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Power of 3

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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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Prateek Prasanna and Chao Chen at the NCI Informatics Technology for Cancer Research meeting in St. Louis in 2022.

By Daniel Dunaief

Cancer often involves numerous small changes before it become a full blown disease. Some of these alterations are structural, as otherwise healthy cells make subtle shifts that favor out of control growth that often defies the immune system and threatens the health of tissues, organs and the entire body.

Associate Professor Chao Chen and Assistant Professor Prateek Prasanna, both in the Department of Biomedical Informatics at Stony Brook University, recently received a four-year, $1.2 million grant from the National Cancer Institute to continue to develop an enhanced breast cancer imaging tool that could detect some of those changes.

Using advanced mathematical modeling and machine learning and working with clinical collaborators in radiology, radiation oncology, surgery and pathology, the researchers are developing a tool called TopoQuant. They hope they can provide a way to look at the changes in tissue architecture that occur during the growth and development of cancer and during radiation treatment.

Receiving the grant means “other researchers also think highly about the subject,” Chen explained. “This further boosts our confidence and is an approval for our effort so far.”

By combining two-dimensional and three-dimensional data, the Stony Brook researchers, including radiation oncologist Dr. Alexander Stessin, hope to provide an analytical tool that helps doctors and patients confronting cancer all the way from the early steps the disease takes to the ways it resists various treatments.

The researchers are using tomosynthesis and MRIs, both of which are three dimensional, and conventional mammographs, which are two dimensional.

Stessin will work closely to evaluate the efficacy of the TopoQuant framework to provide a predictive and useful interpretation of breast images.

The diagnostic and prognostic tool these scientists are developing has potential applications outside the world of breast cancer. The deep learning technique could help analyze images and information for other types of cancer as well as for various neurological challenges.

“In the tools we develop, a lot of the algorithms are domain agnostic,” said Prasanna.

The approach should work as long as the researchers can get structure-rich imaging data. To be sure, while this approach has had some promising early results, it has to proceed through numerous steps to help in the clinic.

In the meantime, the researchers plan to use the funds, which will support salaries and travel budgets for researchers, to continue to develop TopoQuant.

Chen and Prasanna envision providing physicians with an explanation of why artificial intelligence is guiding them towards a particular decision.

Doctors could “place more trust in a system like this,” Prasanna said. “It lends interpretability to an analysis that is typically more opaque.”

Healthy cells

When health care technicians gather information about breast cells, they often focus on developments in and around the cancer cells.

“The premise of the work” Chen and Prasanna are doing is to look at signals “even in the normal [healthy] areas of the breast, Prasanna said. “It’s important for physicians to look at these normal areas before they begin any treatment. What our tool lets them do is extract these signals.”

The process of developing this tool started about five years ago, as the scientists shared ideas and did preliminary studies. The work became more involved and detailed around 2020.

“The challenge is to have a harmonic combination between mathematical modeling and deep learning,” Chen explained. “Incorporating principled math modeling into deep learning is important yet not trivial.”

In their work, the researchers used phantom data called VICTRE from the Food and Drug Administration. They used simulated magnetic resonance images and validated that the method can extract the tissue structure faithfully across different breast density types. They are also using data from The Cancer Imaging Archive for initial model development.

At this point, the researchers have some evidence that the alpha version of the tool has been “promising” in the context of neoadjuvant chemotherapy, which they demonstrated in a paper they published in 2021.

The results from that study indicated different topological behavior of breast tissue characterized by patients who had different responses to therapy.

The researchers plan to continue to establish that the tools are properly characterizing what is happening. After that, they will validate the effort with a Stony Brook University Hospital cohort.

Clinicians from Rutgers are working with Chen and Prasanna and will do additional testing through external data sets.

Complementary skills

Chen and Prasanna, who have joint lab meetings and discuss their research every week, work in different parts of the campus. Chen’s lab is on the west campus, while Prasanna is in the east campus.

The researchers have combined their interests and skill sets to apply a computer science driven approach to medicine and the field of bioimaging analysis.

Chen does considerable work with topological information and machine learning. Prasanna, meanwhile, is also involved in the clinical world, combining his passions for engineering and medicine.

A native of Gansu Province in China, Chen lives near New York City and commutes to the university two or three times per week, working the other days from home and meeting with students and collaborators by Zoom.

When he first joined Stony Brook in 2018, Chen was concerned about jumping into a different department.

After visiting the department and speaking with Chair Joel Saltz and other faculty, he developed greater confidence when he learned of their passion for research, their research philosophy and the chemistry within the department.

Six years later, he thinks it was “the best career decision” he made.

A native of Cuttack, India, Prasanna and his wife Shubham Jain, who is in the faculty of Computer Science at Stony Brook, have worked together professionally.

