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Gov. Kathy Hochul speaking with Cold Spring Harbor Laboratory CEO Bruce Stillman during a recent visit. Photo courtesy of Darren McGee/ Office of Governor Kathy Hochul

By Daniel Dunaief

The transition from studying pancreatic cancer’s playbook to attempting new moves to wrestle it into submission is getting closer at Cold Spring Harbor Laboratory, thanks to support from New York State.

Recently, Governor Kathy Hochul (D) announced that the Empire State would contribute $15 million to a new Pancreatic Cancer Center at Cold Spring Harbor Laboratory as a part of the lab’s Foundations for the Future Expansion.

The funds will support the construction of a new center that will continue to try to defeat this insidious type of cancer as CSHL aims to develop new treatments.

“Patients should not feel there’s no chance and no hope” after a pancreatic cancer diagnosis, said David Tuveson, Director of the CSHL Cancer Center and a researcher whose lab has taken innovative approaches to pancreatic cancer. “They are watching the evolution of an area in a disease that previously has been challenging to treat. Through fundamental research, we are coming up with new approaches.”

As CSHL works with human organoids, which are tissues grown from a patient’s own cancer cells that can be used to test the effectiveness of various treatments and any resistance from cancer, animal models, and other techniques, they have moved closer to finding targets that could lead to new therapies.

Any novel treatment would likely involve creating new companies, likely on Long Island, that could develop these treatments, file for patents, and build a commercial presence and infrastructure.

“It’s an investment by the state to accelerate our translational research so we can go from preclinical to clinical,” said Tuveson. “Part of that will be to generate private entities that can focus on turning a lead to first-in-class, first-in-human products. It allows us to build that infrastructure.”

Tuveson has been working on a potential treatment for several years. Other potential treatments are also in the earlier stages of development.

Governor Hochul suggested that the state’s investment fits in the context of an overall goal to boost the local economy with new biotechnology companies.

“New York State is leading on innovative healthcare space, and this funding will advance research to better understand pancreatic cancer – one of the most devastating forms of cancer,” Governor Hochul said in a statement.

Big Picture

The Pancreatic Cancer Center will take a wide range of approaches to this particular type of cancer.

The Center will be, along with Northwell Health, a “pipeline from fundamental discovery science” to clinical trials conducted with hospital partners, explained Bruce Stillman, CEO of Cold Spring Harbor Laboratory.

The center will address early detection as well.

For Tobias Janowitz, Associate Professor and Cancer Center Program Co-Leader at CSHL, the investment means “we can strengthen collaborations between experts in metabolism, immunology, cancer cell biology, and whole body effects of cancer, all of them interconnected and relevant to therapy development in pancreatic cancer.”

Janowitz explained that patients with pancreatic cancer have the highest incidence of cachexia, in which chronic illness causes a reduction in muscle and fat, lowers people’s interest in food and causes extreme and potentially terminal weight loss. Pancreatic cancer patients almost universally experience a loss of appetite and profound weight and muscle loss.

Understanding cachexia in the context of pancreatic cancer will “enable care for patients with other cancers, too,” Janowitz added.

From that perspective, Janowitz hopes the New York State funds could enable discoveries that reach beyond pancreatic cancer.

As an MD/PhD, Janowitz could be involved in the translation of fundamental discoveries into clinical research and, ultimately, clinical care.

Janowitz has a specific interest in optimizing the therapeutic window for patients with pancreatic cancer.

“We are looking for management options that intensify the anti-cancer effect,” while, at the same time, protecting or reconditioning the whole body, Janowitz added.

Janowitz is using special transcriptomics on clinical samples in collaboration with Jon Preall, who leads the genomics core facility.

In a statement, Cold Spring Harbor Laboratory Chair Marilyn Simons described the state funding as a “catalyst to mobilize further private investment in pancreatic cancer research at CSHL.”

Simons added that her father was diagnosed with pancreatic cancer at the age of 75. A doctor offered him an exploratory operation, which enabled him to live another 14 years.

“Few people are so lucky,” Simons added in a statement. “Our wonderful scientists at Cold Spring Harbor are working with Northwell Health and the Feinstein Institutes to help more people get access to the latest biomedical advances.”

Camila dos Santos Photo courtesy of CSHL

By Daniel Dunaief

People often think of and study systems or organs in the body as discrete units. 

In a healthy human body, however, these organs and systems work together, sometimes producing signals that affect other areas.

Recently, Cold Spring Harbor Laboratory Associate Professor Camila dos Santos and graduate students Samantha Henry and Steven Lewis, along with former postdoctoral researcher Samantha Cyrill, published a study in the journal Nature Communications that showed a link in a mouse model between persistent bacterial urinary tract infections and changes in breast tissue.

The study provides information about how a response in one area of the body could affect another far from an infection and could provide women with the kind of information that could inform the way they monitor their health.

To be sure, dos Santos and her graduate students didn’t study the processes in humans, which could be different than they are in mice.

Indeed, they are in the process of establishing clinical studies to check if UTIs in women drive breast alterations.

The body’s response

In this research, the scientists demonstrated that an unresolved urinary tract infection itself wasn’t causing changes in breast tissue, but that the body’s reaction to the presence of the bacteria triggered these changes.

By treating the urinary tract infections, Henry and Lewis showed that breast cells returned to their normal state.

Further, when they didn’t treat the UTI but blocked the molecule TIMP1, which causes collagen deposits and milk duct enlargements, the breast cells returned to their normal state.

The TIMP1 role is “probably the main eureka moment,” said Lewis, who is an MD/ PhD student at Stony Brook University. “It explains how an infection in the bladder can change a faraway tissue.”

