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Power of 3

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From left, postdoctoral researcher William Thomas, Professor Liliana Dávalos and former undergraduate fellow Maria Alejandra Bedoya Duque. Photo courtesy of William Thomas

By Daniel Dunaief

Captivity causes changes in a brain, at least in the shrew.

Small animals that look like rodents but are related to moles and hedgehogs, shrews have different gene expression in several important areas of their brain during captivity.

In a study led by 2022 Hearst summer Undergraduate Research Fellow Maria Alejandra Bedoya Duque in the lab of Stony Brook Professor Liliana Dávalos, shrews in captivity had  different gene expression in the cortex, hippocampus and olfactory bulb. These brain areas are important for cognition, memory and environmental sensing.

“I was very surprised by what we found,” said Dávalos. While she expected that the research might uncover differences between the brains of captive and wild animals, she didn’t expect the changes to be as many or as strong.

The change in brain activity could offer potential alternative explanations for studies that explore the effect of various experiments on animals kept in captivity.

“It could be very useful to find out if these environmental influences could be confounding,” said Dávalos. “We don’t know all the dimensions of what captivity is doing.”

Additionally, brain activity changes in captivity for shrews in terms of the transcripts that are over or under expressed mirror those found in humans who have neurological changes such as major depressive disorder or neuro degenerative disorders.

“How these [changes] influence behavior or cognition is a separate question,” Dávalos added.

To be sure, extrapolating from shrews to humans is different and requires careful analysis, Dávalos explained.

Humans and shrews have distinct life history, ecology, body size and other characteristics. While scientists can study genes they think might have similar functions, more studies are necessary to determine the effects of those genes in expression and how similar they are to those studied in humans or mice.

Dávalos does not expect to find a silver bullet that reorganizes human brains or a gene or pathway that’s going to revolutionize neurodegenerative research.

Nonetheless, in and of itself, the study suggested opportunities for further research and exploration into the effects of captivity on animals in general and, in particular, on their mental processes, which are affected by changes in conditions and needs in their environment.

A foundation for future work

Maria Alejandra Bedoya Duque

The study, which was recently published in the journal Biology Letters, grew out of a two-month internship Bedoya did at Stony Brook in which she studied the brains of four captive shrews and four wild animals. The analysis of the results involved numerous calls and discussions when she returned to Colombia to finish her undergraduate degree.

At the end of the summer, Bedoya was “going to present her work internally at Stony Brook,” explained William Thomas, a postdoctoral researcher in Dávalos’s lab and one of Bedoya’s mentors throughout the project. “Instead, she turned it into a paper.”

Thomas appreciated how Bedoya “put in a lot of work to make sure she got this out,” he said.

The shrew’s brain changed after two months in captivity, which is about 20 percent of their total lifespan, as shrews live an average of one year.

“We don’t know what the limits are,” in terms of the effect of timing on triggering changes in the shrew’s brain, Thomas said. “We don’t know how early the captive effect is.”

Thomas suggested that this paper could “lay the foundation for future studies with larger samples.”

Dávalos was pleased that the study resulted in a meaningful paper after a summer of gathering data and several years of analyzing and presenting the information.

“I’m immensely proud and happy that we had this unexpected finding,” said Dávalos. “It is one of the most gratifying experiences as a mentor.”

A launching pad

Bedoya, who graduated from Universidad Icesi in 2023 and is applying to graduate school after working as an adjunct professor/ lecturer at her alma mater, is pleased her work led to a published paper.

“I was so happy,” said Bedoya. “If it hadn’t been for [Thomas] and [Dávalos] cheering me on the whole time when I came back to Colombia, this study could have ended as my fellowship ended.”

Bedoya believes the experience at Stony Brook provided a launching pad for her career.

“It is a very valuable experience to have conducted this research all the way up to publication,” she said.

Thomas and Dávalos each recalled their own first scientific publication.

“I’m happy and relieved when they come out,” said Thomas. “While internal validation is important, the pleasure comes from providing something that you believe can help society.”

Dávalos’s first publication involved some unusual twists and turns. When she submitted her first paper about deforestation in the Andes, the journal wrote back to her in a letter telling her the paper was too newsy. She submitted it to several other publications, including one that indicated they had a huge backlog and weren’t publishing new research.

When it was published, the paper didn’t receive much attention. That paper, and another on her thoughts about how peace between the Colombian government and the FARC rebels might be worse for the rainforest, have since been cited frequently by other researchers.

Winter brain

At around the same time that Bedoya published her work about the effect of captivity on the shrew brain, Thomas published a study in the journal eLife in which he examined how shrew brains shrank during the winter and then regrew during the spring.

This work could offer genetic clues to neurological and metabolic health in mammals. Thomas focused on the hypothalamus, measuring how gene expression shifts seasonally.

A suite of genes that change across the seasons were involved in the regulation of energy homeostasis as well as genes that regulate cell death that might be associated with reductions in brain size.

Temperature was the driver of these seasonal changes.

The genes involved in maintaining the blood brain barrier and calcium signaling were upregulated in the shrew compared with other mammals.

After the winter, the shrew’s brains recovered their size, although below their pre-winter size.

Originally from Syracuse, Thomas attended SUNY Albany.

When he was younger, he entertained ideas of becoming a doctor, particularly as his grandmother battled ALS. On his first day shadowing a physician, he felt claustrophobic in the exam room and almost passed out.

He wanted to be outside instead of in “the squeaky clean floors” of a doctor’s office, he explained in an email.

As a scientist, he feels he can meld his passion for nature and his desire to help those who suffer from disease.

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From left, Iwao Ojima, Ashna Garg and Maurizio Del Poeta. Photo by Kathryn Takemura

By Daniel Dunaief

It worked for mice and now, several years later, has shown promise for cats.

Researchers from Maurizio Del Poeta’s lab, working closely with those from Iwao Ojima’s team at Stony Brook University, have demonstrated that an experimental treatment against a fungus resistant to the current standard of care can work with cats battling a ferocious infection, albeit on a small sample size.

The Stony Brook team, along with scientists and veterinarians in Brazil, used a drug they created in 2018 called D13 to treat 10 cats with severe forms of a fungus that affects cats and humans called sporotrichosis.

With this treatment, which the researchers introduced as a powder into the cat’s food, half of the 10 felines whose skin was under insidious attack from the fungus staged remarkable recoveries, offering a potentially promising development that could one day also offer an alternative care for cats and for people.

“The prevalence in South America is 25 to 20 cases per 100,000 people, which is not low,” explained Del Poeta, Distinguished Professor of Microbiology and Immunology. “It affects mostly immunocompromised people and particularly people who have cats or people taking care of infected cats.”

Tis cat presented no improvement of the tumor-like lesion and of an ulcerated lesion on the nasal region upon treatment with ITC. After adding D13, the cat significantly improved, even though clinical cure was not achieved after 4 weeks of treatment with ITC and D13 combination.

Typically, people get superficial infections, but a person who is severely immunocompromised could have an infection that spreads and becomes fatal.

The work taps into the expertise of Ojima, a Distinguished Professor in the Department of Chemistry. Ojima worked on the structure elucidation, the structure activity relationship and development of efficient synthetic methods for large scale synthesis of the drug.

