Science & Technology

Veronica Sanders. Photo from BNL

By Daniel Dunaief

If doctors could somehow stick numerous miniature flashlights in human bodies and see beneficial or harmful reactions, they would be able to diagnose and treat people who came into their offices.

That’s what Vanessa Sanders, Assistant Scientist at Brookhaven National Laboratory, is working to develop, although instead of using a flashlight, she and her colleagues are using radioisotopes of elements like arsenic. Yes, arsenic, the same element at the center of numerous murder mysteries, has helpful properties and, at low enough concentrations, doesn’t present health threats or problems.

Arsenic 72 is useful in the field of theranostics, which, as the name suggests, is a combination of therapeutics and diagnostics.

Isotopes “allow us to observe visual defects and through using these radioactive agents, we can also observe the functionality of organs,” Sanders explained in an email. These agents can assist in diagnosing people, which can inform the treatment for patients.

What makes arsenic 72 and other radioisotopes helpful is that they have a longer half-life than other isotopes, like fluorine 18, which only lasts for several minutes before it decays. Arsenic-72 has a half life of 26 hours, which matches with the life of an antibody, which circulates through bodies, searching for targets for the immune system. The combination of arsenic-72 and arsenic-77 allows the former to act as a diagnostic agent and the later as a therapeutic partner.

By attaching this radioisotope to antibodies of interest, scientists and doctors can use the decay of the element as a homing device. Using Positron Emission Tomography, agents allow for the reconstruction of images based on the location of detected events.

“When you want to use an antibody as a target for imaging, you want an isotope that will be able to ride with the antibody and accumulate at an area of interest,” Sanders said.

A radiochemist, Sanders is working to develop systems that help researchers and doctors diagnose the extent of problems, while also tracking progress in fighting against diseases. She is working to produce arsenic-72 through the decay of selenium-72.

Using the Brookhaven Linac Isotope Producer, scientists produce selenium-72. They then create a generator system where the selenium 72 is absorbed onto a solid substrate. As it decays, the solid substrate is washed to obtain arsenic-72.

Sanders is hoping to create a device that researchers could ship to clinical institutions where institutions could use arsenic-72 in further applications.

The system BNL is creating is a research and development project. Sanders and her colleagues are working to optimize the process of producing selenium-72 and evaluating how well the selenium, which has a half life of eight days, is retained and how much they can load onto generators.

“We want [arsenic 72] in a form that can easily go into future formulations,” Sanders said. “When we rinse it off that column, we hope to quickly use it and attach it to biomolecules, antibodies or proteins and use it in a biological system.”

With the increasing prevalence of personalized approaches to diseases, Sanders explained that the goal with these diagnostic tools is to differentiate the specific subtype.

A person with pancreatic cancer, for example, might present a specific target in high yield, while another patient might have the same stage cancer without the same high yield target.

“We want to have different varieties or different options of these diagnostic tools to be able to tailor it to the individual patient,” explained Sanders.

Cathy Cutler, Director of the Medical Isotope Program at BNL, said the isotopes Sanders is working on “have a lot of promise” and are “novel.” She described Sanders as “very organized” and “very much a go-getter.”

Cutler said the department feels “very lucky to get her and have her in the program.”

In her group, Sanders explained that she and her colleagues are eager to develop as many radioisotopes as possible to attach them to biomolecules, which will enable them to evaluate disease models under different scenarios. Other researchers are working with arsenic-77, which acts as a therapeutic agent because it emits a different particle.

Scientists are working on a combination of radioisotopes that can incorporate diagnostic and therapeutic particles. When the arsenic 77 destroys the cells by breaking the DNA genetic code, researchers could still observe a reduction in a tumor size. Depending on the disease type and the receptor targeted, scientists could notice a change by observing less signal.

Sanders is working on attaching several radioisotopes to biomolecules and evaluating them to see how well they are produced and separated.

“We make sure [the isotope] attaches to the thing it’s supposed to stick to” such as an antibody, she said.

A resident of Sound Beach, Sanders grew up in Cocoa, which is in central Florida. When she was younger, she wanted to be a trauma surgeon, but she transitioned to radioisotopes when she was in college at Florida Memorial University. “I liked the problem solving aspect of chemistry,” she said. While she works with cancer, she said she would like to investigate neurological diseases as well.

Sanders, who has been living on Long Island since 2017 when she started her post doctoral work at BNL, enjoys the quieter, suburban similarities between the island and her earlier life in Florida.

At six feet, one and a half inches tall, Sanders enjoys playing center on basketball teams and, prior to the pandemic, had been part of several adult leagues in the city and on Long Island, including Ladies Who Hoop and LI Hoops. She is also involved in a sorority, Zeta Phi Beta Sorority Inc, that contributes to community service efforts.

Sanders and her fiancee Joshua Morancie, who works in IT support, had planned to get married in July. They set a new date in the same month next year. If the pandemic continues to derail their party plans next year, the couple plan to wed in a smaller ceremony.

As for radioisotopes, Sanders hopes people become inspired by the opportunities radioisotopes provide for science and medicine.

“There are so many good things that come out of radioisotopes,” Sanders said. “There are so many promising advantages.”

From left, Kamazima Lwiza aboard the hospital ship Jubilee Hope which is owned by a British NGO known as Vine Trust and provides services to several islands on Lake Victoria with Deogratias Kabogo, Chief Engineer of the ship. Photo by Pascal Ferdinand

By Daniel Dunaief

In tropical and subtropical countries, including Brazil and the Ivory Coast, a parasite moves from snails to humans, causing 220 million illnesses a year and as many as 200,000 annual deaths.