Lewis suggested that collagen, among other factors, changes the density of breast tissue. When women get a mammography, doctors are looking for changes in the density of their breasts.

Taking a step back from the link, these graduate students and dos Santos considered whether changes in the breast tissue during an infection could provide an evolutionary benefit.

“From an evolutionary standpoint, there should be some adaptive advantage,” suggested Henry, who is earning her PhD in genetics at Stony Brook University and will defend her thesis in July. Speculating on what this might be, she suggested the mammary gland might change in response to an infection to protect milk production during lactation, enabling a mother to feed her young.

Epidemiological studies

A link between persistent UTIs and breast cancer could show up in epidemiological studies.

Dos Santos and collaborators are exploring such questions in the context of European data and are working with US collaborators to collect this information.

In addition, dos Santos believes women should consider how other ongoing threats to their overall health impact their bodies. Women with clinical depression, for example, have worse prognoses in terms of disease. Humans have health threats beyond UTIs that could predispose them to developing cancer, dos Santos said.

Division of labor

Henry and Lewis took over a study that Samantha Cyrill, the third co-first author on the paper started. When Cyrill finished her postdoctoral work, Henry and Lewis “put on their capes and said, ‘We are going to take this to the end line.’ They are incredible people,” said dos Santos.

They each contributed to the considerable work involved.

Henry primarily analyzed the single cell RNA sequencing data, specifically identifying changes in the epithelial compartment. Gina Jones, a visiting CSHL undergraduate research program student, and Lewis also contributed to this.

Henry also participated in TIMP1 neutralizing antibody treatment in post-lactation involution mice, contributing to tissue collection and staining.

Working with Cyrill and Henry, Lewis contributed to the mouse work, including experiments like neutralizing TIMP1 and CSF3. Lewis also worked with Cyrill on the UTI infections in the animals and with Henry in processing tissues for single cell RNA sequencing and assisted Henry on the sequencing analysis.

While this result is compelling and offers an opportunity to study how an infection in an area of the body can trigger changes in another, dos Santos recognized the inherent risk in a new project and direction that could have either been disconnected or a been a dead end.

“It was an incredible risk,” said dos Santos. She was rejected from at least four different funding opportunities because the research is “so out there,” she said. She tapped into foundations and to CSHL for support.

Back stories

A resident of Brooklyn, Lewis was born in Queens and raised in Scarsdale. He joined the dos Santos lab in March of 2021. One of the appeals of the dos Santos lab was that he wanted to understand how life history events drive disease, especially breast cancer.

A big Mets fan, Lewis, whose current favorite payer is Pete Alonso, is planning to run his third marathon this fall.

Lewis is dating Sofia Manfredi, who writes for Last Week Tonight with John Oliver and accepted an Emmy award on behalf of the staff.

Lewis considers himself Manfredi’s “biggest cheerleader,” while he appreciates how well she listens to him and asks important questions about his work.

As for Henry, she grew up in Greenport. She joined the lab in May of 2020 and is planning to defend her thesis in July.

Her father Joseph Henry owns JR Home Improvements and her mother Christine Thompson worked as a waitress and a bartender in various restaurants.

Henry is married to Owen Roberts, who is a civil engineer and works in the Empire State Building for HNTB as a civil engineer, where he focuses on traffic.

Henry hopes to live in Boston after she graduates. She’s adopted the rooting interests of her husband, who is a fan of Beantown teams, and will support the Bruins and the Celtics. A lifelong Yankees fan, however, Henry, who watched the Bronx Bombers with her father growing up, draws the line at supporting the “Sawx.”

As for the work, Henry and Lewis are excited to see what the lab discovers in the next steps.

“I do think this work is extremely informative, defining a relationship between an infection, UTI, and the mammary gland that has not previously been appreciated,” Henry explained.

“This provides information to the public,” said Henry. “I always think it is worth knowing how different events may impact your body.”

Gabrielle Pouchelon with technician Sam Liebman. Photo by Constance Brukin/CSHL

By Daniel Dunaief

Gabrielle Pouchelon doesn’t need to answer the age-old debate about heredity vs. environment. When it comes to the development of the brain, she’s studying the response both to sensory cues and genetics.

Gabrielle Pouchelon.
Photo courtesy of CSHL

An Assistant Professor who joined Cold Spring Harbor Laboratory in March of 2022, Pouchelon studies the interplay between sensory and neuromodulatory inputs and genetic programs in circuit maturation. She also studies other neuromodulatory inputs, usually associated with states of adulthood, which could control development.

A combination of genetics and environment shapes the way neurons connect in a healthy brain. In people who develop non-neurotypical behaviors, through autism, schizophrenia or other conditions, the development of neurological connections and architecture is likely different.

Researchers have associated genes of susceptibility with schizophrenia and autism spectrum disorders. Scientists believe environmental cues provide the brain with activity that interact with these genetic components.

“We are trying to understand whether we can [intervene] earlier that can have different outcomes at later times,” said Pouchelon. “We are studying ways to intervene with these transient processes and examine whether dysfunctions associated with the disorders are improved.”

During critical periods of development, the brain has a high level of plasticity, where various inputs can alter neurons and their connections. This not only involves building connections, but sometimes breaking them down and rebuilding other ones. As people age, that plasticity decreases, which is why children learn faster than adults in areas such as the acquisition and development of language skills.

While the timing of critical periods is less well-defined in humans and language is a complex function, the ability to learn new languages at a young age reflects the high plasticity of the brain.