Recent Stony Brook PhD graduate Ashna Garg contributed to this ongoing effort.

Ojima described the work as “solidly encouraging” and added that the scientists have “even better compounds in the same series for human use” that are more potent and more selective to fungi compared to humans which makes systemic toxicity “very low.”

Del Poeta’s lab has been studying sphingolipids metabolism and signaling in fungal and mammals cells to identify new markers for early diagnosis and microbial enzymes/ molecules essential to cause infections in the attempt to develop new antifungal targets.

To be sure, in the cat research, five out of the 10 cats didn’t complete the study. One of them died, although the cause of death was unknown, and four of the other cats abandoned the study.

Additionally, one of the cats for whom the drug worked showed an elevated level of a liver enzyme, which returned to normal within weeks of the conclusion of the study.

Still, the results were promising and provided encouraging improvements for cats battling an infection that threatened their health.

“I am very pleased with the efficacy of D13 on cats in Brazil,” explained Ojima, adding that it is “a compelling result.”

Additionally, in other preliminary studies, D13 works against various fungal infections, including cryptococcosis, aspergillosis and candidiasis. A new derivative of D13 is more effective for those other infections, the scientists said.

Del Poeta explained that the scientists chose to do the research in Brazil because of the prevalence of sporotrichosis in the area and because he had established collaborations in the country in earlier research.

‘Proud and grateful’

For her part, Garg was thrilled to contribute to research that provided a remedy to a deteriorating condition in an animal some of her friends own as pets.

Cat owners often reacted emotionally when she told them about her work, appreciating the significance of the results.

“I am deeply proud and grateful to have contributed to this work,” said Garg. “Its remarkable effectiveness continues to inspire and motivate me.”

A significant part of her PhD revolved around taking the initial lead compounds and developing second and third generation compounds to enhance their effectiveness and bioavailability.

With three bromine atoms, D13 is an unusual therapeutic treatment.

Bromine is “relatively rare among the top 200 pharmaceuticals,” Garg explained. “Bromine can be toxic or can act as an irritant. Part of my work involved exploring ways to reduce the bromine content” to make the treatment more viable in drug development. The scientists are working to understand why and how this treatment works.

“The exact mechanism of action of D13 is not fully understood yet but we are getting very close,” Garg explained.

With the third generation of D13, the team identified compounds that are highly fungal specific with broad spectrum activity, effectively eradicating 100 percent of the three malignant type of fungi.

“It’s important to note that some first and second generation compounds also demonstrated excellent antifungal activity at very low drug concentrations, even if they did not achieve complete eradication on one of the three fungal strains,” Garg added.

While promising, this study does not indicate a new human treatment will be on the market in the short term.

The scientists are doing toxicology studies and hope a new therapeutic option might be available as soon as five years, Del Poeta estimated.

From Delhi to Stony Brook

Garg, who defended her thesis in December, grew up in Delhi, India, where she pursued her undergraduate studies in Chemistry at Delhi University.

After that, she earned her Master’s in Chemistry at Vellore Institute of Technology in Tamil Nadu, India.

Garg arrived at Stony Brook in 2019 and joined Ojima’s lab in early 2020, just at the start of the pandemic.

“It was indeed a challenging time to start a new position,” Garg acknowledged.

Currently a resident of Poquott, Garg enjoys living on Long Island, where she visits beaches, drives around the area and cooks.

Garg, who attended meetings in the labs of both Professors Ojima and Del Poeta, is grateful for the support of these senior scientists, who were also part of her thesis committee.

Del Poeta described Garg as a “dedicated scientist” with an “impeccable” work ethic.

“Drug synthesis can be very challenging,” Del Poeta described. “She is tirelessly resilient.”

Garg is staying at Stony Brook for another year as a post-doctoral researcher.

Del Poeta is pleased with the productive collaboration he’s had with Ojima, whom he described as “passionate, intellectually stimulating, dedicating, inspiring and hard working.”

If Del Poeta sends an email on Saturday night, Ojima typically replies by Sunday morning.

“It is an honor to collaborate with him,” Del Poeta explained. Ojima’s work “makes these impressive results possible.”

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A 3D constructed building in Ukraine. Photo courtesy of Utu (Ukraine)

By Daniel Dunaief

Instead of discarding concrete from damaged or destroyed buildings during Russia’s attack on Ukraine, Alexander Orlov, Professor in Materials Science & Chemical Engineering at Stony Brook University wants to try to figure out ways to recycle these materials to create new and desperately needed shelters.

Alexander Orlov. Photo courtesy of SBU

Leading a team of researchers in the United States, Poland and Ukraine, Orlov received about $700,000 worth of funding from the National Science Foundation, the Office of Naval Research, and the Polish National Science Centre to develop ways to create these potentially life-saving structures by using three-dimensional printers.

Far larger than the desktop printers, these three-dimensional printers build one layer of a building at a time, reducing the time and labor needed in construction. 

The idea behind the project is to “turn the tragedy of these damaged buildings into new structures,” said Orlov.

In some cases, these buildings could be cheaper and faster than conventional construction methods.

“This research will address challenges in building resilient and sustainable infrastructure by using novel, inexpensive and energy efficient solutions,” Marija Krstic, assistant professor in the Department of Civil Engineering at Stony Brooks said in a statement.

The family of Ukrainian soldier Yaroslav Berezov, who died during the beginning of the Russian invasion, received the first 3D printed house earlier this year, according to the Odessa Journal.

The walls of the house were printed in 58 machine hours, as the printer laid down the inside and outside of the house at the same time.

The idea of doing 3D printing is becoming more popular in Ukraine. The leader in this type of printing is a company called COBOD, which used the technique to rebuild a school in the city of Lviv. The school, which has weatherproof construction and is expected to last for more than 20 years, has four classrooms with a capacity for 100 students.

One layer at a time

Orlov explained that the 3D printing process acts like an ice cream machine, as it lays down one layer of a building at a time with material squeezed through a cone.

In the design of these structures, the machine pauses for some length of time — five or 10 minutes in some cases — to ensure that the layer is strong enough to support additional weight. The structure also requires some time to settle, which could be about two weeks, before adding heavier objects, such as a roof.

Assistant professor Marija Krstic in the Department of Civil Engineering along with a graduate student. Photo from SBU

The machines use waste and add it to a cement mix to form concrete.

In this project, the research is focused on a proof of concept that Ukrainian construction companies might use to build additional homes or shelters.

The National Science Foundation is providing $300,000 in funding for Orlov’s portion of the work.

Stony Brook University is building a 3D printer and is adding parts to it to make it more efficient and reliable. Poland is also purchasing a printer while Ukraine already has one.

The Office of Naval Research is providing funding directly to Ukraine and the Polish National Science Centre is supporting efforts in that country.

“The Navy supports disaster relief and typically offers assistance in any part of the world” after catastrophes including hurricanes and earthquakes, Orlov said.

It takes about two to three days to build a building the size of a house. The process still requires manual labor to add the roof because it has different materials.

The timing of the research is particularly important because of the escalating scale of Russian attacks and amid the approach of winter. People in the capital of Kyiv endure seven hours of bombing each night. The civilian experience is similar to what people in London experienced during World War II, when they hid in shelters and had to be quiet amid the shattering of buildings.