People contract the parasite when they enter shallow, warm waters, where the schistosomiasis larvae known as cercariae enters through the skin, moves through the blood stream and settles near the stomach or bladder.

Once it’s near the bladder, the parasite reproduces, sending its eggs out through urine or feces, which, if directed towards warm, shallow water bodies, can enter the snail and begin the process again.

Schistosomiasis causes anemia, malnutrition and learning difficulties, according to the Centers for Disease Control and Prevention, as the parasite robs humans of zinc and vitamins A and D. Prolonged infection can also cause bladder cancer.

Kamazima Lwiza, Associate Professor at the School of Marine and Atmospheric Sciences at Stony Brook University, is part of a new, five-year study on the effects of climate change on schistosomiasis.

Lwiza’s part of the research, which is lead by Stanford University and involves several institutions, is analyzing the latest Global Climate Models known as Coupled Model Intercomparison Project phase 6 results. Lwiza studies the models under four-kilometer resolution to look for patterns and trends.

By creating a model that predicts temperature changes, Lwiza’s part of the efforts hope to help other collaborators apply those temperature expectations to epidemiological models. The ability of the parasite to survive, reproduce and infect humans depends on the viability of the snails, which are temperature sensitive. The temperature range is between 14 and 35 degrees Celsius, with an optimal temperature of between 30 and 32 degrees Celsius.

A warmer climate would likely increase the prevalence of schistosomiasis in the regions of Brazil and the Ivory Coast that this study is exploring, as well as in newer areas.

Kamazima Lwiza prepared instruments before installation aboard the hospital ship Jubilee Hope, which is owned by a British NGO known as Vine Trust and provides services to several islands on Lake Victoria. Photo by Pascal Ferdinand

Depending on the regional topography, human population and amount of rainfall, the area that is conducive to Schistosomiasis could expand. An area that is relatively flat and where rainfall increases and human population is low but increasing could cause the infection rate to climb.

As waterways that were too cold either reach the minimum temperature threshold for snails, or increase the temperature into the optimal range, snail populations are likely to flourish.

Part of the funding for the SoMAS portion of the study is coming from the National Science Foundation and the National Oceanic and Atmospheric Administration. These national funding agencies recognize that increasing temperature and land use has created an environment that fosters the expansion of snails and increased prevalence of parasites into areas in the southern United States.

“Given the climate change,[some parts of Florida and Georgia] will be falling within that temperature range,” Lwiza said. “The worry is that, if this disease is going to spread, how are we going to be prepared to keep it off.”

Lwiza had originally planned to travel to Brazil this past summer to collect baseline data on water temperatures. The pandemic caused him to cancel his travel. Next year, he hopes to build on data around significant water bodies where the disease is prevalent.

While the portion of the study that includes Lwiza focuses on temperature, the Stony Brook scientist is working with other researchers who are exploring a range of other analytical and mitigation measures.

For starters, in some countries that have battled against this parasite, the use of dams has exacerbated the problem. Dams have kept out prawns, who are natural predators for snails.

Scientists are considering reintroducing prawns. These shellfish, which look somewhat like shrimp, could not only reduce the population of snails and the parasites they carry, but could also become an economic boon, as a part of an aquaculture project.

The goal of that part of the study is to “see if [prawns] can be used as biological control agents,” Lwiza said. “If we can find a way of introducing these back to where they used to be, we can cut down the snail population.”

The third aspect of the study involves the use of artificial intelligence. Researchers are putting together a program that will allow people to take pictures of the parasites they find and upload them to a web site to identify them.

“That way, we are doing crowd sourcing” which will allow “people to contribute to our investigation,” Lwiza said. Researchers will be able to map the location of the parasites.

Lwiza said Schistosomiasis can affect anyone who goes in the water. The illness doesn’t get as much attention as malaria. When people go to a rural clinic, if they have malaria, they can get medicines from 20 vendors. A person with Schistosomiasis, however, may need to go to a district or regional hospital for medication.

Originally from Tanzania, Lwiza grew up on the western shores of Lake Victoria, where strong waves don’t favor the development of snails. He currently lives in East Northport with his wife Catherine Kentuha, who works in the United Nations Development Program. The couple has three children — Philip, Johnathan and Mulokozi.

Lwiza has worked at Stony Brook University for 29 years and has lived in Port Jefferson Village and East Setauket.

When he lived in Port Jefferson Village, he was pleased and surprised by how his neighbors brought him candles during a brown out and made sure he and his family were okay.

“It was like, ‘Wow, this is really great. This is like Africa,’” he recalls thinking.

When he’s not working, Lwiza enjoys riding a bike and listening to Indian, Arab, African and Latin music. He is also interested in computer programming.

As this study of Schistosomiasis progresses, Lwiza hopes the incidence of disease decreases and that the science helps protect the population against a widespread illness.

At an Oct. 19 press conference announcing a new study to help youth in Paterson, New Jersey, from left, Paterson Mayor André Sayegh; Antoine Lovell; Director of Paterson Youth Services Bureau Christina Barnes Lee; Ijeoma Opara; Program Coordinator at Municipal Alliance Prevention Program Tenee Joyner; Councilman Luis Velez and Chief Operating Officer of OASIS Paterson Jim Walsh. Photo from Ijeoma Opara

By Daniel Dunaief

Stony Brook University’s Ijeoma Opara, a new Assistant Professor in the School of Social Welfare, is starting her promising early scientific career by making history, becoming the first social worker to receive an Early Independence Award from the National Institutes of Health.