Scientists are studying language processes, which are specific to humans, with functional magnetic resonance imaging.

Pouchelon, who isn’t studying language skills, hopes that understanding the architecture of developing brains and how they respond to sensory and neuromodulatory cues could shed light on the studies performed in humans. Since behavioral therapy and pharmaceutical treatments can help children with autism, she believes understanding how external cues affect genetic elements could uncover drug targets to alleviate symptoms of neurodevelopmental disorders at an early age.

Neurons & the environment

From left, technician Sam Liebman, Gabrielle Pouchelon and postdoctoral researcher Dimitri Dumontier. Photo courtesy of Gabrielle Pouchelon

In her lab, which currently includes three researchers but she expects to double within a month, Pouchelon uses sophisticated tools to target not only the effect of the environment, but also to look at the specific neurons that transmit information.

She is trying to “understand at a very precise level what a sensory input means and what are the neurons that integrate that sensory input.”

Sam Liebman, who became a technician in Pouchelon’s lab two years ago after graduating from the University of Vermont, appreciates the work they’re doing and her mentorship.

The lab is “unique and special” because he has that “close relationship” in what is now a smaller lab with Pouchelon, Liebman said.

Growing up in Huntington, Liebman, who hopes to go to graduate school in the fall of 2025, came to Cold Spring Harbor Laboratory for field trips in middle school and high school.

“I idolized this place and this campus,” said Liebman.

Pouchelon has asked for Liebman’s opinion on potential candidates to join the lab, even summer interns.

Fragile X Syndrome

Most of the work Pouchelon conducts is done on animal models. She is mainly studying animals with a mutation linked to Fragile X Syndrome. 

In Fragile X Syndrome, which can affect boys and girls, children can have developmental delays, learning disabilities and social and behavioral problems. Boys, according to the Centers for Disease Control and Prevention, typically have some degree of intellectual disability, while girls can have normal intelligence or some degree of intellectual disability.

Other models for autism exist, such as genetic mutations in the gene Shank3. “We are trying to utilize these models to apply what we understand of development in brains that are healthy and compare them” to the mutated models, Pouchelon explained.

While clinical trials are exploring receptors as drug targets for Fragile X Syndrome, she hopes to find new ones that are selective in early stages of the disease to modify their use depending on the stages of development.

An annoying nerd

Born and raised in Paris, France to a family that showed considerably more artistic talent than she, Pouchelon struggled with games she and her sisters played when they listened to music on the radio and they had to guess the composer.

“I was the one always losing,” said Pouchelon. Her family, including her two older sisters who currently live in France, knew “way more about art and history than I did. I was the nerd scientist.”

When she was young, she was curious and asked a lot of “annoying questions” because she was interested in the “mystery of everything.” In high school, she became interested in the brain.

Pouchelon, who isn’t actively searching for French food but finds the baguettes at the Duck Island Bakery exceptional, lives on the Cold Spring Harbor Laboratory campus with her husband Djeckby “DJ” Joseph, a naturalized American citizen originally from Haiti who works in law enforcement at the VA Hospital in Manhattan, and their two-year old son Theo.

Eager to ensure her son benefits from a multicultural identity, Pouchelon speaks to Theo in French. He also attends on campus day care, where he learns English.

As for the decision to come to Cold Spring Harbor Laboratory, Pouchelon, who conducted her PhD research at the University of Geneva in Switzerland and completed her postdoctoral research at New York University and at Harvard Medical School, is thrilled to discuss her work with the talented and collegial staff at the lab.

Cold Spring Harbor Laboratory, which is known internationally for meetings and courses, is an “exciting place” where scientists conduct cutting edge research.

Cold Spring Harbor Laboratory’s Grace Auditorium, One Bungtown Road, Cold Spring Harbor hosts a lecture titled Tomatoes in Space on Wednesday, April 10 from 7 to 9 p.m. HHMI Investigator, and CSHL Director of Graduate Studies Zachary Lippman leads the audience on a captivating journey as he reveals how CRISPR gene-editing technology is shaping the future of agriculture.

From making crops grow in busy cities to reaching for the stars so plants can grow in space, Dr. Lippman’s lecture walks listeners through the importance of diversifying our agricultural system here on Earth, and beyond. Q&A will follow the lecture. Light refreshments will be served. Free but registration required at www.cshl/edu. For more information, call 516-367-8800.

Zhe Qian

By Daniel Dunaief

Addition and subtraction aren’t just important during elementary school math class or to help prepare tax returns.

As it turns out, they are also important in the molecular biological world of healthy or diseased cells.

Some diseases add or subtract methyl groups, with a chemical formula of CH3, or phosphate groups, which has a phosphorous molecule attached to four oxygen molecules.

Nicholas Tonks. Photo courtesy of CSHL

Adding or taking away these groups can contribute to the progression of a disease that can mean the difference between sitting comfortably and watching a child’s performance of The Wizard of Oz or sitting in a hospital oncology unit, waiting for treatment for cancer.

Given the importance of these units, which can affect the function of cells, researchers have spent considerable time studying enzymes such as kinases, which add phosphates to proteins.

Protein tyrosine phosphatases, which Professor Nicholas Tonks at Cold Spring Harbor Laboratory purified when he was a postdoctoral researcher, removes these phosphate groups.

Recent PhD graduate Zhe Qian, who conducted research for six years in Tonks’s lab while a student at Stony Brook University, published a paper in the journal Genes & Development demonstrating how an antibody that interferes with a specific type of protein tyrosine phosphatase called PTPRD alters the way breast cancer spreads in cell cultures.