The couple enjoys hiking and has been to 47 of the 63 national parks. One of their favorite parks is Katmai National Park and Preserve in Alaska.

Prasanna’s father’s family includes many physicians and his mother’s is involved in engineering. In his career, he has combined the professional focus from both sides of his family.

Early in his career, Prasanna worked on a project that used a smart phone to obtain fundus images of the eye to predict diabetic retinopathy.

At the time, he thought “this is where I want to be,” he recalled.

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Ellen Pikitch at the United Nations when she spoke at the 9th International Day of Women and Girls in Science back in February. Photo from E. Pikitch

By Daniel Dunaief

Even as Covid threatened the health of people around the world, a group of 30 leading researchers from a wide range of fields and countries were exchanging ideas and actions to ensure the sustainability of ocean fisheries.

Starting in 2020, the researchers, including Stony Brook University’s Endowed Professor of Ocean Conservation Science Ellen Pikitch, spent considerable time developing operating principles to protect the oceans and specific actions that could do more than ensure the survival of any one particular species.

Earlier this week, the researchers, who come from fields ranging from biology and oceanography to social sciences and economics, published a paper titled “Rethinking sustainability of marine fisheries for a fast-changing planet” in the Nature Journal npj Ocean Sustainability, as well as a companion 11 golden rules for social-ecological fisheries.

The researchers, who were led by first author Callum Roberts, Professor of Marine Conservation at the University of Exeter, plan to share their framework with policy makers and government officials at a range of gatherings, starting with Brussel’s Ocean Week and including the United Nations Ocean Conference in Nice.

“We felt something like this was needed in order to reach these audiences effectively,” said Pikitch.

The extensive work, which included two series of workshops, outlines ways to regenerate the ocean’s health and to put people before profits.

The authors suggest that fisheries need to address their contributions to the climate crisis through activities that are polluting, such as dumping fishing gear or plastics in the ocean, carbon intensive or destructive, through the disturbance of sediment carbon stores.

The paper suggests that lost or discarded fishing gear often make up the largest category of plastic waste in the open sea. This gear is not only polluting, but leads to ghost fishing, in which fish die in abandoned or discarded nets.

The authors suggest that labelling fishing gear could encourage better stewardship of the ocean. They also argued that fisheries management has historically focused on economic output, without considering social value and effects.

“We take the view that marine life is a public asset, and its exploitation and management should work for the benefit of local communities and the public,” the authors wrote in their paper.

Pikitch described the work as an “urgent” call to action and added that the researchers will be “meeting with policy makers, retailers, fishery managers and others to discuss these results and how they can be implemented.”

The researchers engaged in this effort to find a way to compile a collection of best practices that could replace a hodgepodge of approaches that overlook important elements of sustainability and that threaten fish species as well as ocean habitats.

“Fisheries are in bad shape worldwide and are degrading rapidly with overexploitation and climate change,” Philippe Cury, Senior Emeritus Researcher at the Institute of Research for Development in Marseille, France, said in a statement. “Efficient and renewed fisheries management can really help to restore marine ecosystems and to reconcile exploitation and biodiversity.”

Pikitch anticipated that some might offer pushback to the suggestions. “If you don’t get pushback, you’re probably not saying something that is important enough,’ she said.

Ecosystem focus

Using research Pikitch led in 2004 from a paper in Science, the group constructed one of the 11 actions around developing a holistic approach to the ocean habitat.

Pikitch’s expertise is in ecosystem based fishery management.

“Fish interact with one another, feed on one another, compete with one another and share the same habitats,” Pikitch said. “For those reasons alone and more, we need to stop managing species one at a time.”

Some policies currently protect ecosystems, including the spatial and temporal management of the Canadian lobster fishery to protect whales and the no-take marine reserves to protect artisanal reef fisheries in the Caribbean.

Still, these approaches need to be applied in other contexts as well.

While some people believed that researchers didn’t know enough to create and implement holistic guidelines, Pikitch and her colleagues suggested that it’s not “necessary to know everything if we use the precautionary principle.”

Pikitch suggested that the Food and Drug Administration takes a similar approach to approving new medicines.

The FDA requires that researchers and pharmaceutical companies demonstrate that a drug is safe and effective before putting it on the market.

Fisheries are making some headway in this regard, but “much more is needed,” she said.

Subsidy problem

The authors highlighted how government subsidies are problematic.

“Many fisheries are highly carbon intensive, burning large quantities of fossil fuels often made cheaper by capacity-enhancing government subsidies,” the authors noted in the paper. “Among the worst performers in terms of fuel burned per tonne of landing gears are crustacean fisheries, fisheries that operate in distant waters, deploy heavy mobile gears like trawls, or target high value, low yield species like swordfish; most of them propped up by subsidies.”