Opara, who hopes the award opens doors to other social workers and to other scientists of color, plans to use the funds to create a research study and intervention program that will make a difference.

Opara will study the link between mental heath and substance abuse in Paterson, New Jersey, where she conducted her PhD training while attending Montclair State University and where she hopes to help youth who may not attend school often enough to benefit from programs in academic settings. She also hopes to understand issues that youth may be facing that lead to substance abuse and poor mental health.

Opara plans to use the $1.84 million, five-year grant to conduct venue-based sampling, where she will search for at-risk youth and where she can tailor mental health and substance abuse questions that are relevant to the experience of the children she hopes to help.

“A lot of youth that needed these services, who had substance abuse and serious issues with mental health, weren’t going to school,” said Opara. “They weren’t in locations [where] a lot of researchers collect data.”

It didn’t make sense to collect the survey information from students in school when the people who need these services are not present in the system. “Meeting them where they are to figure out how to get them engaged” became a critical element to conceptualizing this study, said Opara. “There is no such thing as hard-to-reach populations.”

The NIH award Opara received encourages young researchers who recently completed their graduate work to engage in high-risk, high-return studies.

The risk in Opara’s work is that she won’t be able to recruit enough youth. She is, however, is convinced that her past experience in Paterson, a city filled with communities she’s grown to love, will enable her to find and reach out to targeted youth.

She’s currently in the first phase of her two-part effort; finding staff, figuring out ways to find people for her studies and designing questions relevant to them and their lives. In the second part of her research, she plans to provide mental health and substance abuse services.

Michelle Ballan, Associate Dean for Research in the School of Social Welfare, applauded Opara’s approach to her research.

“Venue-based sampling takes considerable work,” Ballan said. “It’s much easier to send a survey to schools.”

Indeed, this kind of effort “takes time, manpower and a tremendous understanding of how [Opara’s] inter-disciplinary focus is intertwined,” Ballan said. “She’s a family studies researcher, a social worker, and a public health researcher. Having those three areas of expertise, it’s not surprising that venue-based sampling was the one she chose.”

Opara is turning to some of the leaders in Paterson to advise her during this effort. She has created a community advisory board that represents youth and includes community leaders.

One of the challenges this year is that some of the sites where these youth might typically congregate may have fewer people during the pandemic. “It’s something we’re really focusing on in our first couple of meetings: where are the youth going?” Opara asked. She suggested sites could include basketball courts and parks. She is also exploring ways to recruit youth (between ages 13 and 21) online.

Opara is hoping to understand how the environment may impact people in the community as either a protective or a risk factor for substance abuse and mental health.

“What are some structures that could be serving as a protective buffer for kids who aren’t engaging in substance abuse and who don’t have negative mental health symptoms?” she asked.

On the other hand, she would like to identify those buildings or features that increase the trauma or risk and that might cause youth to mask their symptoms.

Once she finds these at-risk youths, Opara will ask about drug and alcohol use, lifetime drug use, their feelings about mental health and their levels of anxiety and depression. She also expects to ask about suicidal ideation.

When she understands the challenges and stressors, she hopes to create a culturally relevant, community based and neighborhood focused intervention. For this to work, she plans to recruit some of the people involved in the study to inform these solutions.

Opara is determined to make a difference for the city of Paterson.

“I don’t want to leave the community with nothing,” she said. “I don’t want to come in, collect data and leave. It’s important to create a sustainable change” that will “empower the community and empower youth.”

In Paterson, Opara recognizes the diversity of different neighborhoods, with people from different backgrounds, experiences and languages living in different blocks.

As a research assistant at Montclair, Opara said she encountered resistance at efforts to change neighborhoods, particularly when she was involved in programs to reduce the hours when liquor stores were open. She said youth mobilization, which included speaking about their experiences witnessing alcoholism in their neighborhoods, helped encourage the city council to pass the ordinance.

People came from other neighborhoods, bought alcohol, drank until they passed out and created a “really dangerous environment” as youth and teenagers were afraid to walk home past people who were drunk in the streets.

Opara appreciates the support of educators in the Paterson School District and the mayor, André Sayegh. She said her efforts may be particularly important in this environment, as New Jersey has cut funding from school-based youth services amid a declining budget caused by a slowing economy triggered by the pandemic.

If the program Opara creates works, she hopes other researchers can extend it to other communities.

 

By Daniel Dunaief

Noah Strycker once made a bet with a cruise ship full of passengers: if any of them spotted him without binoculars at any point during a 14-day trip, he would buy them all drinks. Even with that incentive, no one won a free drink, in large part because Strycker’s passion for birds means his binoculars are never out of arm’s reach.

A master’s candidate in Heather Lynch’s lab at Stony Brook University, Strycker, who has turned his world travels in search of his feathered friends into books, is working through the second year on Lynch’s specialty: penguins.

As a part of the team, Strycker is contributing to a population analysis of chinstrap penguins. Last year, he ventured to Antarctica with a field team for several months to count colonies of these six-to-ten pound birds.

The “piece de resistance” of that journey was a trip to Elephant Island, which is where, over 100 years earlier, Ernest Shackleton and his crew were marooned for several months before their rescue.

During Strycker’s journey to the famous but uninhabited island, the team counted the number of chinstrap and compared the population to the last known count, which occurred 50 years ago.

They determined that the chinstrap has had a significant decline, in some cases losing more than half its population in some areas. After a survey of Elephant Island and Low Island, the research team suggested that the decline in the chinstrap’s main source of food, krill, likely caused this reduction.