“The PTPs are important regulators of the process of signal transduction — the mechanisms by which cells respond to changes in their environment,” explained Tonks. “Disruption of these signal transduction mechanisms frequently underlies human disease.”

To be sure, Tonks cautioned that the study, which provides a proof of concept for the use of antibodies to manipulate signaling output in a cancer cell, is a long way from providing another tool to combat the development or spread of breast cancer.

The research, which formed the basis for Qian’s PhD project, offers an encouraging start on which to add more information.

Blocking the receptor

Qian, who goes by the name “Changer,” suggested that developing a compound or small molecule to inhibit or target the receptor for this enzyme was difficult, which is “why we chose to use an antibody-based method,” he said.

By tying up a receptor on the outside of the cell membrane, the antibody also doesn’t need to enter the cell to reach its target.

The Antibody Shared Resource, led by Research Associate Professor Johannes Yeh, created antibodies to this particular receptor. Yeh created an antibody is shaped like a Y, with two arms with specific attachments for the PTPD receptor.

Once the antibody attaches, it grabs two of these receptors at the same time, causing a dimerization of the protein. Binding to these proteins causes them to lose their functionality and, ultimately, destroys them.

Cell cultures of breast cancer treated with this antibody became less invasive.

Limited presence

One of the potential complications of finding a new target for any treatment is the side effects from such an approach.

If, for example, these receptors also had normal metabolic functions in a healthy cell, inhibiting or killing those receptors could create problematic side effect.

In this case, however,  the targeted receptor is expressed in the spine and the brain. Antibodies normally don’t cross the blood-brain barrier.

Qian and Tonks don’t know if the antibody would affect the normal function of the brain. Further research would help address this and other questions.

Additionally, as with any possible treatment, future research would also need to address whether cancer cells developed resistance to such an approach.

In the time frame Qian explored, the cells in culture didn’t become resistant.

If the potential therapeutic use of this antibody becomes viable, future researchers and clinicians might combine several treatments to develop ways to contain breast cancer.

Eureka moment

In his research, Qian studied the effect of these antibodies on fixed cell, which are dead but still have the biochemical features of a living cell He also studied living cells.

When the antibody attaches to the receptor, it becomes visible through a staining process. Most antibody candidates stain living cells. Only the successful one showed loss-of-signal in living staining.

The antibody Qian used not only limited the ability of the receptor to send a signal, but also killed the receptor. The important moment in his research occurred when he discovered the antibody suppressed cancer cell invasion in cell culture.

Outside of the lab, Qian enjoys swimming, which he does between four and five times per week. Indeed, he combined his athletic and professional pursuits when he recently raised funds for Swim Across America.

“I not only want to do research, but I also want to call more attention to cancer research in the public,” said Qian.

The Swim Across America slogan suggests that each stroke is for someone who “couldn’t be with us” because of cancer. In the lab, Qian thinks each time he pipettes liquids during one of his many experiments it is for someone who couldn’t make it as well.

Qian, who currently lives in Hicksville, grew up in Suchow City, which is a village west of Shanghai and where Cold Spring Harbor Asia is located. 

Qian has been living on Long Island since he arrived in the United States. Qian graduated from Stony Brook University in October and is currently looking for a job in industry.

Looking back, Qian is pleased with the work he’s done and the contribution he’s made to breast cancer research. He believes the antibody approach offers a viable alternative or complement to searching for small molecules that could target or inhibit proteins or enzymes important in the development of cancer.

Jasmine Moss. Photo by Susan Anderson

By Daniel Dunaief

As the first chemist in the history of Cold Spring Harbor Laboratory, Professor John Moses has forged new connections at the lab, even as he maintains his affinity for and appreciation of his native Wrexham in Wales.

Indeed, Moses recently created and funded a fellowship for disadvantaged students in Wales, giving them an opportunity to visit the lab, learn about the science he and others do, and, perhaps, spark an interest in various science, technology, engineering and math fields.

Called Harbwr y Ffynnon Oer Scholarship, which means “Cold Spring Harbor” in Welsh, Moses’s laboratory recently welcomed Jasmine Moss, the first recipient, in early August.

“I hope it broadens” the horizons of those who travel to the lab, explained Moses in an email. “Wales is a small country” with a population of about three million. Coming to New York — a city with a much bigger population than Wales — “can only be an eye-opening experience.”

Jasmine Moss with postdoctoral fellow Dharmendra Vishwakarma. Photo by Theresa Morales

For Moss, who is studying for an integrated masters degree in biomedical engineering, the opportunity proved exciting and rewarding.

“I was expecting to feel intimidated” with everyone knowing so much more than she, Moss said during an interview on the morning of her third day in the lab. “I was expecting maybe a little bit not to understand everything. Everyone is amazing” and made her feel welcome.

The experience started with a walk around the campus, which included considerable information not only about the science but also about the history of the 133-year old laboratory.

Moss, who said this was the first time she’d been in a professional chemistry lab, helped conduct an experiment in which a reaction caused a liquid to change color because of the presence of copper.

“I did the measuring and putting it together,” said Moss, who added that she was “heavily supervised.” She did some calculations as well.

Moss suggested that her interest in science originated with a proficiency in math.

If she were having a bad day in secondary school, she could turn her mood and her mentality around by spending an hour in math class.

Beyond the science

Theresa Morales, a senior scientific administrator, created a schedule of activities and coordinated Moss’s visit.

“We want to do the same thing for any scholarship awardee,” Morales said. “We want to give them the overall experience. It’s not just about the science. We invite the person to realize the culture of Cold Spring Harbor Laboratory” which has a “beautiful campus and great people” who occupy its labs, attend meetings, and share scientific insights and experiences.

