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Power of 3

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Rob Martienssen with Nobel Prize winning scientist Barbara McClintock in 1990. Photo by Tim Mulligan, CSHL

By Daniel Dunaief

Cells, like the organisms they are a part of, are trying to balance between staying the same and making the kind of changes that might save a life or increase fitness.

At the cellular level, pieces of important genetic information, called small RNA, have the ability to introduce important so-called epigenetic changes. These alterations allow an individual to survive a potential threat, such as a disease or a toxin in the environment, without altering their DNA.

In a recent publication in the journal Nature Structural & Molecular Biology, scientists at Cold Spring Harbor Laboratory and the University of Cambridge demonstrated that a slightly altered form of uridine, which is a combination of the base uracil and ribosome, can act as something of a master key throughout nature.

“When you see something like that conserved in plants and animals, it has to be basic in terms of inheritance or mechanisms,” said Rob Martienssen, a Howard Hughes Medical Institute Investigator who has been at CSHL since 1989.

Indeed, pseudouridine guides epigenetic inheritance, which, unlike a mutation, can represent a temporary change in gene function.

Pseudouridine helps transport small RNAs into reproductive cells in both plants and mammals.

Without pseudouridine, these small RNAs that lead to epigenetic changes can become the target of the body’s immune system, which reacts to anything that introduces changes into the genetic machinery as a potential threat, such as a virus.

The body’s Rig-1 pathway, which monitors the extracellular space for foreign genetic material, triggers a cascade of reactions that lead to the release of interferon by white blood cells.

“We think a conserved protein called RTL1 might provide this function in plants (and animals),” explained Martienssen.

Pseudouridine can signal to the body that these genetic codes that are heading towards the nucleus are “self,” keeping the immune system’s reaction at bay.

“It is known that pseudouridine (and other RNA modification) prevent recognition of long RNA as a virus by human cells and we think the same is true in plants,” Martienssen said.

Some viruses have effectively slipped behind the immune defenses by incorporating pseudouridine into their codes. The most famous example of this, Martienssen suggested, is the Human Immunodeficiency Virus, or HIV.

Parasitic nematodes and plants also transfer small RNA into the plants they are parasitizing.

Martienssen speculates that those RNA depend on pseudouridine. In his current experiments, he is testing that hypothesis.

Vaccinations

The immune system initially treated the developing mRNA vaccines that were so instrumental in providing an immune defense against COVID-19 as a viral threat, rather than a potential life-saving shot.

A strong immune response prevented the vaccine from providing any benefit.

By adding pseudouridine, among other chemical modifications, to the mix, the pharmaceutical companies created vaccines that functioned effectively without triggering an immune reaction that would otherwise block their effectiveness.

By contributing to a filter that evades immune detection, pseudouridine can also enable the kinds of epigenetic changes — apart and aside from human intervention — that contribute to survival during challenging conditions.

Small RNA that contains pseudouridine can induce epigenetic changes that might be caused by the environment or some disease, enabling an important alteration in the genetic code that could protect an individual against harm.

Martienssen and his team believe pseudourilyation is required to get into the germ line, the cells that are a part of contributing to the next generation. He believes pseudourilyation might also make the germ line more stable.

Martienssen’s collaborator from Cambridge, Tony Kouzarides, independently found pseudouridine in mouse small RNA.

Shorter term changes

As for the long term impact of these changes, epigenetic inheritance typically only lasts a half a dozen generations in animals like worms.

Well known enzymes, such as demethylases, can remove epigenetic marks over time, as several mechanisms are trying to “clean up” the genome before these changes become permanent.

Lower organisms, such as fungi, can become epigenetically resistant to drugs. Epigenetics gives them a lot more variation than they would otherwise have had under natural selection.

An example includes cryptococcus, an infection that can be deadly for immunocompromised people, Martienssen explained.

About five percent of the bases in ribosomal RNA are pseudouridine and 100 percent of ribosomal RNA molecules have these bases rather than uridine at these locations.

Martienssen interfered with the process in his experiments by knocking out an exportin, which is a protein required to export small RNAs. He was able to knock it out without killing the plant.

English origins

Martienssen grew up in Essex, England by the Blackwater estuary near Maldon, which is famous for its sea salt.

Martienssen lived his childhood close to London. Long Island and New York City remind him of home.

When he was eight years old, his father Anthony Kenneth Martienssen gave him the book “The Double Helix’ by former CSHL chair and Nobel Prize winner James Watson.

Martienssen’s father was an author and an aviation consultant who pioneered computer guided air traffic control, his son said. The family recently reprinted some of his father’s books from 50 to 75 years ago.