As for this year, Strycker had planned to travel back to Antarctica until the pandemic caused the cancellation of the trip. He is conducting a literature search to find previous chinstrap penguin counts. In the final part of his master’s program, he will help provide an updated assessment for the International Union for the Conservation of Nature.

While the IUCN provides information on threatened or endangered species, Strycker recognizes that the chinstrap won’t likely be on that list. “There are many millions of them,” he explained in a recent interview. “[But] they are declining. We are trying to give the IUCN updated information.”

Lynch’s lab will provide information for IUCN’s green list, which is for species that aren’t endangered. Species on this list might benefit from additional information that could help shape a future conservation strategy.

Strycker, who traveled to 41 countries in 2015 to count as many birds as possible in a year, appreciated and enjoyed his interaction with penguins. These flightless birds have no fear of humans so they waddled up to him and untied his shoelaces. They also fell asleep next to his boot and preened the side of his black wind pants.

Strycker landed in the world of penguins when he was working as a naturalist guide on a cruise ship and met Lynch, whose team was on the same boat.

Lynch was delighted with the chance to add Strycker to her team. “One of the most difficult things about our work is that there is such a steep learning curve for doing Antarctic field research,” Lynch explained in an email. “To grab someone like [Strycker] with so much Antarctic experience under his belt was just fantastic.”

Lynch appreciates how Strycker led the chinstrap survey work, not just in collecting the data but also in analyzing and writing it up. Strycker is “a terrific writer (and very fast, too) and his finesse with writing helped us get our research out for review faster than would normally be possible,” she said.

After seeing and hearing birds around the world, Strycker has an unusual favorite — the turkey vulture. When he was in high school in Eugene, Oregon, Strycker watched a nature documentary with David Attenborough in which the host put rotting meat out in a forest. In no time at all, turkey vultures discovered the feast. “That is the coolest thing I’ve seen,” Strycker recalls thinking.

Months later, he discovered a road kill deer while he was driving. He put the dead animal in the trunk of his ’88 Volvo Sedan and dumped it in his front yard, waiting to see if he could duplicate Attenborough’s feast. Fairly soon, 25 turkey vultures arrived and were sitting on the roof of his house. The neighbors didn’t complain because Strycker grew up on a dead end, 20 acres from the nearest house.

Fortunately for him, his parents didn’t seem too upset, either. “When they realized that their only child had become addicted to birds at a young age, they rolled their eyes and said that there’s much worse things that he could become addicted to,” Strycker recalled.

As for Long Island, Strycker said the area is currently in fall migration season. All the birds that nested in Canada are passing through New York on their way to spend the winter in warmer climates.

The migration patterns typically start with shorebirds in August, transition to warblers in September and to waterfowl, such as ducks and geese, which appear in October and November.

“This fall has also been exciting because several species of northern songbirds have ‘irrupted’ south, so we’re seeing unusually high numbers of them on Long Island,” said Strycker. This month, red-breasted nuthatches, purple finches, and pine siskins have appeared in large numbers, which doesn’t happen every year.

At this time of year, birds sometimes get lost outside their usual range. Last week, a painted redstart, which should be in Arizona, arrived in Floyd Bennett Field in Brooklyn.

“I was out there at dawn the next morning, along with half the birder population of New York, but unfortunately it had already moved on,” said Strycker.

People interested in tracking bird migration by radar can use the website birdcast.info, which can predict bird migration like the weather using radar data. Strycker advises interested birders to type “Stony Brook” into their local Bird Migration Alert tool.

Once he earns his degree, Strycker plans to build on and share his experiences.

He would like to write books, give presentations and “generally inspire the world about birds.”

Partha Mitra at the Shanghai Natural History Museum in China where he was giving a talk to children on how birds learn to sing.

By Daniel Dunaief

Throw a giant, twisted multi-colored ball of yarn on the floor, each strand of which contains several different colored parts. Now, imagine that the yarn, instead of being easy to grasp, has small, thin, short intertwined strings. It would be somewhere between difficult and impossible to tease apart each string.

Instead of holding the strings and looking at each one, you might want to construct a computer program that sorted through the pile.

That’s what Partha Mitra, a professor at Cold Spring Harbor Laboratory, is doing, although he has constructed an artificial intelligence program to look for different parts of neurons, such as axons, dendrites and soma, in high resolution images.

Partha Mitra at the Owl Cafe in Tokyo

Working with two dimensional images which form a three dimensional stock, he and a team of scientists have performed a process called semantic segmentation, in which they delineated all the different neuronal compartments in an image.

Scientists who design machine learning programs generally take two approaches: they either train the machine to learn from data or they tailor them based on prior knowledge. “There is a larger debate going on in the machine learning community,” Mitra said.

His effort attempts to take this puzzle to the next step, which hybridizes the earlier efforts, attempting to learn from the data with some prior knowledge structure built in. “We are moving away from the purely data driven” approach, he explained.

Mitra and his colleagues recently published a paper about their artificial intelligence-driven neuroanatomy work in the journal Nature Machine Intelligence.

For postmortem human brains, one challenge is that few whole-brain light microscopic data sets exist. For those that do exist, the amount of data is large enough to tax available resources.

Indeed, the total amount of storage to study one brain at light microscope resolution is one petabyte of data, which amounts to a million megapixel images.

“We need an automated method,” Mitra said. “We are on the threshold of where we are getting data a cellular resolution of the human brain. You need these techniques” for that discovery. Researchers are on the verge of getting more whole-brain data sets more routinely.