A postdoctoral researcher in Moss’s lab, Josh Homer suggested that Morales did “the heavy lifting” in coordinating three days of activities and opportunities for Moss. Homer, who is collaborating with Professor Bo Li to develop new opiates that are non addictive for pain treatment, appreciated Moss’s reactions to the opportunities in the lab.

“I thought [Moss’s] face lit up,” he said. When people are exposed to science in a “manageable and digestible way, they learn that they can do it.”

Indeed, Homer, who grew up in New Zealand, recalled how a high school teacher inspired his interest in science.

“My journey genuinely kick started from one good teacher” who sparked an “inquisitiveness” within him, Homer said. 

Coming from a smaller country, Homer can relate to the opportunities science has provided for him.

“Chemistry has been a fantastic way to see the world and explore,” said Homer, who conducted his PhD research at the University of Oxford in the United Kingdom. “Science is a universal language. Chemistry is the same in India, China” and all over the world.

A family experience

Jasmine Moss with her dad, Stephen Moss, front, with members of John Moses’s lab. Photo by Lorraine Baldwin

Moss traveled to New York for the first time with her parents Stephen and Emma, who stayed with her on campus, toured the grounds and library and attended a picnic.

While the library tour was less interesting to Moss, she said her father “really enjoyed it.”

Morales suggested that the lab “wants parents to feel just as good” and that the parents will have “the same enthusiasm for science and the experience as the scholar if they can feel they are a part” of the visit.

In addition to getting an inside look at Cold Spring Harbor Laboratory, Moss and her parents ventured into the city, where she ate her first pizza and visited the Empire State Building and the Statue of Liberty. She was particularly impressed with the speed at which the Empire State Building was constructed, which took a year and 45 days.

Prior to her visit, Moss’s understanding of the city of New York came from the version she observed through the sitcom “Friends.”

As for the next phase of her life, she expressed an interest in helping people, which could be through medical engineering, biology or in some other field.

“I want to do something meaningful,” Moss said.

Next steps

Moses hopes to bring students to the lab each year, particularly those who might have had problems or difficulties or are from a disadvantaged background. Moss suffers from anxiety and feels every new experience makes similar opportunities easier.

“The team really put me at ease almost immediately,” said Moss.

Moss was surprised by the similarities between Long Island and the United Kingdom. She suggested the best parts of Wales are the countryside and beaches. If she returned the favor and hosted guests in her native Wales, she would take them to an international rugby match in Cardiff.

As for other area sports, Moses comes from the little soccer town that could in Wrexham, which is now famous for the purchase of the local team by actor Ryan Reynolds and co-owner Rob McElhenney. While the actors have brought soccer dreams to life, Moses hopes Cold Spring Harbor Laboratory might help young students realize their science dreams.

A statue of Charles Darwin (and finch) created by sculptor Pablo Eduardo overlooks the harbor on the campus of Cold Spring Harbor Laboratory. Photo courtesy of CSHL

By Tara Mae

Scientific study is a perpetual testimony to the feats and foibles of human nature, intricately intertwined in ways that continue to be excavated by inquiring minds bold enough to imagine. 

Cold Spring Harbor Laboratory (CSHL), which has largely been a titan in such innovative investigations, will offer a series of walking tours on select weekends from Saturday, May 20, through Sunday, August 27, starting at 10 a.m. The hour and a half long tours will traverse the past, present, and future of the complex and its work therein. 

“We are most excited to get people to the Laboratory who have always wondered what goes on here. So many have heard about us, driven by us, read about us, but they have never dug deeper. This walking tour is the chance to learn who we are,” said Caroline Cosgrove, CSHL’s Community Engagement Manager.

Conducted by trained tour guides, including Cold Spring Harbor Laboratory graduate students and postdoctoral fellows, the walks strive to bridge the gap between the physical realm and scientific theory. 

“These tours encompass the stunning grounds, the Lab’s history, and our current facilities and work. Community members, whether they have a background and interest in science, can come and learn from current graduate students about the world-renowned work going on in their very backyard,” explained Cosgrove. 

Probing CSHL’s ongoing research and program development for plant and quantitative biology, cancer, and neuroscience, the tours will encompass details about its historic and modern architecture, Nobel legacy, and identity evolution. Additionally, these scenic, scholarly strolls explore the practices and procedures of CSHL, with behind-the-scenes sneak peaks into the inner workings of scientific investigation. 

“As long as the tour guide’s laboratory is open and available, folks get a walk through and see the student’s own lab station,” Cosgrove said. “Whether it’s a cancer research lab, a neuroscience lab, a plant research lab, you get to see where all the magic happens.” 

Established in 1890, CSHL’s North Shore campus is a beacon of biology education, with 52 laboratories and more than 1100 staff from more than 60 countries. Eight scientists associated with CSHL have earned a Nobel Prize in physiology or medicine. This internationally recognized center of scientific research is also a local history and education site, where students of all ages and backgrounds come to study. 

“History has been, and will continue to be, made here. Please come get to know us,” said Cosgrove. 

Cold Spring Harbor Laboratory, One Bungtown Road, Cold Spring Harbor offers walking tours on May 20 and 21, June 24 and 25, July 29 and 30 and Aug. 26 and 27 at 10 a.m. Tours begin in the lobby of the Grace Auditorium. Tickets are $5 per person. To order, visit www.cshl.edu/public-events/tour-cshl/. For more information, call 516-367-8800.