When he arrived at CSHL, Martienssen worked with Nobel Prize winner Barbara McClintock, who studied transposable genetic elements.

“She showed me how to isolate male germline cells (pollen precursors) from maize plants,” Martienssen recalled. “She told me not to make models, but to stick to the observations.”

McClintock’s earlier models had been more accurate than she realized at the time, he said.

As for his study of epigenetics, Martienssen explained that such alterations are “amazingly useful” in theory, as they can “be induced in many individuals at the same time (random mutations would only occur in one individual at a time), inherited, but then reversed when conditions change.”

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METRO photo

By Daniel Dunaief

Smartphones are an attractive nuisance not just during family time, when parents might otherwise struggle to see anything other than the top of the heads of their children, but also during school.

Lauren Hale. Photo courtesy of Stony Brook Medicine

In a recent research letter published in JAMA Pediatrics, scientists led by Lauren Hale, Professor in the Department of Family, Population and Preventive Medicine at Stony Brook University, found in a study of 117 students from the ages of 13 to 18 that smartphone use during school hours typically consumed an average of about 1.5 hours. That’s about 23 percent of a typical school day.

“School time should be a time for being present,” said Hale. It should involve interacting with peers and learning from teachers. “When a quarter of your day is spent with your finger on the phone” students are missing opportunities for academic and social growth.

The study, which was funded by the Della Pietra Family Foundation, comes as Governor Kathy Hochul (D) has unveiled a plan to restrict cell phone use during the day for students from kindergarten through 12th grade. 

The governor’s plan allocates $13.5 million for pouches, cubbies and other storage devices and comes as other states and countries seek to limit the kinds of distractions that diminish learning and that prevent face-to-face social interactions.

The JAMA study “really does underscore the need to help children reduce their screen time, both at school and at home,” said Kris Perry, Executive Director of Children and Screens: Institute of Digital Media and Child Development.

At this moment, “we are seeing a crisis in childhood that is highly correlated with the introduction of the smartphone and social media platforms,” Perry added.

In the JAMA Pediatrics study, the researchers found that a quarter of the participants spent more than two hours on their phone during school.

The top five most used apps or categories, other than internet browsing, were messaging, Instagram, video streaming, audio and email.

The study may underestimate the amount of time typical students spend on their phones, in part because the participants in the research knew that their phone use was being tracked.

Study design

The students in the study, who were divided almost equally between boys and girls and who came from a representative sampling of different backgrounds, completed a 15-minute smartphone-based survey and installed RealityMeter to measure their smartphone use.

The researchers examined data from these students, whose phones sent signals throughout the day about the time they are using the phone.

The average number of hours these students were on their phones during the day was 5.59, which excludes other electronic devices such as video games, desktop computers or laptops.

To be sure, the survey didn’t analyze the times during the day that these students were on their phones. Some of these participants, for example, could have used their smartphones during their lunch or free periods rather than during calculus classes or lectures about American History, French or any other subject.

“We didn’t have the granularity of each student’s schedule to know” when the phone usage was the highest, Hale said.

Still, using the phone instead of interacting directly with students in the room, at a lunch table, or in a hallway is a “missed opportunity for eye-to-eye contact in real life,” said Hale.

In the study, about 22 percent of the participants indicated that their parents restricted their phone use when they are at home.

The data for this group during school tracks, however, closely with the students who said they didn’t have any such similar phone restrictions at home. The study also compared phone usage for students whose parents attended college with those who didn’t attend or finish college.

The children of college graduates used the phone about 30 minutes less per school day.

Combination of factors

Several factors may have contributed to any potential increase in the use of smartphones in school.

During the Covid-19 pandemic, the lockdown and remote learning, students relied on technology to log in to their classrooms. Adolescents who couldn’t interact with each other in person also spent considerable time texting and interacting with each other on social media.

Additionally, various apps have enhanced their platforms to encourage users to stay on them for longer periods of time.

“The algorithms know that I like Shih Tzus, so I keep getting reels for tiny white dogs doing tricks,” said Hale. “If they put up cats, I wouldn’t watch.”

The same is true for adolescents, who see sports clips or other content regularly that compels them to stay online and that may interfere with their ability to learn in class or to socialize with people around them. 

These apps and the devices adolescents use could provide information about usage patterns.

“I would love to see social media platforms share more information,” said Hale.

Perry added that parents act as important role models for their children when it comes to screen time. “What you’re modeling is going to be replicated,” she said. “Things that adults do without thinking, their children are copying.”

Next steps

Hale indicated that the research team has just finished collecting a second wave of data on the same participants. The scientists will be following up to see screen use patterns as well as any observed changes in mental health and physical well being.