Ukraine has lost about 50 percent of its energy infrastructure, a number that is likely to climb even as colder weather descends on the country. The estimated cost to repair that energy infrastructure is about $60 billion and is likely to climb as the war continues, Orlov added.

Without energy and heat, “this could be the worst winter in the history of the country,” Orlov said.

In developing ways to build these structures, Orlov hopes to create buildings that are mechanically the same or better than traditional homes and with thermal properties that are increasingly important amid temperature extremes.

The biggest challenge for scientists and engineers is that these buildings may not be reproducible, depending on the different available materials. The researchers need to figure out if they can have high-quality printing from different sources.

Personal experience

For Orlov, the horrors of war and the threat of injury and death are all too real. He extracted his mother Tetiana and his father Mykhailo, out of Kyiv, where their apartment windows were blown out after a Russian rocket leveled a nearby five-story building.

Orlov’s parents are struggling even on Long Island, where the sound from nearby fire station causes them to try to run and hide each time they hear the alarm. Motorcycle noises, which have the same vibrating hum as Iranian drones, also terrify them.

Project origins

The research Orlov is doing started when he was working with a Polish researcher. Orlov saw the funding opportunity and reached out to professors in Kyiv to ask how he could help. The researchers worked together to write the proposal.

Orlov, who works in the Consortium for Inter-Disciplinary Environmental Research and has secondary appointments in the Chemistry Department, the Institute for Advanced Computational Science, the Advanced Energy Center, and the Department of Technology and Society, is spending considerably more time than he expected on this project. That, he said, comes in part from the need to cross cultural barriers in working with people from different countries.

Any construction of 3D printed shelters would face the challenge of finding energy to power these machines. Some of that power could come from mobile generators, while the printers could also use intermittent power.

“There are unique challenges that have to be tested during the war,” Orlov explained.

At each of the research sites, students have the opportunity to contribute to the project. Stony Brook has two faculty members and several graduate students who are involved at this point.

Orlov is hoping to provide Ukrainian companies with recipes that might lead to the construction of these shelters.

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Olaf Kleingbeil at the Pezcoller24 Symposium in Italy in June, 2024. Photo by Claudia Tonelli

By Daniel Dunaief

The wreck-and-check method sometimes works, providing the kind of clues that lead to cures.

In the case of cancer, however, taking out one gene or one protein may not be enough, particularly when a combination contributes to cancer growth or to inactivating the body’s defenses against the disease.

Olaf Klingbeil. Photo courtesy of CSHL

Over the course of seven years, first developing a technique, then searching for possible clues about what the work might reveal, Olaf Klingbeil, a postdoctoral researcher in the lab of Professor Chris Vakoc at Cold Spring Harbor Laboratory, discovered two proteins that work together to do cancer’s bidding.

Called Mark 1 and Mark 2, these two proteins in combination keep a tumor suppressor called Hippo from doing its job, enabling a wide range of cancers from continuing to grow.

The Hippo pathway is one of the most dysfunctional in all human cancer biology.

The journey to this discovery is as compelling as the finding itself.

Klingbeil honed a technique that took out a series of genes, hoping to find out how more than one protein might be involved in the kind of on-off switch geneticists are often seeking to slow or squelch cancer.

Indeed, disrupting either of the proteins on its own would not have been enough, as the disease would have progressed with a singular inhibitor.

“When you manipulate A or B individually” you don’t see much difference in the cancer cells, Vakoc said. “When you manipulate A plus B, you get a massive effect.”

Vakoc suggested that his lab developed a new technology to find cancer targets, enabling them to search for processes and contributors that were otherwise invisible. Klingbeil used lentiviruses to introduce CRISPR gene editing into cancer cells.

“What [Klingbeil] developed, a method where you can introduce two [changes] at the same time, can be engineered to target combinations of genes,” Vakoc said. “It took years to figure out how to do this.”

Klingbeil explored the effect of making these double knockouts through many perturbations.

“It was the largest project in my lab to this point,” said Vakoc.

A eureka moment

Klingbeil examined several potential leads that might provide clues about how to attack cancer cells. He published 1,719 single gene knockouts and 2,529 paralog double knockouts and expected to find a few jewels. 

Christopher Vakoc. Photo courtesy of CSHL

He likens the process to panning for gold at a creek, which involves getting rid of numerous stones before discovering that gold nugget, which, in this case came in the form of two kinases, which add phosphate labels to macromolecules.

When Klingbeil honed in on Mark 2 and Mark 3, he couldn’t immediately understand why inhibiting these enzymes affected some forms of cancer, but not all of them. 

The postdoctoral researcher read a study in which the researchers looked at the tumor suppressive function of Yap/Taz in leukemia and neuroendocrine cancers and realized that these were the cancer types that didn’t show a reaction to inhibiting these kinases.

This was the first hint that Marks 2 and 3 and Yap/Taz might work together, Klingbeil explained.

The affected cancers include liver, lung, colorectal, ovarian, triple negative breast cancer, pancreatic cancer and prostate cancer. That list also includes rhabdomyosarcoma, a rare form of pediatric cancer for which Vakoc, in particular, is eager to develop new treatments.

While numerous scientists are seeking ways to block this pathway directly, the focus on Mark 2 and Mark 3 presents a new potential opportunity.

Marks are “totally overlooked in the community” and are “not a known target,” said Vakoc. “This is the first paper that announces these as cancer targets in a compelling way.”

An existing drug

Once he discovered this link, Klingbeil searched for existing drugs that might target Marks 2 and 3. Fortunately, he found one that Merck had tried to develop for Alzheimer’s disease.

While that didn’t work as well as the pharmaceutical company had hoped, the CSHL researchers are looking to use it as a starting point for a future therapy.

“We are excited that there’s a chemical matter” that might help treat cancer, Vakoc said, adding that such a treatment will likely require “a lot of love by chemists to give them the ideal attributes” for any therapeutic approach.

The drug Merck produced inhibited Marks 1 and 4 as well as 2 and 3, which provides opportunities to tailor it for the most relevant enzymes. By increasing the specificity of the drug for two of the four proteins, researchers and pharmaceutical companies could reduce the side effects of inhibition.

To be sure, Vakoc and Klingbeil cautioned that this discovery, while encouraging, wouldn’t likely provide a magic bullet for cancer, which has a way of becoming resistant to treatments and to tapping into other unknown or unseen pathways to continue to cause harm.

Effective future treatments that involve inhibiting Marks 2 and 3 could require the use of a combination of therapies, which might outmaneuver or slow the progression of cancer.

A personal message

Earlier this year, Klingbeil learned that the journal Cancer Discovery had accepted the paper for publication in an unusual way. He was attending a dinner one night at a conference in Italy when Elizabeth McKenna, the Executive Editor of the journal, approached him.

“She told me she was about to send an email” to Vakoc that the paper was accepted, Klingbeil said. “I was very excited. I’m happy to publish it and that I could convince the most critical reviewers about the value of the work.”

After a productive and rewarding collaboration with Vakoc, Klingbeil is preparing for the next steps in his career. He is speaking with various institutions, particularly in Europe, where he can be closer to his family and his native Berlin, Germany while continuing to advance his scientific career. He plans to continue to work with Vakoc after he leaves.

“The discovery was big enough to carve out a piece for him and me,” Klingbeil said and suggested he would study Mark function in pancreatic cancer in more detail.