CSHL Associate Professor Stephen Shea and Postdoc Yunyao Xie in Shea’s lab. Photo from CSHL/2020

By Daniel Dunaief

Good parenting, at least in mice, is its own reward.

No, mice don’t send their offspring to charter schools, drive them to endless soccer and band practices or provide encouragement during periods of extreme self doubt.

What these rodents do, however, protects their young from danger.

When a young mouse wanders, rolls or strays from the nest, it becomes distressed, calling out mostly to its mother, who is the more effective parent, to bring it back to safety.

Responding to these calls, the mother mouse carries the young back to the safety of the nest.

This behavior involves a reward system in a region of the mouse brain called the ventral tegmental area, or VTA. When the mouse effectively retrieves its young, the VTA releases the neurotransmitter dopamine, which is the brain’s way of saying “well done!”

In a paper published in December in the journal Neuron, Cold Spring Harbor Laboratory Associate Professor Stephen Shea and his postdoctoral researcher Yunyao Xie, who worked in the lab from 2019 to 2021, likened the release of dopamine in this area to a neurological reward for engaging in the kind of behavior that protects their young.

The research “proposes a mechanism that shapes behavior in accordance with that reward,” Shea said. The connection between dopamine in a reward system is an established paradigm.

“There was plenty of smoke there,” he said. “We didn’t pull this out of thin air.”

Indeed, in humans, mothers with postpartum depression have disrupted maternal mood, motivation and caregiving. PPD is linked to dysfunction of the mesolimbic dopamine system, which is a neural circuit that involves the VTA, Xie explained.

“Studies using functional magnetic resonance imaging (fMRI) revealed that the reward brain areas including VTA in healthy mothers have higher response to their own babies’ smiling faces than those in mothers with PPD,” Xie added.

What’s new in this research, however, is that it is “a study of how these signals use mechanisms to shape behavior and social interaction,” Shea said.

How the process works

The feedback loop between dopamine in the VTA and behavior involves a cumulative combination of dopamine interactions.

Dopamine is not at its highest level when the mouse mom is engaging in effective pup retrieval.

“Dopamine is shaping future, not current behavior,” Shea said. “If dopamine was driving the mouse on a current trial, a high dopamine level would be associated with high performance. The trial found the opposite: a low dopamine level was associated with high performance in a given trial, and vice versa.”

Like a skater laying her blades down effortlessly and gracefully across the ice after spending hours exerting energy practicing, the mother mouse engaged in the kind of reinforcement learning that required less dopamine to lead to effective pup saving behavior.

As the performance increases, dopamine diminishes over time, as the reward is “more expected,” reflecting a nuanced dynamic, Shea said.

To test the correlation between dopamine levels in the VTA and behavior, Shea and Xie created an enclosure with two chambers. They put a naive virgin female mouse, which they called surrogates, on one side and played specific sounds behind a door on each side of the chamber. The test mice initially had “no experience in maternal behaviors,” Xie explained.

As these surrogates became more experienced by either observing mothers or practicing on their own, the amplitude of the VTA dopamine signals got smaller.

To provide a control for this experiment, Xie monitored a group of naive virgin female mice who spent less time with pups and had to figure out how to retrieve them on their own under similar neurological monitoring conditions. The dopamine signals in this group stayed elevated over days and their performance in maternal behaviors remained poor.

Through these experiments, Xie and Shea concluded that “there is a negative correlation between the dopamine signals in the VTA and their performance in maternal behaviors,” explained Xie.

‘Mind blowing’ moment

In her experiments, Xie used optogenetic tools that allowed her to inhibit the activity of dopaminergic neurons in the VTA with high temporal precision.

Shea appreciated Xie’s hard work and dedication and suggested the discoveries represent a “lot of her creativity and innovation,” he said.

A native of China, Xie said her grandparents used to have a garden in which they taught her the names and morphologies of different plants during her childhood. She enjoyed drawing these plants.

In graduate school, she became more interested in neuroscience. She recalls how “mind-blowing” it was when she learned about the work by 1963 Nobel laureates Alan Hodgkin, Sir Andrew Fielding Huxley and John Eccles, who established a mathematical model to describe how action potentials in neurons are initiated and propagated.

In the study Xie did with Shea, she found that the dopamine signals in the VTA encoded reward prediction errors in maternal behaviors that was consistent with the mathematical model.

In the bigger picture, Xie is interested in how neural circuits shape behaviors. The neural circuits of most natural behaviors, such as defensive behaviors and maternal behaviors are hard-wired, she added.

Mice can also acquire those behaviors through learning. She is interested in how pup cues are perceived as rewards and subsequently facilitate learning maternal behavior. She found a great fit with Shea’s lab, which focuses on the neural mechanism of maternal behavior.

Xie enjoyed her time at Cold Spring Harbor Laboratory, where she could discuss science with colleagues by the bench, at the dining room or at one of the many on site seminars. She also appreciated the opportunity to attend neuroscience seminars with speakers from other schools, which helped expand her horizons and inspire ideas for research.

Next steps

As for the next steps, Shea said he believes there is considerable additional follow up research that could build on these findings. He would like to apply methods that measure the activity in individual neurons. Additionally, with a number of targets for dopamine, he wants to figure out what areas the neurotransmitter reaches and how the signals are used when they get there. More broadly, he suggested that the implications for this research extend to human diseases. 

From left, Alea Mills and Xueqin Sun Photo from CSHL

By Daniel Dunaief

People have natural defenses against cancer. Proteins like P53 search for unwelcome and unhealthy developments. 