Mitra is interested in the meso-scale architecture, or the way groups of neurons are laid out in the brain. This is the scale at which species-typical structures are visible. Individual cells would show strong variation from one individual to another. At the mesoscale, however, researchers expect the same architecture in brains of different neurotypical individuals of the same species.

Trained as a physicist, Mitra likes the concreteness of the data and the fact that neuroanatomical structure is not as contingent on subtle experimental protocol differences.

He said behavioral and neural activity measurements can depend on how researchers set up their study and appreciates the way anatomy provides physical and architectural maps of brain cells.

The amount of data neuroanatomists have collected exceeds the ability of these specialists to interpret it, in part because of the reduction in cost of storing the information. In 1989, a human brain worth of light microscope data would have cost approximately the entire budget for the National Institutes of Health based on the expense of hard disk storage at the time. Today, Mitra can buy that much data storage every year with a small fraction of his NIH grant.

“There has been a very big change in our ability to store and digitize data,” he said. “What we don’t have is a million neuroanatomists looking at this. The data has exploded in a systematic way. We can’t [interpret and understand] it unaided by the computer.”

Mitra described the work as a “small technical piece of a larger enterprise,” as the group tries to address whether it’s possible to automate what a neuroanatomist does. Through this work, he hopes computers might discover common principals of the anatomy and construction of neurons in the brain.

While the algorithms and artificial intelligence will aid in the process, Mitra doesn’t expect the research to lead to a fully automated process. Rather, this work has the potential to accelerate the process of studying neuroanatomy.

Down the road, this kind of understanding could enable researchers and ultimately health care professionals to compare the architecture and circuitry of brains from people with various diseases or conditions with those of people who aren’t battling any neurological or cognitive issues.

“There’s real potential to looking at” the brains of people who have various challenges, Mitra said.

The paper in Nature Machine Intelligence reflected a couple of years of work that Mitra and others did in parallel with other research pursuits.

A resident of Midtown, Mitra, his wife Tatiana and their seven-year-old daughter have done considerable walking around the city during the pandemic.

The couple created a virtual exhibit for the New York Hall of Science in the Children’s Science Museum in which they described amazing brains. A figurative sculptor, Tatiana provided the artwork for the exhibition.

Mitra, who has been at Cold Spring Harbor Laboratory since 2003, said neuroanatomy has become increasingly popular over the last several years. He would like to enhance the ability of the artificial intelligence program in this field.

“I would like to eliminate the human proofreading,” he said. “We are still actively working on the methodology.”

Using topological methods, Mitra has also traced single neurons. He has published that work through a preprint in bioRxiv.

Above, a Vanderbilt educator conducts science demonstrations for children.

Did you know? The Suffolk County Vanderbilt Museum’s Reichert Planetarium, 180 Little Neck Road, Centerport offers free earth science and astronomy demonstrations all day for young children each Saturday and Sunday from noon to 5 p.m.

Dave Bush, director of the Planetarium, said the demonstrations, which are included in the price of admission, are performed by Vanderbilt educators using science kits.

One demonstration (see photo on right) shows how clouds are created in the atmosphere. A few drops of isopropyl alcohol are placed in a clear soda bottle, and the bottle is pressurized. When the pressure is released, a cloud is formed by condensation.  This shows that clouds can form when the atmospheric pressure is low.

“Although the planetarium theater remains closed, we are happy to be able to share these Earth and space science toolkits with families,” he said. “This is yet another opportunity to explore, learn and have fun while visiting the museum.”

For more information, visit www.vanderbiltmuseum.org.

Photos courtesy of Suffolk County Vanderbilt Museum

Christina Joselevitch

By Daniel Dunaief

Children knock on the door of 1313 Gluto Lane, a favorite house for Halloween. The resident, known for providing coveted confections at a rapid rate, immediately comes to the door, asks no questions about the Halloween costumes that might slow the process down and, with almost super-human speed, dumps candy into open bags and closes the door.

Word spreads about the house on Gluto Lane. Soon, the doorbell rings at a furious pace, with children eager to get the best candy of this difficult year and move on to the next house.

At first, with Trick or Treaters coming at a regular pace, the process works, but then, something goes awry, creepy music begins and the door doesn’t open.

That’s what’s happening in bipolar retinal cells in the goldfish Christina Joselevitch, a Postdoctoral Associate in the Neurobiology and Behavior Department at Stony Brook University’s Renaissance School of Medicine, is studying.

Known for their incredible speed at releasing neurotransmitters stored in circular vesicles, these bipolar retinal cells go through a depression in which they can’t release the neurotransmitter glutamate despite repeated signals for the release of the neurotransmitter.

“When you stimulate those cells very strongly, with two stimuli close apart, they suffer depression,” Joselevitch said. “Nobody knew why, if they’re able to signal constantly, they should suffer from depression.

To be sure, Joselevitch was working with extreme stimulation to probe the limits of the system and understand its underpinnings. This is not necessarily how these cells work. She said the researchers don’t know if retinal neurons experience synaptic depression under normal conditions and what function depression would have in bipolar cell physiology, in vision or in signaling processing in general.

In a recent publication in the Journal of Neuroscience, Joselevitch described at least two processes that contribute to this slowdown, which she describes as the rate limiting steps. The vesicles need to get to the membrane and they need to get ready to mature before they are release. Once vesicles move towards the cell membrane, they don’t immediately fuse and send their neurotransmitter into the synapse between cells. In some cells, such as the retinal photoreceptors and bipolar cells and in hair cells of the ear and lateral line in fish and in cells of the pineal gland, they gather in a ribbon close to calcium entry points.