The recent work published in JAMA Pediatrics is a “descriptive baseline” of smartphone usage in school, said Hale. She suggested that researchers need to conduct further research to understand the impact of phone usage patterns on education. “We need replication in science” to uncover more details over a larger population for smartphone use.

Like Gov. Hochul and others who have focused on this issue, Hale believes these personal electronics may hinder the learning process.

“I’m concerned about kids losing precious school hours to distracting devices,” Hale said. When students go to school, they should “be ready for learning and social time. That’s what’s going to make a difference in their education.”

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These composite brain images from the study of WTC responders reveal evidence of amyloidosis. Areas shaded in red and yellow indicate regions of the brain with amyloid. Image courtesy of Sean Clouston, Stony Brook Medicine

By Daniel Dunaief

Even over 23 years after first responders raced to the smoldering site of the World Trade Center terrorist attacks, many emergency crews continue to battle the effects of their exposure.

With a combination of toxic aerosolized particles infusing the air, first responders who didn’t wear personal protective equipment and who had the highest degree of exposure have suffered from a range of symptoms and conditions.

Sean Clouston

In a recent study of 35 World Trade Center first responders in the Journal of Alzheimer’s Disease, lead author Sean Clouston, who is a Professor in the Department of Family, Population and Preventive Medicine in the Renaissance School of Medicine, found evidence of amyloid plaques, which are often linked to Alzheimer’s Disease.

The paper links exposure to a neurodegenerative protein.

Research with World Trade Center first responders not only benefits those who worked tirelessly to try to find survivors and to restore the area after the attack, but also could help other people who inhale aerosolized toxins.

Indeed, such research could help those who are spending hours battling the ongoing wildfires in Los Angeles, which have been consuming forests and trees, homes and commercial buildings, at a furious and uncontrolled pace.

People have a feeling that fresh air is safe, but what scientists have learned from their studies of the World Trade Center first responders is that “just being six feet away from a pile of rubble that’s smoldering, even if you can’t see that it’s dangerous, doesn’t mean it isn’t,” said Clouston. “There is at least some risk” to human health from fires that spew smoke from burned computers and refrigerators, among others.

Given the variety of materials burned in the fires, Minos Kritikos, Senior Research Scientist and a member of the group in the collaborative labs of Clouston and Professor Benjamin Luft, suspects that a heterogeneity of particles were in the air.

People in Los Angeles who are inhaling these particles can have them “linger in their circulation for years,” said Kritikos. “It’s not just a neurological issue” as the body tries to deal with carrying around this “noxious” particulate matter. Since most neurons don’t regenerate, any toxicity induced neuronal death is irreversible, making damage to the brain permanent.

Even in non-emergency situations, people in polluted cities face increased health risks.

“There is a recognition that air pollution is a major preventable cause of Alzheimer’s Disease and related dementias, as noted by the latest Lancet Commission,” Clouston explained.

Two likely entry points

People who breathe in air containing toxic chemicals have two likely pathways through which the particulates enter the body. They can come in through the nose and, potentially, travel directly into the brain, or they can enter the lungs, circulate through the body and enter the head through the blood-brain barrier. The olfactory route is more direct, said Kritikos. 

Minos Kritikos in front of Stony Brook Hospital.

The amyloid plaques in these first responders was found primarily in the area near the nose, which supports the idea that maybe inhaling the dust was the problem, Clouston said.

Once these chemicals enter the brain, Clouston and his team believe the body engages defenses that are designed much more for viruses than for toxic compounds. The immune system can encapsulate these chemicals in amyloid plaques.

Amyloid plaques, in moderation and under conditions that protect the brain against pathogens, are a part of a protective and helpful immune response. Too much of a good thing, however, can overwhelm the brain.

“When there’s too much plaque, it can physically disturb neuronal functions and connections,” said Kritikos. “By being a big presence, they can also molecularly and chemically react with its environment.”

A large presence of amyloid can be toxically necrotic to surrounding neural tissue, Kritikos added.

What the scientists believe they are tracking is the footprint of an adaptive response that may not help the brain, Clouston added.

Clouston cautioned that the plaques and cognitive decline could both be caused by something else that scientists haven’t yet seen.

The findings

The research, which used positron emission tomography and magnetic resonance imaging scans to search for evidence of amyloid plaques, found evidence that doesn’t look like old age Alzheimer’s, explained Clouston. Usually these levels of plaques are not located in one spot, but occur throughout the brain during Alzheimer’s. 

The immune response may be causing some of these plaques.