When overfishing occurs, companies switch to catching less exploited species, even when they don’t have any data about new catches. The new species, however, soon become overfished, the authors argued.

In urging fisheries management to support and enhance the health, well-being and resilience of people and communities, the scientists add that abundant evidence of widespread human rights abuses occurs in fishing, including coercive practice, bonded, slave and child labor and unsafe, indecent and unsanitary living and working conditions.

“Abuses at sea continue and more needs to be done to stop this,” Pikitch explained.

Additionally, the authors hope to give a voice to the global south, which is “often ignored in many of these discussions about how to appropriately manage these fisheries,” she suggested.

A beginning

While the paper was published, Pikitch explained that she sees this as the beginning of change and improvement in creating sustainable fisheries policies. She anticipates that the collection of talented scientists will continue the work of protecting a critical resource for human and planetary survival.

“This group will continue to work together to try get this work implemented,” she said. “I’m enormously proud of the result.”

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From left, Oscar Rivera-Cruz from the University of Puerto Rico, BNL materials scientist Anibal Boscoboinik, Alexander Bailey from West Virginia State University, and Jeremy Lopez from the University of Puerto Rico. Photo courtesy of BNL

By Daniel Dunaief

It’s been a banner year for ideas and potential products that trap noble gases at Brookhaven National Laboratory. So-named for their full complement of electrons, noble gases tend to be less reactive than other atoms that can add electrons to their outer shells.

While their name sounds grandiose, these gases are anything but, particularly when people inhale the radioactive and prevalent gas radon, which can cause lung cancer or when the decay of uranium into xenon makes a nuclear reactor less efficient.

When he was studying how hydrocarbons react at the active site of zeolite models, Brookhaven National Laboratory’s material scientist Anibal Boscoboinik made an accidental discovery about a decade ago that some nanomaterials, which are incredibly small, trap these gases.

Among several other projects he’s working on, Boscoboinik has since studied these nanocages, learning about the trapping mechanism and making variations of these materials and trapping methods that can be useful for a wide range of applications. 

The Battelle Memorial Institute, which partners with Stony Brook University to form Brookhaven Science Associates and manages nine national labs across the country, named Boscoboinik an “inventor of the year” for his work developing these materials.

Battelle awards an inventor of the year to a researcher from each institution under its management, recognizing efforts that contribute to science or engineering and that can have a positive impact on society.

“It feels really good to be recognized for the work,” said Boscoboinik, who is proud of the many people who made this progress possible directly and indirectly. “It would be amazing if we get to see something that stemmed from an accidental discovery doing very basic fundamental research becoming a real-life application that can benefit society.”

At the same time, three students from minority serving institutions were selected to receive seed grants as a part of MSI (for Minority Serving Institutions) Connect at BNL, in which they seek to commercialize a way to remove radon from the air.

They may work in a business to business model to supply other companies that can incorporate their materials into products.

The students, Jeremy Lopez Flores and Oscar Rivera-Cruz from the University of Puerto Rico and Alexander Bailey from West Virginia State University, will enter phase 2 in the process. The next phase of funding comes from other sources, such as FedTech. Boscoboinik will advise the students as they develop the company and any potential products.

These undergraduate students are looking to remove radon from the air at a concentration of four picocuries per liter, which is equivalent to smoking eight cigarettes a day.

“I am certainly pleased that the value of our collective output was recognized,” said Bailey, who is from St. Albans, West Virginia, in an email. Bailey, a sophomore double majoring in chemistry and math, plans to attend graduate school after completing his undergraduate studies.

Rivera-Cruz, who is a senior majoring in Cellular and Molecular Biology, appreciated the guidance from Boscoboinik, whom he described in an email as an “incredible resource for the team” and suggested that the team was “extremely grateful and lucky” to have Boscoboinik’s support.

In other research

As a staff member at the Center for Functional Nanomaterials, Boscoboinik spends half his time working with scientists from around the world who come to the CFN to conduct experiments and half his time working on his own research.

The process of granting time to use the facilities at BNL is extremely competitive, which means the projects he works on with other scientists are compelling. “While I help them with their research, I get to learn from them,” he said.

Boscoboinik regularly works with the group of Professor Guangwen Zhou from Binghamton University. In recent work, they explored the dynamics of peroxide formation on a copper surface in different environments.

In his own work, Boscoboinik is also interested in trying to help the nuclear energy community.

During the breakdown of radioactive uranium, the process heats up water in a tank, moving a turbine that produces energy.

The breakdown of uranium, however, produces the noble gas xenon, which is a neutron absorber, making reactors less efficient.