Scientists have two theories of the ribbon function. The first is that it could act as a conveyor belt and speed up vesicle priming and delivery to the membrane and the second is that it could set a constant pace for vesicle delivery.

Joselevitch’s results suggest that the vesicles attach to the ribbon, where they go through a maturation process. These paired-pulse depressions don’t just occur in fish: they also affect the ability of mammalian cells to respond to a second stimulus.

These cellular phenomena show the limits of the system. Indeed, Joselevitch likened the process to a car that has reached its maximum speed. Pushing down harder or more on the accelerator won’t enable further acceleration.

The impact of this work is “broad,” she said. Studying this process could enable a stronger awareness of the steps in fast-acting processes in the nervous system. Such research could also provide an understanding about processes that go awry in various neurological diseases.

In an email, Professor Lonnie Wollmuth, who is the principal investigator for the Stony Brook lab in which Joselevitch works, described Joselevitch as “invaluable to our on-going efforts to study presynaptic mechanisms in the retina.” He wrote that she was an “outstanding and very careful scientist” who is “passionate” about her research and has served as a mentor for others in the lab.  Joselevitch has been working in Wollmuth’s lab for about 16 months.

Synaptic transmission is fundamental to all brain function, Wollmuth explained. “Changes in the strength of synaptic transmission underlie basic higher order brain functions like learning and memory,” the Stony Brook Professor wrote. Joselevitch’s experiments “reveal mechanisms of presynaptic vesicle release at all synapses and provide novel insights into the processing of vesicles at ribbon synapses.”

Based on Joselevitch’s work, Wollmuth’s lab has submitted a large National Institutes of Health grant to the National Eye Institute to study the molecular components of presynaptic release in the retina. She has also started to integrate her work with Alzheimer’s Disease, as proteins found in that disease disrupt the molecular machinery involved in presynaptic release.

A native of Brazil, Joselevitch has been at Stony Brook University since last July. She is on sabbatical with the University of São Paulo. She is hoping to participate in these studies in New York for a few more years.

She said she was “always a nerd,” and liked to study languages. With varying levels of proficiency, she speaks five languages: Portuguese, English, German, Dutch, and Spanish. At one point, she wanted to be an astronaut, but her mother Carmen dissuaded her from pursuing that interest.

Joselevitch had planned to return to Brazil to see her family in April, but had to cancel that plan because of a travel ban from the COVID-19 pandemic. She said her parents have been “good sports” and her father has bought a smartphone so he can talk through Skype or WhatsApp with his scientist daughter.

Joselevitch enjoys biking, hiking, singing and playing guitar and has been productive during the pandemic, writing papers and proposals. Stony Brook is nominating her work for consideration for the Warren Alpert Distinguished Scholar Award.

Wollmuth wrote that Joselevitch’s research forms “the foundation for future experiments to address the molecular components of vesicle dynamics.” Once they are identified, researchers can modulate and protect them in brain diseases.

Citing author James Joyce, Joselevitch explained her focus on neurons in the fish eye, which, she hopes, may lead to a broader understanding of neurology and disease. When asked why he wrote about Dublin when he could describe other places he’s visited, Joyce responded, “In the particular is contained the universal.”

Jeremy Borniger. Photo from CSHL

By Daniel Dunaief

Much as New Yorkers might want to minimize sleep, even during the pandemic when the need to be active and succeed is hampered by limited options, the body needs rest not only for concentration and focus, but also for the immune system.

Recently, Assistant Professor Jeremy Borniger, who joined Cold Spring Harbor Laboratory in January, collaborated with his former colleagues at Stanford University to publish research in the journal Science Advances that sheds light on the mechanism involved in this linkage.

Doctors and researchers had known for a long time that the release of glucocorticoids like cortisol, a stress hormone, can suppress the ability to fight off an infection. “That happens in people that are chronically stressed, even after surgery,” said Borniger in a recent interview.

A comprehensive understanding of the link between neuronal cells that are active during stress and a compromised immune system could help develop new ways to combat infections. The Stanford-led study provides evidence in a mouse model of the neuronal link between stress-induced insomnia and a weakened immune system.

Ideally, scientists would like to understand the neural pathways involved, which could help them design more targeted approaches for controlling the immune system using natural circuitry, according to Borniger.

Scientists could take similar approaches to the therapies involved with Parkinson’s, depression and obesity to increase or decrease the activity of the immune system in various disease states, instead of relying on a broader drug that hits other targets throughout the body.

In theory, by controlling these neurons, their gene products or their downstream partners, researchers could offer a way to fight off infections caused by stress.

While their studies didn’t look at how to gauge the effect of various types of sleep, such as napping or even higher or lower quality rest, their efforts suggest that sleep can help protect against stress-triggered infections.

The total amount and the structure of sleep play roles in this feedback loop. The variability among people makes any broad categorization about sleep needs difficult, as some people function well with six hours of sleep, while others need closer to eight or nine hours per day.

“Scientists are still working out how the brain keeps track of how much sleep it needs to rest and recover,” Borniger explained. “If we can figure this out, then, in principle, we could mess with the amount of sleep one needs without jeopardizing health.”

Researchers don’t know much about the circuitry controlling sleep amount. Borniger recognizes that the conclusions from this study are consistent with what doctors and parents have known for years, which is that sleep is important to overall health. The research also identifies a brain circuit that may be responsible for the way sleep buffers stress and immune responses.

People who have trouble sleeping because of elevated stress from an upcoming deadline often have a flare up of diseases they might have had under control previously, such as herpes viruses or psoriasis. These diseases opportunistically reemerge when the immune system is weakened.