Sometimes, mutations in P53, which is known as the “guardian of the genome,” rob the protein of its tumor fighting ability. In more than seven out of ten cases, the brain tumor glioblastoma, which has a grim prognosis for people who develop it, has an intact P53 protein.

So what happened to P53 and why isn’t it performing its task?

That’s what Cold Spring Harbor Laboratory Professor and Cancer Center member Alea Mills and postdoctoral researcher Xueqin “Sherine” Sun wanted to know.

Starting with the idea that something epigenetic was somehow blocking P53, Sun conducted numerous detailed experiments with the gene editing tool CRISPR-Cas9.

She knocked out parts of the chromatin regulating machinery, which determines whether factors for DNA replication, gene expression, and the repair of DNA damage can access genes and perform their tasks.

The researchers wanted to find “something specific to glioblastoma,” Mills said in an interview. Working with a team of researchers in Mills’s lab, Sun focused on the protein BRD8.

In experiments with mice, Sun and her colleague inhibited this specific protein by destroying the gene that encodes it. That step was enough to stop the tumor from growing and allowed the mouse to live longer.

Mills and Sun published their work in the prestigious journal Nature just before the holidays.

The article generated considerable buzz in the scientific community, where it was in the 99th percentile among those published at the same time in attracting attention and downloads. It also attracted attention on social media platforms like Twitter and LinkedIn.

“We see this as a major discovery, and are not surprised that many others think that the impact is extraordinary,” Mills said. The paper “has the potential of having a significant impact in the future. The work is completely novel.”

While finding a connection between BRD8 and glioblastoma suggests a target for researchers to consider in their search for new glioblastoma treatments, a potential new approach for patients could be a long way off.

“We cannot predict how long it will take to be able to help patients” who have glioblastoma, Mills said.

A promising step

From left, Alea Mills and Xueqin Sun Photo from CSHL

Still, this finding provides a promising step by showing how knocking out the BRD8 protein can enable P53 to gain access to a life threatening tumor.

Sun and Mills said BRD8 and its partners lock down genes that are normally turned on by P53.

“What you inherit from mom and dad is one thing,” said Mills. “How it’s packaged, the epigenetic mechanism that keeps it wrapped up or open, is key in how it’s all carried out within your body.”

By targeting BRD8, Mills and her team opened the chromatin, so P53 could bind and turn on other cancer fighting genes.

After receiving patient samples from Northwell Health, Stanford and the Mayo Clinic, the team studied tissue samples from patients battling glioblastoma. Those patients, they found, had higher concentrations of BRD8 than people without brain cancer.

Researchers and, down the road, pharmaceutical companies and doctors, are careful to make sure removing or reducing the concentration of any protein doesn’t have so-called “off target effects,” which would interfere with normal, healthy processes in cells.

Mills said they tested such actions in the context of neural stem cells in the brain. At this point, removing BRD8 didn’t have any “deleterious consequence,” she said. 

Her lab is working to see the effect of reducing or removing the mouse version, also called Brd8, during development by engineering mice that lack this protein.

Future research

An important next step in this research involves searching for and developing viable inhibitors of the BRD8 protein.

For histone readers like BRD8, researchers look for an active domain within the protein. The goal is to interrupt the interface in their interactions with histones.

In creating molecules that can block the action of a protein, researchers often start with the structure of the protein or, more specifically, the active site.

Sun, who is currently applying for jobs to run her own lab after working at Cold Spring Harbor Laboratory for over eight years, is hoping to purify enough of the protein and determine its structure.

Sun is working on x-ray crystallography, in which she purifies the protein, crystallizes it and then uses x-rays to determine the atomic structure.

Sun described the search for the structure of the protein as an “important direction” in the research. “Once we solve the structure” researchers can focus on drug design, testing and other experiments.

She suggested that the search for a small molecule or compound that might prove effective in inhibiting BRD8 would involve optimizing efficiency and activity.

There is a “long way to go” in that search, Sun added.

She is working to generate a chemical compound in collaboration with other groups.

A long, productive journey

Born and raised in China, Sun has been an active and important contributor to Mills’s lab.

“I’ll miss [Sun] personally as well as in the lab,” Mills said. “She’s been a really good role model and teacher across the Cold Spring Harbor campus and in my lab.”

Mills is “really excited about [Sun’s] future,” she said. “She’ll be really great” at running her own lab.”

For her part, Sun enjoyed her time on Long Island, where she appreciated the natural environment and the supportive culture at Cold Spring Harbor Laboratory.

Sun described her time on Long Island as a “very exciting and satisfying journey.” 

She is determined to study and understand cancer for a number of reasons.

“I know people who died of cancer,” she said. “It’s a terrible disease and it’s urgent to find more efficient therapeutic strategies to stop cancers and improve human heath.”

Sun is also eager to embrace the opportunity to mentor and inspire other students of science.

“Teaching is very important,” she said. She looks forward to helping students grow as professionals to create the “next generation of scientists.”

Joanna Wysocka

By Daniel Dunaief

This is part one of a two-part series featuring Cold Spring Harbor Laboratory alums Joanna Wysocka, Robert Tjian, Victoria Bautch, Rasika Harshey and Eileen White. Part two will be in the issue of Aug. 25.

Often working seven days a week as they build their careers, scientists plan, conduct and interpret experiments that don’t always work or provide clear cut results.

Driven by their passion for discovery, they tap into a reservoir of ambition and persistence, eager for that moment when they might find something no one else has discovered, adding information that may lead to a new technology, that could possibly save lives, or that leads to a basic understanding of how or why something works.