On the personal front, fate lent a hand when Klingbeil first arrived on Long Island.

He started his life here in the middle of the winter, without a car or a driver’s license. The lab provided temporary housing on campus. He had a choice to share an apartment with either a French or an Italian postdoctoral researcher.

He chose to live with postdoctoral researcher Claudia Tonelli, who works in the lab of Cancer Center Director David Tuveson and is now his partner. The two researchers, who started dating a few months after living together, have a daughter Lily.

As for his work, he is cautiously optimistic that this discovery may one day help with new and effective therapies.

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Participants of last year's Human Library event. Photo by Rachael Eyler, Stony Brook University

By Daniel Dunaief

Stony Brook University is providing another opportunity for students and the community to venture beyond the labels that define and, at times, limit our views and understanding of each other.

Chris Kretz

For the second year, the university is hosting the Human Library, which gives participants an opportunity to learn about other people’s lives.

Started in 2000 in Denmark, the Human Library brings “books” (people from different walks of life, which has included a refugee, disabled parent, and person with bipolar disorder) with “readers,” who have a chance to ask questions for 30 minutes with each book.

The chapters these books share has surprised readers and given them a chance to reconsider how they view people whose lives or life experiences are different from their own.

“It’s not meant to teach people something or have them leave being converted to some new thought process,” said Chris Kretz, Head of Academic Engagement at Stony Brook University Libraries. “It gives [readers] an opportunity to speak with someone they may never normally encounter or have a conversation they may not get to have.”

The Human Library event occurs on Wednesday, Nov. 20 from noon to 3 p.m. and from 5 p.m. to 7 p.m. at the Frank Melville Jr. Memorial Library’s Central Reading Room. Participants don’t need to pre-register and can show up at the library, where about 110 readers visited last year.

Kretz recommended the latter session for interested community members, which would allow them to park for free to attend the event.

Following the defined structure created by the original Human Library, attendees won’t know about the specific backgrounds of the books until they arrive. The people that represent the books will all sit at desks wearing the same black t- shirts.

“In the conversation, the colors come out,” Kretz said.

Indeed, Richard Tomczak, Director of Faculty Engagement in the Division of Undergraduate Education at SBU and a reader at last year’s Human Library, can attest to that. Tomczak spoke with a book who grew up in the outer boroughs of New York as a member of the working class.

“When you’re having a conversation about shared experiences or experiences that are new to you, it brings out the human characteristics,” said Tomczak. “I wanted to listen and absorb it all.”

Choosing a book

When readers sit down, the book offers a prologue about their lives, providing some details about their experiences. Readers who aren’t sure where to start asking questions or perusing through different chapters in the book can use prompts at each desk to begin their interaction. Readers who stay for an entire session  will be able to interact with three or four books.

Participants of last year’s Human Library event.
Photo by Rachael Eyler, Stony Brook University

“This is an opportunity for people to hone their conversational skills,” said Kretz, as well as to learn about the lives of the books who are offering details that may surprise and move the readers.

Indeed, this year, the university is stocking tissues near each book for those readers who may feel particularly touched by the stories they hear.

The university would like to ensure that the conversation is respectful and that both sides are comfortable with the discussion.

“We have rules for readers,’ said Kretz. “When they sit down with the book, the pages are in mint condition. We want to make sure everyone is on the same page. Books don’t necessarily have to answer every question.”

Kretz urged attendees to recognize that the interaction is not a debate, but presents ways for people to understand more about their own judgments and, as the Human Library website suggests, to “unjudge” each other. In addition to speaking and asking questions, readers and the books will have a chance to process what they’ve heard.

“By design, it’s a session where you have to listen,” said Kretz. “One of the values is that people get a chance to practice this muscle.”

Second year

In the second iteration of the Human Library, Stony Brook added the later time so people could come after work. The administrators have also reached out to journalism classes and to people in international programs. 

Students from other countries will “have a chance to meet people they wouldn’t have met” during their time abroad, Kretz added.

After speaking with the people who served as books last year, Stony Brook heard that the books also wanted to serve as readers of some of the other people’s lives.

University officials were pleased with the exercise last year.

“I’m impressed by how open our community was,” said Kretz. “People learned a great deal from listening to each other.”

The university is considering making this an ongoing annual tradition and might even bring people together each semester.

Other New York schools and libraries have embraced the Human Library process, including Adelphi and SUNY Albany. The Human Library has also caught on globally, as people in 85 countries on six continents have helped facilitate these conversations.

While the participants engage in meaningful discussion, the exchange isn’t designed to create a lasting social network or lead to ongoing connections between the readers and the books.

“It’s not meant for them at the end of the reading to shake hands and exchange business cards,” explained Kretz.

The event is sponsored by the University Libraries and the DEIA (Diversity, Equity, Inclusion, Accessibility) Team with the Division of Student Affairs, Office of Diversity Inclusion and Intercultural Initiative, Office of Military and Veteran Affairs, and Diversity, Intercultural and Community Engagement, and the Program in Public Health.

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By Daniel Dunaief

A male mouse embryo surrounded by a group of female embryos during development in some cases is protected against developmental delays caused by a viral infection of their mother.

That’s one of a host of intriguing observations and findings from a recent set of experiments conducted by postdoctoral researcher Irene Sanchez Martin, who works in the lab of Assistant Professor Lucas Cheadle at Cold Spring Harbor Laboratory.

Irene Sanchez Martin and Lucas Cheadle at Cold Spring Harbor Laboratory. Photo by Justin Park

Sanchez Martin is studying how maternal exposure to viruses triggers immune responses, particularly inflammation, which can contribute to developmental delays characteristic of autism. 

In mice as in humans, males are much more susceptible to the onset of the kinds of neurological developmental behaviors that are characteristic of autism than their female counterparts.

“The advantage of our model is that it helps us understand why this happens, providing insights into the underlying mechanisms driving this increased vulnerability in males,” Sanchez Martin explained.

Researchers have been studying viral exposure and developmental disorders for a while. The new element in Sanchez Martin’s research is that she can observe phenotypic changes as early as 24 hours after a pregnant mouse is exposed to a virus, providing a much earlier window into how maternal immune activation affects development.

At an early stage of gestation, when sensory organs, the head, spine and other organs are starting to develop, the male mice demonstrate disruptions in normal development, which affects these structures in different ways. Sanchez Martin hopes these kinds of studies help uncover the pathways through which environmental factors contribute to the development of some cases of autism.

Sanchez Martin’s work is part of a broader effort in Cheadle’s research.

“My lab is interested in understanding how interactions between the nervous system and the immune system shape the development and plasticity of the brain,” Cheadle explained. One goal is to understand how systemic inflammation during prenatal stages leads to heightened risk of autism in offspring.

To be sure, the genetic component suggests that inflammation is not necessary for the development of autism. Nevertheless, exposure to prenatal inflammation can increase autism risk by about three times, making inflammation a likely “key contributor to the development of autism in some, but not all, individuals,” said Cheadle.

Sanchez Martin found that female mice did not develop the same changes as males. She believes this is one of the most valuable applications of the model she’s working on with Cheadle, as it can reveal the biological and developmental differences that contribute to this gender disparity.