The major finding in this study is not that the connection exists, but that the researchers, including principal investigator Luis de Lecea and first author Shi-Bin Li at Stanford, found the neural components.

While the studies of these linkages in the hypothalamus of mice were consistent across individuals, the same can’t be said for anecdotal and epidemiological evidence in humans, in part because the mice in the study were genetically identical.

For humans, age, sex, prior experiences, diet, family history and other factors make the linkage harder to track.

Even though researchers can’t control for as many variables with humans as they can with mice, however, several other studies have shown that stress promotes insomnia and poor immune function.

Borniger emphasized that he is the second author on the paper, behind Li and was involved in tracking the immune system component of the work.

Borniger and de Lecea are continuing to collaborate to see if drugs that target the insomnia neurons block the effect of stress on the immune system.

Now that he has moved into the refurbished Demerec Laboratory at CSHL, Borniger plans to work on projects to investigate how to use the nervous system to control anti-tumor immunity in models of breast and colorectal cancer, among others.

By understanding this process, Borniger can contribute to ways to manipulate these cells and the immune system to combat cancer and other inflammatory diseases.

Ideally, he’d like to be a part of collaborations that explore the combination of manipulating nervous and immune systems to combat cancer.

Borniger came to Cold Spring Harbor Laboratory because he was eager to collaborate with fellow scientists on site, including those who look at the immune system and metabolism. He appreciates how researchers at the famed research center look at how bodies and the brain respond to a growing tumor and would like to explore how tumors “influence nerves and then, reciprocally, how nerves influence tumor progression.”

The first few steps towards working at CSHL started in 2018, when Tobias Janowitz, Assistant Professor at CSHL, saw a paper Borniger published on breast cancer and asked him to give a 15-minute talk as a part of a young scholars symposium.

Borniger grew up in Washington, DC, attended college at Indiana University, went to graduate school at Ohio State and conducted his post-doctoral work at Stanford. Coming to CSHL brings him back to the East Coast.

Borniger and his fiancée Natalie Navarez, Associate Director of Faculty Diversity at Columbia University, met when they were in the same lab at Stanford. The couple had planned to get married this year. During the pandemic, they have put those plans on hold and may get married at City Hall.

Borniger and Navarez, who live on campus at Hooper House at CSHL, look forward to exploring opportunities to run, hike and swim on Long Island.

The new CSHL researcher appreciates the new opportunities on Long Island.

“This sort of collaborative atmosphere is what I would have in my Utopian dream,” Borniger said.

Taken around 1890, the photo above includes Lucas Cheadle’s great, great grandparents Martin Van Buren Cheadle and his wife Mary Vera with their children, from left, Overton, Ellis, Lurena and Thomas (who is Cheadle’s great grandfather).

By Daniel Dunaief

In joining Cold Spring Harbor Laboratory, Lucas Cheadle has continued his professional and personal journey far from his birthplace in Ada, Oklahoma.

Then again, his travels, which included graduate work in New Haven at Yale University and, most recently, post doctoral research in Boston at Harvard Medical School, wasn’t nearly as arduous or life threatening as the forced trip his ancestors had to take.

In 1837, Cheadle’s great, great, great grandparents had to travel from Pontotoc, Mississippi to southern Indian Territory, which is now near Tishomingo, Oklahoma as a part of the Trail of Tears. Native American tribes, including members of Cheadle’s family who are Chickasaw, cleared out of their lands to make way for Caucasian settlers.

Lucas Cheadle

Proud of his biracial heritage, which includes Chickasaw, Choctaw, and Cherokee lineages, Cheadle hopes to make his mark professionally in his studies of the development of the brain (see article on page B). At the same time, he hopes to explore ways to encourage other members of the Chickasaw tribe to enter the fields of science, technology, engineering and mathematics.

One of three sons of a mixed Chickasaw father named Robert Cheadle and a Caucasian mother named Cheryl, Cheadle would eventually like to provide the kind of internship opportunities through his own lab that he had during his high school years.

Indeed, during the summer of his junior year, Cheadle did a health care internship, in which he shadowed different types of physicians. He watched active surgeries and observed a psychiatrist during patient visits. After that summer, Cheadle thought he might become a psychiatrist as well because he knew he was interested in the study of the brain.

Down the road, Cheadle envisions having one or two people learn as interns in the lab during the summer. Longer term, Cheadle hopes other investigators might also pitch in to provide additional scientific opportunities for more Native American high school students.

Growing up in Oklahoma, Cheadle never felt he stood out as a member of the Chickasaw tribe or as a biracial student.

His father, Robert, was active with the tribe, serving as a tribal judge and then as a legislative attorney for the Chickasaw. His grandfather, Overton Martin Cheadle, was a legislator.

Through their commitment to the Chickasaw, Cheadle felt a similar responsibility to give back to the tribe. “It was an incredibly important part of their professional lives and it was a passion” to help others, he said. “I’m driven by that spirit.”

His father took people in who had nowhere to go. In a few cases, people he put up robbed the family. Even after they robbed him, Cheadle’s father took them back. When Robert Cheadle died earlier this year, one of the people whom Cheadle supported helped out with his funeral arrangements.

Driven to accomplish his mission as a scientist, Lucas Cheadle feels he can reach out to help high school students and others interested in science during his research journey.

“The better I can do, the more I can help,” Cheadle said. He hopes to “open doors for other people.”

With some of these efforts to encourage STEM participation among Native Americans, Cheadle hopes to collaborate with John Herrington, a Chickasaw astronaut who took a Native American flute into space during one of his missions. “It would be wonderful to discuss this” with Herrington, “if he has time for me,” said Cheadle.