Boscoboinik anticipates that any new product that could help the field of nuclear energy by removing xenon could be a decade or more away. “This is a highly regulated industry and changes in design take a very long time,” he explained.

Boscoboinik is also collaborating with researchers from Johns Hopkins University on metal organic frameworks. Some molecules pass through these frameworks more rapidly than others, which could enable researchers to use these frameworks to separate out a heterogeneous collection of molecules.

Additionally, he is developing processes to understand dynamic conditions that affect different types of reactions. At this point, he has been looking at the oxidation of carbon monoxide, which he called the “drosophila” of surface science for its widespread use and versatility, to develop the methodology. In oxidation, carbon monoxide mixes with oxygen to make carbon dioxide.

In his work, Boscoboinik has collaborated with Qin Wu, who deploys artificial intelligence to interpret the data he generates in his experiments.

The long-term plan is to develop complex-enough algorithms that suggest experiments based on the analysis and interpretation of data.

Outside the lab

Boscoboinik is a part of a collaborative effort to combine science and music. “We use music as a way to enable conversations between scientists and the general public” to help make the sometimes complex and jargon-laden world of science more accessible, he said.

In Argentina, research groups have taken famous musicians to the lab to perform concerts while encouraging conversations about science. During the course of their visits, the musicians speak with scientists for the benefit of the public. In prior seasons, the musicians used popular songs to relate to the research the scientists they interview do. Part of the plan is to make new songs related to the research.

Boscoboinik is part of a collaboration between Music for Science, the network of Argentinian scientists abroad, and the Argentinian diplomatic missions, including the embassies and the consulates. At some point in the future he may create a show that relates noble gases and music.

As with his some of his scientific work, the connection between music and research is a developing proof of concept that he hopes has broader appeal over time.

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Minghao Qiu presenting at the American Geophysical Union Conference in San Francisco last year. Photo courtesy of M. Qiu

By Daniel Dunaief

When Minghao Qiu woke up in Beijing on Jan. 12, 2013  during his freshman year in college, he couldn’t believe what he was seeing or, more appropriately, not seeing. The worst air pollution day in the history of the city mostly blocked out the sun, making it appear to be closer to 8 p.m. than a typical morning.

Minghao Qiu

While Qiu’s life path includes numerous contributing factors, that unusual day altered by air pollution had a significant influence on his career.

An Assistant Professor at Stony Brook University, Qiu straddles two departments that encapsulate his scientific and public policy interests. A recent hire who started this fall, Qiu will divide his time equally between the School of Marine and Atmospheric Sciences and the Renaissance School of Medicine’s Program in Public Health.

Qiu studies fundamental questions in atmospheric sciences as they influence human health.

He is part of several new hires who could contribute to the climate solutions center that Stony Brook is building on Governors Island and who could provide research that informs future policy decisions.

Noelle Eckley Selin, who was Qiu’s PhD advisor at the Massachusetts Institute of Technology and is Professor in the Institute for Data, Systems and Society and the Department of Earth, Atmospheric and Planetary Sciences, suggested Qiu is a valuable scientific, policy and educational asset.

“Stony Brook is doing a lot to address climate in a serious way with great research,” Selin said. Qiu joining the institution “could really help out the university’s broader climate efforts and make them more impactful.”

Selin appreciated how Qiu was eager to dive deeper into questions, wanting to ensure that conclusions were valid and asking how to use data to test various ideas.

As a mentor, Qiu has proven inspirational.

“A lot of my current students will go and talk to him and come back to me and say, ‘[Qiu] had five excellent ideas on my project,’” Selin said. “That’s characteristic of how he works. He’s really generous with his time and is always thinking about how to look at problems.”

Policy focus

Using causal inference, machine learning, atmospheric chemistry modeling, and remote sensing, Qiu focuses on environmental and energy policies with a global focus on issues involving air pollution, climate change and energy transitions.

Qiu would like to address how climate change is influencing the air people breathe. Increasing heat waves and droughts cause people to use more energy, often through air conditioning. The energy for the electricity to power temperature controls comes from natural gas, coal, or fossil fuels, which creates a feedback loop that further increases pollution and greenhouse gases.

“Our work tries to quantify this,” Qiu said.

He also analyzes the impact of climate change on wildfires, which affects air quality.

In a research paper published last year, Qiu joined several other scientists to analyze the impact of wildfires on air quality.

The study, published in the journal Nature, found that since at least 2016, wildfire smoke eroded about a quarter of previous decades-long efforts to reduce the concentration of particulates above 2.5 microgram in several states.

Wildfire-driven increases in ambient particulates are unregulated under air pollution laws.

The authors showed that the contribution of wildfires to regional and national air quality trends is likely to grow amid a warming climate.