Timing

Sanchez Martin studied mice that were exposed to a virus between 12 to 13 days after fertilization, which is similar to the end of the first trimester in a human embryo. Mice develop more rapidly, so the process doesn’t track exactly the same as it would in humans.

About a day after the maternal exposure, some males looked different through ultrasound than they would during typical development. The differences are subtle and it is still too early to assume these changes could serve as a diagnostic marker for autism spectrum disorder.

A host of disruptions could affect the growth of the embryo. The placenta serves as a bridge between the mother and the developing embryo, allowing communication, filtering substances, and protecting the embryo during development. Each mouse embryo has its own placenta and its own amniotic fluid in its amniotic sac, creating a unique microenvironment.

In her lab work, Sanchez Martin is collaborating with Dr. Brian Kalish at Boston Children’s Hospital, who is helping to analyze molecular changes in the placentas of affected and unaffected embryos. Sanchez Martin has data indicating differences between the placentas of affected and healthy individuals, as well as in the amniotic fluid.

“This suggests a dysfunction in the placenta in affected cases” indicating it is not adequately performing its protective and filtering function, she explained.

Female mouse embryos may be more protected in part because of their more active immune response. Other studies have shown that female immune systems, as early as the developmental stage, express higher levels of interferon-stimulated genes and have stronger responses to infections, which may offer better protection than males.

While male mice in some cases benefit from the protection provided by their nearby sisters, Sanchez Martin and Cheadle are “still working to fully understand the underlying mechanism,” she explained.

Epidemiology

By looking at the prevalence of conditions such as autism in the aftermath of larger viral infections, researchers have demonstrated that these illnesses can and do have impacts on the incidence of autism and schizophrenia, among other conditions. It’s not only the pathogen that is responsible, but also the immune response triggered by the infection, as well as the timing of the infection during pregnancy.

Covid, which infected over 100 million Americans, may cause an increase in the number of children born with autism.

“There is precedent from studies of other viral infections during pregnancy, which suggest that maternal immune activation can contribute to altered neurodevelopment in offspring,” Sanchez Martin said. “There is some evidence that male children exposed to SARS-CoV-2 during pregnancy might have a slightly elevated risk of other neurodevelopmental disorders.”

Additional research with longer-term follow up is necessary to confirm these findings. The timing and the immune response during pregnancy could be key factors in determining the outcomes​​.

Cheadle appreciated the effort and dedication of Sanchez Martin, whom he described as being “bright, talented, motivated and an excellent experimentalist. Her work is among the most important projects in the lab.”

From Madrid to CSHL

Born and raised in Madrid, Spain, Sanchez Martin has been a master of motion. During her final years of her Veterinary Medicine studies at Universidad Alfonso X El Sabio in Madrid, she moved to the University of Helsinki to complete her clinical rotations.

She later earned her PhD at the Centre National de la Recherche Scientifique in Marseille, France and defended her thesis at the Aix- Marseille University. During her PhD, she was a visiting student at Biocenter Oulu in Finland.

Her first job was at Laboklin in Bad Kissingen, Germany, where she worked in a clinical laboratory.

She did her first postdoctoral research in the Microbiology Department at Mount Sinai. During the pandemic, she was involved in studying innate and adaptive immune responses in different in vitro models, focusing on vaccine candidates for Covid-19 and influenza.

A resident of Manhattan, Sanchez Martin has contributed to Cheadle’s lab for two years.

She enjoys listening to classical music, reading, and swimming, which she likes to do several times a week as she has some of her best ideas when she’s in the water.

As for her work, Sanchez Martin appreciates the opportunity to conduct her research as a part of Cheadle’s team that is hoping to identify the molecular mechanisms that contribute to autism in mice.

“It’s an ongoing effort and we hope that with time and collaboration, we can gain more insight,” she explained.

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Kate Alexander. Photo courtesy of CSHL

By Daniel Dunaief

In the nucleus of the cell, researchers often focus on the genetic machinery, as the double-helical DNA sends signals that enable the creation of everything from my fingers that are typing these words to your brain that is processing what you’ve read.

But DNA, which occupies most of the nucleus, is not alone. Scattered through the nucleus are protein and RNA filled structures that have an influence on their important gene-bearing nuclear cohabitants, including speckles.

One of the newest members of the Cold Spring Harbor Laboratory team, Assistant Professor Kate Alexander, who joined the lab in August, is focused on a range of questions about these speckles, which represent about 10 to 30 percent of the nuclear volume.

Preliminary data from Alexander’s lab support the idea that speckles can signal how a person responds to various types of therapy, although careful extensive follow up studies are needed, Alexander explained. She would like to know how the speckles are affecting the genetic machinery.

While speckles have been known since 1910, the ways they affect healthy cells and diseased cells remains a mystery. In some cases, normal or aberrant speckles can signal how a person responds to various types of therapy.

Normal speckles are in the center of the cell nucleus, while aberrant speckles are more scattered. Aberrant speckles can activate some of the surrounding DNA.

At this point, Alexander and her colleagues have “found that normal or aberrant speckle states correlate with survival of clear cell renal cell carcinoma. This accounts for over 80 percent of all kidney cancers.”

Medical choices

After a patient with clear cell renal cell carcinoma receives a cancer diagnosis, the first line of treatment is usually surgery to remove the tumor in the kidney. In addition, doctors could treat the tumor with a systematic anti-cancer therapy. The treatments themselves can and often do cause difficult side effects, as therapies can harm healthy cells and can disrupt normal biological functioning.

Normal speckles look something like the face of the man on the moon and are more centrally located.

Alexander is hoping speckles will help predict the state of the tumor, offering clues about how it might respond to different types of treatments. She could envision how aberrant speckles could correlate with better responses to one drug, while normal speckles might correlate with better responses to another treatment.

In her research, Alexander is exploring how DNA is organized around speckles, as well as how the speckles affect DNA.

“Speckles can change and impact what’s happening to all the DNA that’s surrounding them,” she said. 

Over 20 tumor types show evidence for both normal and aberrant speckles. Aberrant tumors can occur in many types of cancer.

“The consequence of [speckles] becoming normal or aberrant are starting to become more clear,” she said, although there is “still a lot to learn.”

Alexander is trying to figure out how to alter the conformation of these speckles. During cancer, she suspects these speckles may get trapped in a particular state.

In one of the first experiments in her lab, she’s culturing cells in an incubator and is trying to predict what cues may cause speckles in those cells to switch states. 

‘Speckle club’ leader

Alexander previously did postdoctoral research at the University of Pennsylvania in the laboratory of Shelley Berger, where she was also a Research Associate. She led a subgroup in the lab known as the “speckle club.”

Charly Good, who is now Senior Research Investigator in Berger’s lab, worked with Alexander at Penn from 2017 until this summer.

Aberrant speckles are scattered throughout the nucleus.

Alexander “helped recruit me to the postdoc I ended up doing,” said Good who appreciated Alexander’s computational skills in analyzing big data sets. Speckles represent an “up and coming area” for research, which Alexander and Berger are helping lead, Good suggested.

Alexander’s quick thinking meant she would go to a talk and would email the speaker as soon as she got back to her desk. “Her brain is always spinning,” said Good.