The amount of amyloid plaque doesn’t look like Alzheimer’s Disease and does not appear abnormal in the traditional way of testing, but with careful analysis of the olfactory system, the researchers can find elevated levels.

“I was surprised by how little amyloid was necessary to show this association,” said Clouston.

Researchers at Mt. Sinai have examined the effect of exposure to these same particulates in mice.

“The answer is very much similar to what we see in humans,” said Clouston. “That supports this work.”

To be sure, Clouston and Kritikos are hoping to build on this research. They are particularly interested in following up with participants to measure the rate of change in these plaques from the observed amyloid signals they measured at baseline.

“Doing so would enable us to calculate the rate of amyloid buildup allowing us to assess our responders more precisely, opening doors to possible therapeutic interventions such as the recently approved anti-amyloid therapies,” Kritikos explained. 

Additionally, they hope to expand on the study beyond the 35 people who participated.

It is unclear whether tamping down the immune system could make patients better or worse. By reducing amyloid plaques, scientists might enable the harmful dust to cause damage in other areas of the brain. Alternatively, however, a lower level immune response with fewer plaques might, in the longer term, be better for the brain.

This study “does open the door for some of those questions,” Clouston said. Kritikos and Clouston plan to study the presence of tau proteins and any signs of neurodegeneration in the brains of these first responders.

“More research needs to be done,” Clouston said, which specifically targets different ways of measuring exposure, such as through a biomarker. He’s hoping such a biomarker might be found that tracks levels of exposure.

Future research could also address whether post traumatic stress disorder affects the immune response.

“It’s certainly possible that PTSD is playing a role, but we’re not sure what that might be,” said Clouston.

The researchers are continuing this research as they study the effects of exposure on tau proteins and neurodegeneration.

“We are hopeful that this will be an important turning point for us,” Clouston explained

From the Medditerranean to the Atlantic

Born and raised in Cyprus, Kritikos comes from a large family who are passionate about spending time with each other while eating good food.

He earned his doctorate from the University of Bristol in England.

Kritikos met his wife Jennifer LoPresti Kritikos, who is originally from Shirley, New York, at a coffee shop in Aberdeen, Scotland, where he was doing postdoctoral research.

LoPresti, who works at Stony Brook as the Department Head Administrator for Biomedical Engineering, and Kritikos live in Manorville and have an eight year-old daughter Gia and one-year old son Theseus.

As for his work, Kritikos is grateful for the opportunity to contribute to research with Clouston and Luft, who is the Director of the Stony Brook WTC Health and Wellness Program.

“I’m happy to be in a position whereby our large WTC team (the size of a small village) is constantly pushing forward with our understanding for how these exposures have affected” the brain health of WTC first responders, Kritikos explained. He would like to continue to uncover mechanisms that underly these phenomena, not just for WTC responders but also for similarly exposed populations.

 

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Alexandra Nowlan

By Daniel Dunaief

The DNA Learning Center at Cold Spring Harbor Laboratory doesn’t just provide educational opportunities for students; it can also inspire their teachers.

That was the case for PhD graduate Alexandra Nowlan, who worked in the lab of Professor Stephen Shea.

When Nowlan met her required teaching component at the center as a part of the graduation requirement for her doctorate, she found educating the next generation inspiring.

“It’s very rewarding to get kids excited about science,” said Nowlan.

Alexandra Nowlan giving a talk at CSHL. Photo from Constance Brukin

Indeed, Nowlan, who did her postdoctoral work at the University of North Carolina at Chapel Hill in the Bowles Center for Alcohol Studies, has taken a job as assistant teaching professor in the Department of Psychology and Neuroscience at the same institution. She is teaching two neuopsychopharmacology classes and is preparing for an advanced molecular pharmacology class in the fall.

“I was really drawn to outreach opportunities and put more of my focus into teaching,” she said. “The opportunity presented itself, so I jumped at it. I’m having a really good time.”

Established in 1988, the DNA Learning Center was the first site to focus on genetic education for the public, offering classes to students in 5th through 12th grades.

The Learning Center, with sites in five different locations in New York, provides classes and labs for 30,000 students each year.

Amanda McBrien, Assistant Director of the DNA Learning Center, observed Nowlan in action.

“She had a magnetic energy about her,” said McBrien. “She came in and was young, enthusiastic and cool all wrapped into one.”

During a Fun with DNA course in the summer offered in conjunction with Women in Science, Nowlan was the “perfect role model,” McBrien added, who proved to be “utterly approachable” and enthusiastic, making her an engaged presenter.

Students can find information about these classes through the DNA Learning Center and can register for summer courses starting this week.