In his research, Qiu seeks to understand how to use energy and climate policy to address air pollution and greenhouse gases.

“Renewable energy and climate policy in general provides potential benefits,” Qiu said.

He uses publicly available data in his models.

New York pivot

While wildfires have been, and likely will continue to be, an area of focus for his work, Qiu plans to shift his focus to the kind of pollution that is typically more prevalent in New York.

In large urban cities, pollution often comes from a concentration of traffic, as people commute to and from work and drive to the city for entertainment and cultural events.

“We are going to pivot a little bit, especially to factors that are more relevant” to the Empire State, he said.

While climate change is a broad category that affects patterns across the world, air pollution and its impacts are more regional.

“The biggest impact of air pollution happens locally” particularly in terms of health effects, Qiu said.

From Beijing to MIT

Born and raised in Beijing, Qiu began connecting how climate or energy policy influences air pollution at MIT.

“When I started my PhD, there was not much real world data analysis” that linked how much renewable energy helps air quality, Qiu said. “We have historical data to do that, but it’s a lot more complex.”

After he graduated from MIT, Qiu moved to Stanford, where he shifted his focus to climate change.

“There, I got to collaborate more directly with people in the public health domain,” he said, as he focused on wildfires.

Personal choices

Despite studying air pollution and climate change, Qiu does not have HEPA filters in every room and, by his own admission, does not live a particularly green life. He does not have an electric car, although he plans to get one when he needs a new vehicle. He urges people not to sacrifice the living standards to which they are accustomed, which can include eating their preferred foods and traveling to distant points in the world.

Qiu believes there are choices individuals can make to help, but that the kind of decisions necessary to improve the outlook for climate change come from centralized government policy or large enterprises.

“I have great respect for people who change their personal behavior” but he recognizes that “this is not for everyone.”

A resident of Hicksville, Qiu lives with his wife Mingyu Song, who is a software engineer. The couple met when they were in high school.

When he’s not working on climate models, he enjoys playing basketball and, at just under six feet tall, typically plays shooting guard.

As for his research, Qiu does “rigorous scientific research” that draws from historical data.

“I feel a sense of urgency that we would like to get the answers to many of the scientific evidence as quickly as possible to communicate to policy makers,” he said.

He wants his research to be impactful and to help policy makers take “appropriate measures.”

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Assistant Professor Michael Lukey and postdoctoral researcher Yijian 'Evan' Qiu. Photo courtesy of Michael Lukey lab

By Daniel Dunaief

Cancer is a dangerous and wily adversary. Just when researchers think they have come up with a plan to defeat a deadly disease that takes many forms and that attacks different organs, cancer can figure out a way to persist.

Researchers have known that breast cancer uses the amino acid glutamine to power its high energy needs. To their disappointment, when they’ve blocked glutamine or reduced its availability, cancer somehow carries on.

An adaptable foe, cancer has figured out how to find an alternative metabolic pathway that can use the same energy or carbon source when its level gets low.

Cold Spring Harbor Laboratory Assistant Professor Michael Lukey and postdoctoral researcher Yijian “Evan” Qiu have discovered how a form of breast cancer has a back up plan, enabling it to survive despite glutamine deprivation.

“Analysis of tumor samples has revealed that glutamine is often depleted within the tumor microenvironment, so we were interested in understanding how seemingly ‘glutamine addicted’ cancer cells adapt to this challenge,” Lukey explained..

In research published last week in the journal Nature Metabolism, the Cold Spring Harbor Laboratory researchers discovered and quieted a type of breast cancer’s alternate energy source.

This form of breast cancer typically uses glutamine, which is one of the most common amino acids, to power its disease-driven machinery. When Qiu and Lukey blocked the formation of alpha-ketoglutarate, which is a metabolite normally derived from glutamine and then glutamate, they significantly repressed the growth of tumors in animal models of the disease.

Cancer cells turn on this alternative pathway that can catalyze glutamate into alpha-ketoglutarate.

“Cancer is always evolving and adapting,” said Qiu. “We need to stay ahead as scientists.”

The results of this research suggest a possible approach to treating cancer, depriving the disease of ingredients it needs to feed the kind of runaway growth that threatens human health. Limiting key ingredients could come from applying specific inhibitors, extracellular enzymes or antimetabolites.

Their work could have implications and applications in other forms of cancer.

The time between observing a promising result in the lab and a new therapy typically takes years. In this case, however, treatments that use inhibitors of glutamine have been well-tolerated in animals and humans. Qiu also did not observe any side effects in animal models in his study, which could potentially accelerate the process of creating a new therapy.

To be sure, developing treatments that cut off cancer’s primary and back up energy supply may not be sufficient, as cancer may have other metabolic moves up its figurative sleeves.

