now? Do you have any idea how late I stayed up?”

Once I coax him, in between clenched teeth, away from the house, he still stops at random places, eager to turn around and lay down.

The dog loves it when I chat with a neighbor, which gives him a chance to plop down on the grass and pant, as if I’ve taken him much further than the 1/8th of a mile from our home.

During a recent such pause, a neighbor shared the joy/frustration of having his two children in his house. His wife wants to institute strict rules about comings, goings, and living-under-their-roof. His son, a junior at a nearby college, is delighted for the home-cooked meals, but not so much for the home-cooked rules.

Both of our children have become nocturnal. They have no need to hear birds chirping in the morning, to plow through a plate of pancakes, or to share in the start of another day.

In the “late” evening (which is getting earlier for me each day), our children often appear as we’re going to sleep. Excited to see them, we sit up and engage in what can be competing conversations. It’s like that old joke about a lawyer who moves into town and has almost no business, until another lawyer comes and they’re both working nonstop.

Something about hearing a sibling talk greases the wheels for the other one, who then remembers important details to share.

The next morning, when we’re at our desks, our children are happily sleeping, resting and recovering and our dog is flat out on the floor.

Then again, the fatigue is more than offset by the joy of hearing about their adventures, marveling at their maturation, and steadying ourselves for the moments when they head back to their busy lives.

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.

Checklist. Pixabay photo

By Daniel Dunaief

Daniel Dunaief

Some people live from one list to another, checking off boxes only to create new tasks and new goals.

Some of the things on the list are manageable, like picking up medicine from the drug store, shopping for the ingredients to cook dinner, or bringing a friend to or from the airport.

Others are much broader and appear on the list almost daily, even if we take small steps to get closer to them, like getting a job, losing weight, or moving to a new apartment or a new city.

Those bigger goals, while important, can make these lists cumbersome and, seemingly, never-ending. Perhaps we need a few easily achievable tasks that reflect the reality of our lives. To that end, how about a few items from the practical, the mundane and the absurd:

— Walk into a room, forget what you needed, stand in the room for a moment, shrug and walk out. While that doesn’t happen every day, it has certainly happened to me. I’ve also seen it happen to others. Somehow, putting it on a list makes it seem like an accomplishment, rather than a reflection of the distracted state in which we live.

— Pet an animal while working from home instead of finishing an assignment. While deadlines help us accomplish our goals, petting our dogs and cats, or staring at our fish, lowers our blood pressure and soothes us. Take a moment to enjoy the fur of a pet who will likely appreciate the attention.

— Turn off the light in a room when no one is there. Yes, this is small, but it lowers the electricity bill. Checking off this box should be easy and it increases our checked off list. The devilish among us might “accidentally” turn the light off when someone is in the room.

— Take a power nap. Instead of feeling guilty about walking away from your desk or your dog, feel good about the few minutes you get closing your eyes to restore your peace of mind.

— Use a new word, like feckless as often as possible. Feckless sounds kind of angry and frustrated, which can reflect the frustrations of a feckless manager.

— Throw something. Try not to break anything or cause any damage, but the sheer pleasure of throwing something like a football, baseball or even a balled-up piece of paper at a garbage can offer a satisfying outlet and a way to offset the figurative paper cuts we endure each day.

— Stop at a yellow light. I know we’re all in a hurry, but if we put this one on the list, we can feel good about stopping when the light is about to turn red.

— Smile at someone. This one is so easy, and yet it’s worth putting on a list because we might make someone feel better during the day or offer support in an important moment.

— Be grateful. Anger is everywhere around us, particularly on TV, where talking heads share the latest outrage from here, from there, from everywhere. Be grateful for the person who stocks the shelves at the grocery store, the person who takes your insurance information at the doctor’s office, or for the emergency workers who stand by ready to help the rest of us.

— Watch nature do something cool. Enjoy the sight of a wave on the beach, the sound of the wind rustling through the leaves, the parade of ants climbing a tree, or the shades of yellow and orange light that the sun casts on trees and the sides of buildings as it sets at the end of the day and as you’re checking off your list of manageable achievements.

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.

Pixabay photo

By Daniel Dunaief

Daniel Dunaief

Once upon a time, the eight parts of speech came together to compete for supremacy.

Convinced of his invincibility, the arrogant noun stood on top of the mountain, rolling his eyes at the other parts of speech, assured of his victory.

“I am, without a doubt, the most important of the eight of us,” he declared. “I hope you’re not too disappointed when you all eat my dust.”

“You think you’re the best and the brightest,” laughed the adjective. “Without me, you’d be a bunch of people, places and things, without much flavor. Why, you’d be like vanilla ice cream without sprinkles, melting in the hot sun.”

“Well, sure, adjectives are helpful,” the noun acknowledged. “You’re like Robin to my Batman.”

“So, you’re the only superhero with any real value?” the pronoun asked.

“No, you and I are a team, right? You stand for nouns, with your ‘he, she, it’ and your ‘who, which and what,’ but, come on? Where would you be without me? I’m the king, the throne, the empire, the country and the world all at once.”

“Maybe, but people would get sick of reading the same words over and over if they didn’t have pronouns,” the pronoun argued. “I may have smaller words in my part of speech, but I take the place of all your huge words, without needing to repeat them all.”