Alexander is building her lab at CSHL. Sana Mir is working as a technician and is helping manage the lab. Recently, Hiroe Namba joined the group as a postdoctoral researcher. In the next few years, Alexander would like to add a few graduate students and, within five years, have about eight people.

Originally from Tigard, Oregon, Alexander attended Carleton College in Northfield, Minnesota. In her freshman year, she tried to get into a physics class that was full and wound up taking a biology class. She was concerned that biology classes were mostly memorization. When she started the course, she appreciated how the science involved searching for missing pieces of information.

Cold Spring Harbor Laboratory appealed to her because she could go in whatever direction the research took her.

For Alexander, scientific questions are like a layer of cloth with a few threads sticking out.

“You see one sticking out and you start to pull,” Alexander said. “You don’t necessarily know what’s going to come out, but you keep getting the urge to pull at that thread. You realize that it is connected to all these other things and you can look at those, too.”

She is excited to cross numerous disciplines in her work and is eager to think about how her research might “interplay across those fields and boundaries.”

Speckle origins

As for speckles, Alexander observed during her postdoctoral research how one factor seemed to influence a neighborhood of genes.

For that to occur, she realized that something had to affect those genes at the same time in the physical space. She hadn’t known about speckles before. A few of her colleagues, including Good, came across speckles in their analysis. That made Alexander curious about what these speckles might be doing.

She saw an opening to pursue connections between changes in these potential gene activators and illnesses.

Researchers know that viruses can use speckles to help them copy themselves.

If they are used by viruses “they must be important” and they “probably go wrong in a lot of diseases,” Alexander said. There are a series of neurodevelopmental disorders called “speckleopathies” that involve mutations in proteins found inside speckles.

“We have the computational and experimental tools to start investigating them across a wide variety of conditions,” she said.

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Stony Brook University researchers Fusheng Wang and Dr. Richard Rosenthal

By Daniel Dunaief

Health care providers can use all the help they can get amid an ongoing opioid epidemic that claims the lives of 130 Americans each day.

In a cross-disciplinary effort that combines the computer science skills of Fusheng Wang and the clinical knowledge and experience of doctors including Dr. Richard Rosenthal, Stony Brook University is developing an artificial intelligence model that the collaborators hope will predict risk related to opioid use disorder and opioid overdose.

Fusheng Wang

Wang, a Professor in the Department of Biomedical Informatics and Computer Science at Stony Brook and Rosenthal, a Professor in the Department of Psychiatry and Behavioral Health in the Renaissance School of Medicine, received a $1.05 million, three-year contract from the independent funding organization Patient-Centered Outcomes Research Institute (PCORI).

“We have patients, clinical stakeholders, clinician scientists and community-based people within the system of care that have an interest at the table in the development cycle of this AI mechanism from day one,” Rosenthal said. The PCORI required that the scientists identify these stakeholders as a part of the research strategy.

The Stony Brook researchers are combining data from Cerner, a major electronic health record vendor under an institutional data usage agreement, with an awareness of the need to create a program that doctors can use and patients can understand.

Traditional public health studies rely on analyzing incidents that occurred. This approach, however, can be applied to population health management through early interventions, Wang explained.

With artificial intelligence, computer scientists typically plug enormous amounts of data into a model that searches through individual or combined factors and comes up with a prediction through a deep learning process.

The factors, which may be in the hundreds or even more, that contributed to the conclusion about a risk level aren’t always clear, which makes them difficult for doctors to explain and for patients to understand. Many of the factors may not be clinically intuitive.

Deep learning models can provide certain types of information about the prediction, such as a ranking of top factors. These factors, however, may not necessarily be clinically relevant, Wang explained.

To balance the need for data-driven analysis with the desire to create a product that people feel confident using, the scientists plan to become a part of the process.

“We are all going to educate each other,” said Rosenthal. “Patients will tell you what it means to be a patient, to be at the receiving end of some doctors telling them something they don’t know” while each group will share their lived experience.

Each participant will be a student and a teacher. Rosenthal believes this stakeholder in the loop approach will create a tool that is clinically relevant.

“There’s an opportunity to produce a highly accurate predictive mechanism that is highly acceptable based on transparency,” he said.

To be sure, people involved in this process could deemphasize a factor that doesn’t make sense to them, but that might otherwise increase the predictive accuracy of the developing model.

“This might come at the expense of the performance metric,” Rosenthal said.

Still, he doesn’t think any human correction or rebalancing of various factors will reduce the value of the program. At the same time, he believes the process will likely increase the chances that doctors and patients will react to its prognosis.

A program with a personal touch

Wang created the model the scientists are using and enhancing. He reached out to several physicians, including Director of the Primary Care Track in Internal Medicine Rachel Wong and later, Rosenthal, for his addiction research expertise.

Dr. Richard Rosenthal

Rosenthal started collaborating on grant proposals focused on big data and the opioid epidemic and attending Wang’s graduate student workgroup in 2018.

Wang recognized the value of the clinician’s experience when communicating about these tools.

“Studies show that patients have lots of skepticism about AI,” he explained. Designing a tool that will generate enough information and evidence that a patient can easily use is critical.

The kind of predictions and risk profiles these models forecast could help doctors as they seek the best way to prevent the development of an addiction that could destroy the quality and quantity of their patients’ lives.

“If we can identify early risk before the patient begins to get addicted, that will be extremely helpful,” Wang added.

If opioid use disorder has already started for a patient, the tool also could predict whether a patient has a high chance of ending treatment, which could create worse outcomes.

Refinements to the model will likely include local factors that residents might experience in one area that would be different for populations living in other regions.

Depending on what they learn, this could allow “us to frame our machine learning questions in a more context-dependent population, population-dependent domain,” Rosenthal said.

Opioid-related health problems in the northeast, in places like Long Island, is often tied to the use of cocaine. In the Southwest, the threat from opioids comes from mixing it with stimulants such as methamphetamines, Rosenthal added.

“Localization increases the accuracy and precision” in these models, he said.

Eventually, the model could include a risk dashboard that indicates what kind of preventive measures someone might need to take to protect themselves.

The scientists envision doctors and patients examining the dashboard together. A doctor can explain, using the model and the variable that it includes, how he or she is concerned about a patient, without declaring that the person will have a problem.

“Given these factors, that puts you at greater risk,” said Rosenthal. “We are not saying you’re going to have a problem” but that the potential for an opioid-related health crisis has increased.

Unless someone already has a certain diagnosis, doctors can only discuss probabilities and give sensible recommendations, Rosenthal explained.

They hope the tool they are developing will offer guidance through an understandable process.

“At the end of the day, the machine is never going to make the decision,” said Rosenthal. With the help of the patient, the clinician can and should develop a plan that protects the health of the patient.

“We’re aiming to improve the quality of care for patients,” he said.

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By Daniel Dunaief

It’s back, bigger than ever, with an added Peter-and-the-Wolf style musical debut.

This year’s version of Science on Stage at Stony Brook University, which brings together the research and life experiences of three scientists with the artistic interpretation and creative talents of three playwrights, focuses on the theme of climate change.

Before the reading of the plays at the free October 28th event at the Staller Center’s Recital Hall, a group of eight high school students and two graduate students will perform an original piece of music composed by Professor Margaret Schedel called “Carnival of the Endangered Animals” (see accompanying story below).