“Cancer cells typically exhibit metabolic flexibility, such that they can adapt to a variety of metabolic stresses,” said Lukey. “It remains to be seen if they can ultimately adapt to long-term blockade of the axis that we identified, but so far we have not seen this happen.”

A search for the back up plan

Qiu and Lukey speculated at the beginning of Qiu’s Cold Spring Harbor Laboratory experience in August of 2020 that cancer cells likely had another energy option.

“The fact that cancer cells that should be dependent on glutamine adapted in glutamine-free media in weeks made me believe that the cancer cells must have such a plan B,” Qiu explained.

To figure out why glutamine inhibitors weren’t shrinking tumors in animal models or humans, Qiu removed glutamine from cancer cells, causing over 99.9 percent of the cells to die. A few, however, survived and started proliferating in weeks.

Qiu used RNA-seq analysis to compare the parental and adaptive cells and found that the cells that are glutamine independent upregulated a serine synthesis pathway. These adaptive cells used PSAT1, or phosphoserine aminotransferase 1, to produce alpha-ketoglutarate.

As for human patients, the scientists don’t know what kind of stress is activating a Plan B for metabolism, which they are currently exploring.

A ‘passion’ for the field

Lukey and Qiu submitted the paper for publication about a year ago. After conducting additional experiments to verify their findings, including confirming that some of the metabolite entered the cell, these researchers received word that Nature Metabolism would publish the research.

Lukey appreciated Qiu’s passion for science and suggested his postdoctoral researcher combines his technical proficiency with good ideas to generate promising results.

Lukey suggested that researchers in the field have developed a growing consensus that effective strategies to target tumor metabolism will likely involve combination therapies that disrupt a critical metabolic pathway in cancer cells and simultaneously block the adaptive response to that intervention.

From China to Buffalo to LI

Born in Yiyang, Hunan province in China, Qiu moved several times during his childhood, to Sanya, Hainan and Changsha, Hunan.

Qiu knew he wanted to be a scientist when he was young. He enjoyed watching ants, observing the types of food they carried with them. He earned his PhD from Clemson University in South Carolina, where he built his knowledge about metabolism-related research and benefited from the guidance of his mentor James Morris.

Qiu and his wife Peipei Wu, who is a postdoctoral researcher in Chris Hammell’s lab and focuses on epigenetic gene regulation in skin stem cell development, live in Oyster Bay.

The scientific couple don’t have much overlap in their work, but they do get “lots of inspiration from each other, during our discussion outside of work,” said Qiu.

Qiu enjoys fishing and caught and ate a catfish from the Hudson River. He appreciates drawing scenery, animals and a range of other visuals, including cartoon characters. He designed T-shirts for his department during his PhD.

As for his research, Qiu hopes the metabolism finding may lead to new treatments for cancer. He also suggested that this approach may help with other cancers.

“What I have found in my study can be applied for many other cancer types that are also dependent on glutamine, such as lung and kidney cancer,” he said. He also can not rule out “the possibility that the treatment may help reduce metastasis.”

An important topic for follow up studies, Lukey suggested, is to address how the metabolic interventions Qiu used might affect immune cells and the anticancer immune response.

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Pixabay photo

By Daniel Dunaief

Benjamin Luft. Photo courtesy of SBU

They bother us, particularly in the summer, but they don’t need us.

The 23 species of Borrelia bacteria, which cause Lyme disease, have been around for millions of years, dating back to when the continents were all linked together like pieces of a puzzle in Pangea. The bacteria likely infected early mammals in those days.

In a recent paper in the journal mBIO, researchers from over 12 institutions put together the genetic sequence of these bacteria, which include 47 strains.

The scope of the work “was enormous and we were lucky” to have so many dedicated investigators, said Ben Luft, Edmund D. Pellegrino Professor of Medicine at the Renaissance School of Medicine at Stony Brook University, including lead senior author Weigang Qiu, Professor of Biology at Hunter College of the City University of New York.

The work, which took about a decade to complete, could provide a valuable resource to researchers and doctors today and in the future. The genetic information could lead to advances in diagnostics, treatment and prevention of Lyme disease.

Scientist could use the database to compare the genomes of different species and variations that cause different symptoms to help diagnose the likely severity of an infection as well as to search for specific pathways that lead to the virulence of an infection.

Some infections can lead to fever, headaches, fatigue and a skin rash. Starting with the bite of an intermediate host such as a tick, these infections, when left untreated, can lead to problems in the joints, heart, and nervous system.

The number of new cases of Lyme disease each year has been climbing, reaching close to 500,000 per year in the United States.

Researchers added that creating a genetic catalog of the different bacterial species can also help current and future scientists and doctors manage new threats from strains of bacteria that move into new areas amid climate change.