In modern times, the Chickasaw tribe has made “good strides” in being successful. One challenge to that success, however, is that it has included assimilation.“The main goal is to hold onto the heritage as much as we can,” said Cheadle.

As for now, he plans to honor his heritage in his lab by “working hard to create a safe, respectful environment where people’s unique backgrounds and characteristics are supported and embraced. I try to create a space where diversity can thrive.”

Lucas Cheadle. Photo from CSHL

By Daniel Dunaief

One of the newest additions to Cold Spring Harbor Laboratory’s neuroscience program, Lucas Cheadle, who is an assistant professor, is exploring the early environmental factors at a molecular level that shape the neurological development of the mouse visual system.

While nature and nurture combine to produce the individuals each life form becomes, Cheadle is focused on the ways nurture, specifically, shapes the pathways in the brain that affect the development of sight.

Microglia are an unlikely player in this environmentally-triggered development, as doctors and researchers previously saw these cells primarily as participants in neurinflammation.

That is not the case anymore, with Cheadle and other scientists demonstrating over the past decade or so that microglia play important parts in the healthy brain. Cheadle, specifically, has demonstrated that these cells play a role in experience-dependent circuit development.

Indeed, the process of circuit refinement in the developing brain, which Cheadle describe as being among the “most complex structures in the known universe,” is akin to a room full of half-full boxes, which represent synaptic connections between neurons.

The brain begins with numerous little boxes that make the room difficult to navigate. As the brain consolidates the important items into a smaller number of larger boxes and removes the smaller boxes, the room becomes more manageable.

This is consistent with what Cheadle has seen during refinement. A smaller number of synapses become stronger and are maintained, while others are removed. This promotes the efficiency and precision of neural processing, he explained.

When the contents of some of those boxes disappear, however, the result can lead to neurodegenerative diseases like Alzheimer’s, in which a person struggles to find memories that may have been unwittingly cleared out.

Cheadle, who most recently was a post doctoral researcher at Harvard Medical School, is exploring the way microglia shape the connections between the eyes and the brain between when a mouse is born and when it reaches one month of age.

His work has shown that microglial cells are required for the sensory-dependent phase of visual circuit development. Disrupting signals between microglia and neurons affects synapse elimination, akin to removing the smaller boxes, which is important for circuit function.

Indeed, prior to work Cheadle and others have done in recent years with these cells in the brain, researchers thought microglia in the brain were quiescent, or inactive, after birth, except for their role in brain injury, disease pathology and neuroinflammation.

Until the first week of life, microglia engulf and then digest synaptic connections between some neurons, in a process called phagocytosis. During the sensory-dependent phase of refinement in the third week after birth, which Cheadle demonstrated in a paper published this month in the journal Neuron, microglia stop phagocytosis and rely on cytokines to break down synapses.

The cytokine pathway Cheadle discovered, called TWEAK, which is a ligand expressed by microglia, and Fn14, a receptor expressed by neurons, becomes active between eye opening, which is around two weeks, and peaks at about four weeks old.

When mice don’t have exposure to important visual stimuli during this critical period, the circuit has too many synaptic connections, which reduces the effectiveness of the developing visual system.

While Cheadle is working on visual development, specifically, he is interested in the broader implications of this work in the context of the environmental signals that affect the development of the brain.

In that broader context, the processes involved in autism and schizophrenia could reflect a period in which individuals have an overabundance of synapses that weren’t sufficiently pruned and refined.

Despite the fact that researchers hypothesized that synaptic pruning may lead to these disorders decades ago, they still have a limited awareness of whether and how this might happen. Studying the way microglia contribute to healthy circuit development could provide important clues about these processes.

Some epidemiological evidence points to the linkage between immune activity and neurodevelopmental disorders. In 1918 and 1919, during the Spanish Flu pandemic, children born during that period had a higher incidence of an autism or schizophrenia later in life.

Other evidence shows an interaction between immune activation and neurodevelopmental dysfunction, including the genetic loci associated with such disorders and increased inflammatory markers in the blood and brains of people with such disorders. “There’s really no question that there is a link,” Cheadle explained. “The nature of the link is still poorly understood.”

While earlier epidemiological data raises questions about the current pandemic, it doesn’t provide a definitive answer because “we still don’t quite understand what the nuanced molecular factors are that link the immune activation to the increase in disease prevalence,” Cheadle suggested.

“There’s a real chance that having COVID during pregnancy may impact the development of the offsprings’ nervous systems as has been seen in other infections,” Cheadle wrote. “While it is not the current priority of COVID research, it certainly warrants studying.”

Cheadle hopes to understand the “underlying principals of disorders” he said.

A resident of Huntington, Cheadle lives five minutes from the lab. He plans to rent for now because he didn’t want to start a new lab and move into a new house at the same time.

Cheadle has hired a technician and is in the process of hiring another. A post doctoral scientist will join his lab in November.

Early on in his life, Cheadle said he was fascinated with the interface between the world and biology. He wanted to understand how human brains interpret the information that comes from our senses. Everything culminated, professionally, in his interest in neurobiological mechanisms.

Currently, Cheadle is also interested in the looming behavior of mice. In the field, when mice see a bird that is flying slowly overhead, they are more likely to make a mad dash for safety, running into weeds or for cover from a tree. When the bird, however, is flying too rapidly, the mice freeze.

“I’m intrigued to find out whether the dichotomy of fight or flight could be shifted by the function of microglia,” he said. “I like to understand something at a functional level and dissect it to a molecular level.”