Recent publication

In addition to her professional journey into teaching, Nowlan recently published the results of a study she conducted in the journal Current Biology based on research conducted at CSHL.

Working with Shea and other scientists who followed her in Shea’s lab, Nowlan studied the way the mouse brain processes sensory signals such as odor and sound as a part of a pup retrieval process.

Important in the behavior of mothers and of surrogates who care for the young, pup retrieval helps ensure that developing mice stay closer to their mothers or caretakers.

“Pup retrieval is one of the most important things for mothers or caregivers,” Shea said in a statement. “It requires the ability to smell and hear the pup. If these things are both important, that may mean they merge somewhere in the brain.”

Indeed, during pup retrieval, neurons from an area of the brain called the basal amygdala carry smell signals to the auditory cortex, which is the brain’s hearing center. The basal amygdala is involved in learning and processing social and emotional signals, linking perception with emotion and social learning.

When Nowlan and others blocked the ability of maternal mice to access smell signals, the mice  didn’t provide their customary parental pup retrieval.

Shea and his lab suspect that what’s reaching the auditory cortex is being filtered through social-emotional signals from basal amygdala neurons.

“We’ve known that pup odor is important,” said Nowlan. “People have eliminated odors and seen deficits.”

Deficits in vocalizations also can affect this behavior.

“The pathway that would allow olfactory signals to reach the auditory cortex was unknown and we’ve identified a pathway that is functionally capable of linking those two senses,” Nowlan explained.

A winding path

Nowlan, who grew up in Williamstown, Massachusetts, played rugby in college at the University of Massachusetts at Amherst. While three concussions encouraged her to search for a non-contact sport, it also piqued her interest in neurology.

After she graduated, she worked for four years in the laboratory of Sandeep Robert Datta at Harvard Medical School, where she learned about the importance of the olfactory system.

At the Datta lab, she worked with then postdoctoral researcher Paul Greer, who let a flier on her desk about Cold Spring Harbor Laboratory’s graduate program.

“The umbrella program appealed to me,” she said. “You could get an education not only in the subject you’re interested in but you also had an opportunity to learn about cancer biology and plant genetics, which was exciting.”

Nowlan attended courses and meetings, interacting with top scientists across a range of fields.

The first year she lived in a house on campus near the water, where she and her fellow graduate students could see the lights of all the buildings at night.

“My classmates and I felt like we were at Hogwarts, this magical science camp,” she said.

Postdoctoral transition

When she was writing her PhD thesis, Nowlan became interested in motivated behaviors.

She had been following reports about the opioid epidemic and knew it was affecting Berkshire County, where she grew up.

She was curious about how opioid use disrupted noradrenaline signaling, which plays an important role in motivation, rewarding and the body’s stress response.

“I wanted to explore how these motivational circuits can get disrupted in examples where drugs that are commonly misused are involved,” she said.

She and others in the lab of Zoe McElligott at the Bowles Center were trying to understand various brain circuits as people undergo the painful experience of addiction withdrawal.

More information about these processes could reduce the negative experience and lead to better and perhaps more effective treatments.

Born on the same day

Nowlan met her husband Craig Jones, a Long Island native, through a dating app.

“I joked when we first met that the algorithm” from the app that brought them together was lazy, she said. They were both born on the same day, just hours apart.

Jones, who works as a user experience designer for fitness company Zwift, is “older and he won’t let me forget it,” said Nowlan.

As for her current teaching role, Nowlan is hoping to emulate the inspirational approach of Enrique Peacock-López, a college professor at nearby Williams College. In addition to coaching a soccer team with his daughter and Nowlan, Enrique-López took time to share chemistry demonstrations in primary school and to bring high school students into his lab.

Nowlan appreciated how Peacock-López connected with students.

“The way he made science exciting and accessible to members of the community is really inspiring,” said Nowlan.

Peacock-López has known Nowlan for decades.

“There’s a lot of satisfaction that I may have contributed a little bit with my grain of salt in their careers,” said Peacock-López. When he teaches, he seeks ways to motivate students to solve problems.

For younger children as a starter experiment, he works with reagents that reveal considerable color or that has fumes.

“They love to hear sounds or see colors,” he said.

Peacock-López’s advice to future teachers is to “interact with students” and get to know them.

A native of Mexico, he promised himself when he started teaching that he would treat students the way he would want to be treated.

As for Nowlan, she is eager to continue the teaching tradition.

“It makes me want to keep giving back and provide opportunities to educate the public about what we’re doing and why it’s interesting and important,” Nowlan said. 

Her goal is to educate the next generation of neuroscientists and curious community members about how discoveries made in the lab are translated into treatments for disease.

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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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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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