These species haven’t interacted with each other in the past, but climate change may create opportunities for bacteria to create recombinant genes, presenting new threats to human health.

“You may start seeing things that you didn’t see before,” said Luft. “We don’t know what’s going to happen” amid climate change. “There might be new forms” of Lyme disease.

The challenge with Lyme is not necessarily what happens in 2024, but how it might change in 20 years, when organisms develop a new pathogenicity.

Lyme on four continents

An international team of researchers sequenced the genomes of many species of Borrelia, the cause of Lyme disease. By comparing these genomes, the researchers reconstructed the evolutionary history of Lyme disease bacteria. The map shows many of the global regions where the team sequenced a species. Borrelia burgdorferi, the most common cause of disease, is indicated in red. Other species are indicated by different colors. Image created by Saymon Akther

In addition to generating a database of the Lyme disease bacterial genome, the researchers wanted to develop an understanding of its phylogenetic history.

“The goal really was to show how genetically diverse Borelia is throughout the world,” said Luft.

The researchers gathered genetic data from this bacteria, which was sampled in Europe, Asia, and North and South America.

By collecting the genetic information in each of these locations, the scientists were able to recreate the history of a bacteria that’s lasted considerably longer than many other organisms that have since become extinct.

“The genetic make up (genes and plasmids) hasn’t changed very much since the last common ancestor on Pangea (otherwise we would see different sets of genes and plasmids from different continents),” explained Qiu.

An extensive collaboration

Qiu and Luft were grateful for all the work scientists around the world did to contribute to this study.

On Long Island, Lyme disease is transmitted mainly by the bite of an infected deer tick, also is known as the black-legged tick.

The team of Claire Fraser and Emmanuel Mongodin at the University of Maryland School of Medicine and Richard G. Morgan of New England Biolabs helped use next generation sequencing to determine the bacterial genome.

Indeed, Fraser was the first to map the complete genetic code of a free-living organisms. She worked with the Haemophilus influenza, which causes respiratory infections and meningitis in infants and young children, according to the University of Maryland School of Medicine.

Qiu, who earned his Phd from Stony Brook in 1999, suggested that the effort required regular, ongoing work. He supervised Dr. Saymon Akther for her thesis work, which was the basis of the paper. He also performed additional evolutionary analysis.

“For the past two years, we have been having weekly meetings on zoom,” said Qiu. “It’s a big relief” that the researchers published the study and shared the information with the scientific community.

Qiu credited Luft with being a consistent coordinator of the sequencing effort and diversity study for over 20 years.

The next steps

At this point, Luft and his colleagues are eager to share the information with the broader scientific community.

The researchers hope experts in artificial intelligence, bioinformatics and computer programming can use the data to understand more about the genome and develop potential therapeutic targets.

Luft is eager to see “how smart people take advantage of a decade’s worth of work that has been very carefully done, to move it all forward,” he said. “We have certain ideas that we are doing” to fill in the gaps.

Qiu has some existing grants he’s using to work on diagnostics and vaccine development.

Qiu, along with chemistry-department colleague Brian Zeglis, and Lyme diagnostic/ vaccine researcher Maria Gomes-Solecki, has a joint NIH/ NIAID grant to develop a novel PET-based technology to detect Lyme pathogens in vivo. They have also proposed a new Lyme vaccine design strategy.

Additional sequencing of the variable plasmid, which is not a part of the chromosomal DNA but can replicate independently, would continue to help determine what genetic codes contribute to the level of virulence for each strain or species.

“That’s like the last mile for the communication network,” said Qiu. The challenges include annotating the genomes, providing comparative analysis and using informatics development to share the genome variability with the research community.

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From left, Xianghui Xiao, Yang Yang, and Qun Liu Photo by David Rahner/BNL
From left, Yang Yang, Qun Liu and Xianghui Xiao. Photo by David Rahner/BNL
From left, Qun Liu, Yang Yang, and Xianghui Xiao. Photo by David Rahner/BNL
From left, Xianghui Xiao, Qun Liu and Yang Yang. Photo by David Rahner/BNL

By Daniel Dunaief

Superman’s x-ray and heat vision illustrate an important problem.  On the one hand, the x-ray vision comes in handy if Superman is looking outside, say, at a bank and can see thieves dressed like the Hamburgler as they try to steal from a vault. On the other hand, Superman has heat vision, which he uses in battles to blow up concrete blocks or tear open a hole in a wall.

But, aside from a few realities getting in the way, the struggle scientists using x-rays to see inside cells contend with tracks with these two abilities.

Researchers would ideally like to use x-rays to see the inner workings of a cell. X-rays can and do act like Superman’s heat vision, causing damage or destroying the cells they are trying to study.