Christine Gilbert with graduate student Emily Gelardi. Photo by Conor Harrigan

The event, which has a seating capacity of 379, which is almost triple the potential audience size from last year, and requires advance registration, is sponsored by the Collaborative for the Earth (C4E).

The organizers of Science on Stage “want people to be thinking about [climate change] from new ways or with new perspectives,” said Heather Lynch, inaugural director of the C4E and Endowed Chair for Ecology and Evolution at Stony Brook’s Institute for Advanced Computational Science and Professor in the Department of Ecology and Evolution.

In these performances, professional actors, directed by Logan Vaughn, share a dramatic reading of the scripts, titled “Ghost Forest,” “Counterfactual,” and “Resplendence.” After the performance, the scientists and playwrights will participate in a question and answer session led by Lecturer J.D. Allen, who is managing editor of NPR affiliate WSHU.

Provost Carl Lejuez, whose office provides funding for the C4E, celebrated the ongoing collaboration between the humanities and the sciences.

“Science on Stage is one of our true interdisciplinary gems,” Lejuez explained. “In a time of such misinformation, the arts provide such a powerful vehicle to communicate science in accessible and inspiring ways.”

Indeed, in addition to hearing an original piece of music and listening to a reading of the plays, audience members will have the opportunity to share their perspectives on climate science before and after the performance.

Christine Gilbert, who holds a joint appointment at the School of Communication and Journalism and the School of Marine and Atmospheric Sciences and is one of the participating scientists, is conducting a study of the effect of the experience with audience members.

Attendees can participate in a short mobile-based survey before the plays and immediately afterwards. A social scientist, Gilbert will follow up with those members who are willing to engage in individual interviews in the weeks after the performance.

Event organizers wanted to know “what is it that’s so magical in the intersection between science, humanity and art” that drew a crowd so large last year that the fire marshal had to turn people away, said Gilbert.

By polling the audience, Gilbert, who was one of the people who couldn’t watch the show last year, hopes to explore the effect of teaching complex science in this forum.

She also hopes to assess how audience members feel after hearing more about climate change and plans to share what she learns with Stony Brook and with the broader scientific community through a published paper.

Heavy and humorous

The scientists and the playwrights appreciated the opportunity to learn from each other and to engage in a creative effort designed to use science, or the life of scientists, to appeal to audiences.

Lynch, who participated in the Science on Stage effort last year, suggested that this year’s plays are powerful and evocative.

“These are deep, adult serious issues,” she said, cautioning that the language includes some cursing and that the themes include loss, parenthood and grief. “This is not Disney.”

To be sure, the plays blend a wide range of emotions.

“With short plays that deal with heavier topics, playwrights will gravitate towards humor,” said Ken Weitzman, Founder and Associate Professor of Theater at Stony Brook, who started Science on Stage virtually in 2020. “It’s how we engage” and commune with an audience.

Counterfactual

Playwright Mat Smart

Author of the play “The Agitators,” about a true narrative describing the 45-year friendship between suffragist Susan B. Anthony and abolitionist Frederick Douglass, Smart said he has taken long Uber rides with people whose views differ from his, leading to spirited conversations.

When Smart described his experiences to Reed, they discovered they had similar interactions.

While much of the script involves a combination of conversations and ideas, Smart explained that part of the dialogue in the play came from a discussion he and Reed had about food choices and climate change. 

The interaction about cheeseburgers is “based on something [Reed] said to me,” Smart said. Reed explained the high carbon footprint of a cheeseburger, although he urged Smart to cut back rather than eliminate them from his diet.

“The play is about two people who see things very differently who choose to have a dialogue and to have a tough conversation,” said Smart. “They’re both affected by it.”

Ghost forest

Playwright Gab Reisman

Elizabeth Watson, Associate Professor in the Department of Ecology & Evolution, teamed up with Gab Reisman, who wrote “Ghost Forest.”

In this play, a climate researcher’s subjects spring to life as she writes an important grant proposal.

While it doesn’t reflect how field research or grant writing typically goes, it does capture “some things that have happened to me,” Watson said.

Her field work has involved considerable challenges, including getting stuck in the mud, being covered in ticks, crawling across mudflats, and being abandoned on a raft in a lagoon.

Watson appreciates how the artistic effort allows her to connect with people who probably aren’t the same ones who would read a publication she wrote or come to a presentation.

She also added that the world has what it needs to deal with climate change and that people need to understand the kinds of partnerships and actions that make a difference.

Resplendence

Playwright Kareem Fahmy

After speaking with Gilbert, playwright Kareem Fahmy wrote “Resplendence,” which follows three generations of a family who try to save their island off the coast of Maine.

The New England State is an important setting for playwright and scientist. 

“Maine has such a special place in my heart,” said Gilbert, who has family in the state and attended college at the University of Maine. The pull of the “wild, eastern coast of Maine is so ubiquitous.”

Gilbert appreciated how Fahmy did a “great job of personalizing the context” of the state.

The challenge of preserving destinations, particularly those close to sea level, will likely persist.

“When you do any research about climate change, you have to be aware that this is not just a problem for people living today, but for people 200 years from now,” Gilbert said.

Weitzman said the play was an epic despite its short running time and thought it was “quite touching.”

Beyond the performance

Weitzman suggested that the plays can provide an educational component beyond the confines of the Staller Recital Hall. 

While people can’t produce the plays as part of paid entertainment, teachers can read and use them in the classroom. Actors Bill Heck, April Matthis, Tina Benko, Mandi Masden and Taylor Crousore will provide dramatic reading of the plays.

In a short time, the actors are “practically off the book,” as they embrace the opportunity to bring the words to life, Weitzman said.

He suggested the plays offer a glimpse into researchers’ lives. “Here is this person on the front lines. I’m surprised at the angles that are taken” in these plays.

Stony Brook University’s Staller Center for the Arts, 100 Nicolls Road, Stony Brook will present this year’s Science on Stage: Climate Edition on Monday, Oct. 28 at 4 p.m. Doors open at 3:30 p.m. The event is free and open to the public but reservations are strongly recommended.

To register, go to: https://bit.ly/4dcDtsi or click here.

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SBU’s Margaret Schedel brings endangered species to life through musi
Margaret Schedel discusses the ‘Carnival of the Endangered Animals’ with the band and conductor Justin Stolarik during rehearsal. Photo by Heather Lynch

Science on Stage at Stony Brook University added a new dimension to the performance this year, as Margaret Schedel, Associate Professor of Music, composed “Carnival of the Endangered Animals.” The original music, which will debut on Oct. 28 at 4 p.m. at the Staller Center’s Recital Hall, is a recreation of the sounds of a wide range of animals who are in danger of becoming extinct.

“It’s melodic, interrupted by moments of trying to translate” the calls from these animals, Schedel said.

Ken Weitzman, Founder and Associate Professor at Stony Brook, appreciates how quickly music can resonate for audiences.

“Music appeals to the emotions,” said Weitzman. “I’m jealous of how quickly music can do in 10 seconds what it takes me hours to do.”

The animals featured in the piece, along with the instrument that captures their sounds, are: the Atlantic Right Whale (Marimba); the A’kikiki bird, which is a Hawaiian honeycreeper (flute); Sumatran Tiger (trumpet); sage grouse (clarinet); Bajii, which is a Yangtze river dolphin; and the Jiangtun, which is a Yangtze finless porpoise (four-hand piano); gorilla (french horn); African bush elephant (trombone); Koala (bassoon); and the penguin (oboe).