“Good grief,” the interjection interjected. “Come on! I’m not only a conversation stopper, I am often followed by an exclamation point. See? Well, that’s a question, but I’m a forceful part of speech, dang it! Listen to me! I will win this ridiculous competition!”

Slowly and deliberately, the adverb hopped off his adverb couch, gracefully gliding over to the group.

“Seriously, the adverbs gleefully chuckling over there,” he said, pointing to a group of words with “ly” tails, “are highly useful and critically important.”

The preposition had heard enough. He climbed off the fence, down a hill, and near the others.

“The proposition of a preposition winning this contest is high,” she said. “We provide context for so many activities — on the roof, by six o’clock, beneath the surface.”

That’s when they heard a sound without end. When they looked for the source of the noise, they noticed an endless group of words strung together.

“Hello, all you other parts of speech,” the conjunction said. “I have endless storage space and can carry each you indefinitely. I can also sew together seemingly different ideas.”

The noun laughed at the conjunction.

“What good would all those connections be if you didn’t have the rest of us?” he snickered.

Whirring through the air, the verb appeared, disappeared, jumped over the group, slid beneath them, and ricocheted around the meadow.

“Hello everyone,” the verb snickered. “This competition makes me laugh.”

“Crikey! Why is that?” the interjection asked.

“Well, you’d be a pile of stuff without action verbs,” he said. “In fact, you wouldn’t even be anything without a verb. To do anything, to be anything, and to animate your actions, you all need verbs. We lift you off the canvas, transport you to other places, inspire greatness, and demand attention. Yes, all the rest of you have magnificent qualities (special thanks to the adjective for giving us ‘magnificent’), but verbs drive ideas forward, infuse life into your existence, and encourage discourse.”

“I’d be limited without verbs,” the adverb agreed glumly.

“No, verbs soar majestically because of you,” the verb offered reassuringly. “We count on you.”

“Hey! We’re all important!” the interjection concluded.

“That could be true,” the noun concluded. “I still think none of us would be here without me.”

“True, but you’re a long list of stuff that isn’t doing much and that lacks personality without the rest of us,” the verb said, wanting to have the last word. “Now, let the games begin.”

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.

Pixabay photo

By Daniel Dunaief

Daniel Dunaief

Sure, the book “What to Expect When You’re Expecting” could be helpful.

Until you’ve gone through pregnancy and had a child, you don’t really know what’s around the corner. Other parents sometimes expect you to follow their footprints to the promised land, which somehow didn’t always seem like the happiest place on Earth for them or their screaming kids.

You hear about terms like first, second and third trimester, which sound like safe little building blocks you might want to play with on the floor, stacking one on top of another while Mozart plays blissfully in the background.

But, really, so much of life, even during those days before childbirth, when moms are expecting, doesn’t follow a script or textbook cue cards.

My wife and I tried to keep at least a month ahead of the “nesting phase” and the “tired phase” among so many others in the books.

We went to Lamaze classes where, despite being in our mid 30s, we felt remarkably young in New York City compared to so many other first-time parents in their late 30s and early 40s who were sharing pregnancy stories and preparing to “breathe, honey,” and to count the time in between contractions.

Our birth plan went out the window when, after my wife’s three valiant days of pushing, our doctor decided to do a C section. How do you make important decisions when you’re beyond exhausted and when your excitement and anxiety seem to be in an extended foot race for your attention?

Just before the doctor started the procedure, she told me that if I passed out at any time, they were going to leave me on the cold, concrete floor, stepping over me to tend to my wife and daughter.

Fortunately, everything worked out, despite the challenges for my wife of recovering from abdominal surgery that made even the simplest of motions, like rising out of a chair, difficult and painful.

So, here we are, over two decades later, and we and others are still maneuvering around playbooks we’ve had to rewrite. It seemed fitting, given that it’s Mother’s Day this Sunday, to reach out to a few successful scientists — I cover science, so these are my peeps — to ask them a few questions.

IACS Endowed Chair of Ecology & Evolution at Stony Brook University Heather Lynch explained some of the best parenting advice she got was to think of “running the household like running a business, and outsource what can be outsourced with zero guilt.”

Cold Spring Harbor Laboratory Professor and HHMI Investigator Leemor Joshua-Tor, meanwhile, said she learned to trust her gut, especially for the timing of discussions with her daughter. As her daughter enters her teenage years, Joshua-Tor has taken more of an advisory role, letting her have more control over her life while offering a calming presence.

Joshua-Tor wrote in an email that she thought “my daughter would have a good role model with a mom that had a fulfilling career and work life.”

Joshua-Tor was pleased to hear her daughter bragging about her mom’s career.

Lynch, who studies penguins that share parenting duties, credits marrying well for her parental success.

She and husband, Matthew Eisaman, who has a joint appointment at Stony Brook and Brookhaven National Laboratory, “split things 50-50 and if I had to do even 51% of everything, I think this whole house of cards would collapse,” she explained in an email.

Amid the pandemic, which wasn’t in any parenting textbooks (but probably will be in the future), Joshua-Tor said she tried to keep her daughter positive while ensuring her safety.

As a parent, Joshua-Tor added, “nothing was as I expected, but how deep things hit you is a biggy.”

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.”