Recently, scientists at Brookhaven National Laboratory, however, figured out how to protect and preserve cells, providing an opportunity to study them without causing damage.

Not only that, but, to extend the fictional metaphor, they used the equivalent of Wonder Twin Powers, combining the structural three-dimensional picture one beamline at the National Synchrotron Lightsource II can produce with the two-dimensional chemical image from another.

After three years of hard work, researchers including Qun Liu, structural biologist; Yang Yang, associate physicist; and Xianghui Xiao, FXI lead beamline scientist, were able to use both beamlines to create a multimodal picture of a cell on different scales and with different information.

“Each beamline can create a full picture, but providing only partial information (structure or chemicals),” Liu said. “The correlative imaging for the same cell using two different beamlines provides a more comprehensive” image.

The key to this proof of concept, Liu explained, was in developing a multi-step process to study the cells.

“The novelty is how we prepared the samples,” said Liu. “We can take the sample from one beamline, move it to a second one, and can collect data from the same orientation. Before this, it was not easy” to put together that kind of information.

In a paper published in the journal Nature Communications Biology, the scientists detailed the cell preparation technique and showcased the results.

The potential application of this technique extends in numerous directions, from finding the way new pathogens attack cells, to understanding the location and site of action of pharmacological agents, to understanding the progression of disease, among other applications.

“Our technique combines both X-ray fluorescence and X-ray nano-tomography so we can study the entire cell for both the elements and the structure correlatively,” Yang explained.

Supported by the Department of Energy Biopreparedness Initiative, the scientists are doing basic research and developing techniques and protocols and procedures in preparation for the next pandemic. They have 10 projects covering different pathogens and aspects. Liu is the principal investigator leading one of them. 

To be sure, at this point, the technique for preserving and studying cells with these beamlines is in an early stage and is not available to labs, doctors, or hospitals on a routine basis to test biological samples.

Nonetheless, the approach at BNL offers an important potential direction for clinical and fundamental benefits. Clinically, it can help with disease diagnosis, while it can also be used to study stresses of cells and tissues under metal deficiency or toxicity. Many cancers include a malfunction in the homeostasis, including zinc, copper and iron.

Fixing and re-fixing

The process of preparing the samples required three steps.

The researchers started with a chemical fixation with paraformaldehyde to preserve the structure of the cell. They then used a robot that rapidly froze the sample by plunging it into liquid ethane and then transferring it to liquid nitrogen.

They freeze-dried the cells to turn the water into ice that is not crystallized. As a part of that process, they left the cells in a controlled vacuum to turn the ice slowly into gas. Removing water is key because the liquid would otherwise be too mobile for x-rays to measure anything reliably. After absorbing the x-rays, the liquid would heat up and further deform the cells.

The preparation work takes one to two days.

“If you fail in any of the steps, you have to start all over again,” said Yang.

Zihan Lin, who is a postdoctoral researcher in Liu’s lab and the first author on the paper, spent more than a year polishing and preparing the technique.

“We believe the cells were preserved [near] their close-to-native status,” said Yang.

They used an X-ray computed tomography (XCT) beamline, which provides a three-dimensional view of the structure of the cell. They also placed the samples in an X-ray fluorescence beamline (XRF), which provided a two-dimensional view of the same cells.

In the XRF beamline, scientists can find where trace elements are located inside a cell.

Liu is collaborating with researchers at other labs to understand the molecular interactions between sorghum, an important grain crop, and the fungus Colletotrichum sublineola, which can damage the leaves of the plant.

The DOE funded project is a collaboration between BNL and three other national laboratories.

Liu is grateful for the help and support he and the team received from the staff working at both beamlines, as well as from the biology department, NSLS-II, BNL, and DOE. The imaging may help create bioenergy crops with more biomass and less disease-caused yield loss, he suggested.

Future work

Current and ongoing work is focused on the potential physiological states of the cell, addressing questions such as why metals are going to specific areas.

Yang is the science lead for a team developing the Quantitative Cellular Tomography beamline at the NSLS-II. Within five years, this beamline will provide nanoscale resolution of frozen cells without requiring chemical fixation.

This beamline, which will have a light epi-fluorescence microscope, will add more detail about sub-cellular structure and will not require frozen cells to have chemical fixation.

While the proof of concept approach with these beamlines is still relatively new, Yang said she has received feedback from scientists interested in its potential.

“We have quite a few people from biology departments that are interested in this technique” to study biomass related structures, she said.

A future research direction could also involve seeing living cells. The resolution would be compromised, as the X-rays would induce changes that make it hard to separate biological processes from artifacts.

“This could be a very good research direction,” Liu added.

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