Schedel plans to share information about each piece, which eight area high school students and two graduate students will perform, with the audience through a QR code, so they can connect the sounds with the message or visuals she was conveying.

Schedel tried to use a logical progression of the instruments, mixing up the woodwinds, percussion and brass.

Threatened by land development, the sage grouse includes high and low notes from the clarinet that gets covered up by the sounds of a flute and trumpet, imitating the sounds excavators make when they back up and develop McMansions.

Endangered by the spread of avian malaria carried by mosquitoes, the Hawaiian A’kikiki bird had been able to evade these insects by traveling higher up the mountain, where the colder temperatures kills the mosquitoes. That is not happening as much because global warming is enabling the blood sucking creatures to survive at higher elevation.

The sage grouse music starts with a melodic theme on the flute and as it goes higher, the theme becomes compressed. The buzzing brass, meanwhile, gets louder and louder as the mosquito pursues its meal, infecting the bird with a lethal parasite.

Reflecting the struggle for survival these creatures face, the Yangtze river dolphin, which had about 20 members when Schedel first started composing the music, may have become extinct by the time of the performance. That is, in part, why she combined the dolphin and the finless porpoise on the four hand piano.

As for the sounds of the elephant, Schedel recalled a safari she had experienced when she had been in South Africa. Elephants charged at Schedel and her group, who had come too close to the younger ones in the herd.

The elephants growled at Schedel and her companions.

“You can feel it in your chest, the sound waves moving,” she said. “Little by little, the younger ones put up their trunks and eventually a big momma elephant with a broken tusk put up her trunk, which is a symbol of, “we are calm,’” she said. With the trombone representing the elephant, the bass drum connotes its growling sounds.

When she was growing up, Schedel listened to the Leonard Bernstein version of “Peter and the Wolf” so many times that the recording is “nearly dead,” she laughed. She hopes people enjoy her piece with the same energy and excitement, connecting the sounds and the stories with the endangered animals. 

Schedel described the experience of creating the music as a “labor of love.”

 

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Shushan Toneyan and Peter Koo at Cold Spring Harbor Laboratory. Photo by Gina Motisi/CSHL

By Daniel Dunaief

The real and virtual world are filled with so-called “black boxes,” which are often impenetrable to light and contain mysteries, secrets, and information that is not available to the outside world.

Sometimes, people design these black boxes to keep concepts, ideas or tools outside the public realm. Other times, they are a part of a process, such as the thinking behind why we do certain things even when they cause us harm, that would benefit from an opening or a better understanding.

In the world of artificial intelligence, programs learn from a collection of information, often compiling and comparing enormous collections of data, to make a host of predictions.

Companies and programmers have written numerous types of code to analyze genetic data, trying to determine which specific mutations or genetic alterations might lead to conditions or diseases.

Left on their own, these programs develop associations and correlations in the data, without providing any insights into what they may have learned.

That’s where Peter Koo, Assistant Professor at Cold Spring Harbor Laboratory, and his former graduate student Shushan Toneyan come in.

The duo recently published a paper in Nature Genetics in which they explain a new AI-powered tool they designed called CREME, which explored the genetic analysis tool Enformer.

A collaboration between Deep Mind and Calico, which is a unit of Google owner Alphabet, Enformer takes DNA sequences and predicts gene expression, without explaining what and how it’s learning.

CREME is “a tool that performs like large-scale experiments in silico [through computer modeling] on a neural network model that’s already been trained,” said Koo. 

“There are a lot of these models already in existence, but it’s a mystery why they are making their predictions. CREME is bridging that gap.”

Award winning research

Indeed, for her work in Koo’s lab, including developing CREME, Toneyan recently was named a recipient of the International Birnstiel Award for Doctoral Research in Molecular Life Sciences.

“I was genuinely surprised and happy that they selected my thesis and I would get to represent CSHL and the Koo lab at the ceremony in Vienna,” Toneyan, who graduated from the School of Biological Sciences, explained. 

Toneyan, who grew up in Yerevan, Armenia, is currently a researcher in The Roche Postdoctoral Fellowship Programme in Zurich, Switzerland.

She said that the most challenging parts of designing this tool was to focus on the “interesting and impactful experiments and not getting sidetracked by more minor points more likely to lead to a dead end.”

She credits Koo with providing insights into the bigger picture.

New knowledge

Without taking DNA, running samples in a wet lab, or looking at the combination of base pairs that make up a genetic code from a live sample, CREME can serve as a way to uncover new biological knowledge.

CREME interrogates AI models that predict gene expression levels from DNA sequences.

“It essentially replicates biological or genetic experiments in silico through the lens of the model to answer targeted questions about genetic mechanisms,” Toneyan explained. “We mainly focused on analyzing the changes in models outputs depending on various perturbations to the input.”

By using computers, scientists can save considerable time and effort in the lab, enabling those who conduct these experiments to focus on the areas of the genome that are involved in various processes and, when corrupted, diseases.

If scientists conducted these experiments one mutation at a time, even a smaller length sequence would require many experiments to analyze.

The tool Koo and Toneyan created can deduce precise claims of what the model has learned.

CREME perturbs large chunks of input sequence to see how model predictions change. It interrogates the model by measuring how changes in the input affect model outputs.

“We need to interpret AI models to trust their deployment,” Toneyan said. “In the context of biological applications, we are also very interested in why they make a certain prediction so that we learn about the underlying biology.”

Using ineffective and untested predictive models will cause “more harm than good,” added Koo.  “You need to interpret [the AI model’s] programs to trust them for their reliable deployment” in the context of genetic studies

Enhancers

Named for Cis Regulatory Element Model Explanations, CREME can find on and off switches near genetic codes called enhancers or silencers, respectively.

It is not clear where these switches are, how many there are per gene and how they interact. CREME can help explore these questions, Toneyan suggested.

Cis regulatory elements are parts of non-coding DNA that regulate the transcription of nearby genes, altering whether these genes manufacture or stop producing proteins.

By combining an AI powered model such as Enformer with CREME, researchers can narrow down the possible list of enhancers that might play an important genetic role.

Additionally, a series of enhancers can sometimes contribute to transcription. A wet lab experiment that only knocked one out might not reveal the potential role of this genetic code if other nearby areas can rescue the genetic behavior.

Ideally, these models would mimic the processes in a cell. At this point, they are still going through improvements and are not in perfect agreement with each other or with live cells, Toneyan added.

Scientists can use the AI model to aid in the search for enhancers, but they can’t blindly trust them because of their black box nature.

Still, tools like CREME help design genetic perturbation experiments for more efficient discovery.

At this point, the program doesn’t have a graphical user interface. Researchers could use python scripts released as packages for different models.

In the longer term, Koo is hoping to build on the work he and Toneyan did to develop CREME.

“This is just opening the initial doors,” he said. “One could do it more efficiently in the future. We’re working on those methods.”

Koo is pleased with the contribution Toneyan made to his lab. The first graduate student who worked with him after he came to Cold Spring Harbor Laboratory, Koo suggested that Toneyan “shaped my lab into what it is.”

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