Nestled between the shoreline of an inner harbor along the Long Island Sound and deciduous trees that celebrate the passage of seasons with technicolor fall foliage, Cold Spring Harbor Laboratory has been a career-defining training ground for future award-winning scientists.

Five alumni of Cold Spring Harbor Laboratory recently shared their thoughts, experiences, and reflections on the private lab that was founded in 1890.

While they shared their enthusiasm, positive experiences and amusing anecdotes, they are not, to borrow from scientific terminology, a statistically significant sample size. They are also a self-selecting group who responded to email requests for interviews. Still, despite their excitement about an important time in their lives and their glowing description of the opportunities they had to hone their craft, they acknowledged that this shining lab on the Sound may not be paradise for everyone.

Cold Spring Harbor Laboratory is considerably smaller than some of the research universities around the country. Additionally, scientists with a thin skin — read on for more about this — may find their peers’ readiness to offer a range of feedback challenging. Still, the lab can and has been a launching pad.

A suitcase and a dream

Joanna Wysocka’s story mirrors that of other immigrants who came to the United States from their home countries. Wysocka arrived from Poland in 1998 with one suitcase that included mementos from her family, a Polish edition of her favorite book, One Hundred Years of Solitude, and a dream of developing her scientific career.

She was also chasing something else: her boyfriend Tomek Swigut, who had come to Cold Spring Harbor Laboratory. “I was fresh off the boat without any fancy resume or anything,” Wysocka recalls. “They really took a chance on me.”

Joanna Wysocka

While she learned how to conduct scientific experiments, she also recognized early on that she was a part of something bigger than herself. Early on, she found that people didn’t hold back in their thoughts on her work. “You always got critical feedback,” she said. “People felt very comfortable picking apart each other’s data.”

The positive and negative feedback were all a part of doing the best science, she explained.

Wysocka felt the inspiration and exhilaration that comes from a novel discovery several times during her five-year PhD program.

“It’s 11 p.m. in the evening, you’re in the dark room, developing a film, you get this result and you realize you’re a person who knows a little secret that nobody else in the world knows just yet,” she recalled. “That is really wonderful.”

For special occasions, the lab celebrated such moments with margaritas. Winship Herr, her advisor, made particularly strongest ones. 

In one of her biggest projects, Wysocka was working with a viral host cell factor, or HCF. This factor is critical for transcription for the Herpes simplex virus. What wasn’t clear, however, was what the factor was doing. She discovered that this factor worked with proteins including chromatin modifiers. “From this moment, it set me up for a lifetime passion of working on gene regulation and chromatin,” she said.

As for the scientific process, Wysocka said Herr offered her critical lessons about science. When she started, Herr expected two things: that she’d work hard and that she’d learn from her mistakes. During the course of her work, she also realized that any work she did that depended on the result of earlier experiments required her own validation, no matter who did the work or where it was published. “You need to repeat the results in your own hands, before you move on,” she explained.

Despite the distance from the lab to New York City and the smaller size of the lab compared with large universities, Wysocka never felt isolated. “Because of all the conferences and courses, the saying goes that ‘if you want to meet somebody in science, go to a Cold Spring Harbor bar and sit and wait.’” That, however, is not something she took literally, as she put considerable hours into her research. While she wishes she had this incredible foresight about choosing Cold Spring Harbor Laboratory, she acknowledges that she was following in Swigut’s footsteps.

The choice of CSHL worked out well for her, as her research has won numerous awards, including the Vilcek Prize for Creative Promise in Biomedical Science, which recognizes immigrant scientists who have made a contribution to U.S. society. She now works as Professor at Stanford University and is married to Swigut.

Swinging for the fences

In 1976, Robert Tjian had several choices for the next step in his developing scientific career after he completed his PhD at Harvard University. James Watson, who had shared the Nobel Prize in 1962 for the double helix molecular structure of DNA with Francis Crick and Maurice Wilkins and was director at Cold Spring Harbor Laboratory, convinced him to conduct his postdoctoral research at CSHL.

Robert Tjian

The contact with Watson didn’t end with his recruitment. Tjian, who most people know as “Tij,” talked about science on almost a daily basis with Watson, which he considered an ‘incredible privilege.”

Although he only worked at CSHL for two years, Tjian suggested the experience had a profound impact on a career that has spanned six decades. 

Learning about gene discovery was the main driver of his time at CSHL. An important discovery during his work at CSHL was to “purify a protein that binds to the origin of replication of a tumor virus, which was what [Watson] wanted me to do when he recruited me,” he said. That launched his career in a “positive way.”

Tjian feels fortunate that things worked out and suggested that it’s rare for postdoctoral students to achieve a transformative career experiment in such a short period of time either back then or now. He attributes that to a combination of “being in the right place at the right time,” luck and hard work.

At Berkeley, where he is Professor of Biochemistry, Biophysics and Structural Biology and has been running a lab since 1979, he has observed that the most successful researchers are the ones who are “swinging for the fences. If you don’t swing for the fences and get lucky, you sure as hell aren’t going to hit a home run.”

Tjian learned how to run a lab from his experience at CSHL. He selects for risk takers who are independent and feels the only way to motivate people is to ensure that the work they are pursuing involves questions they want to solve.

One of the most important and hardest lessons he learned during his research career was to “fail quickly and move on.” He tells his student that about 85 percent of their experiments are going to fail, so “get used to it and learn from it.”

Despite his short and effective stay at CSHL, Tjian suggested he made “more than his fair share” of mistakes. Terri Grodzicker, who is currently Dean of Academic Affairs at CSHL, taught Tjian to do cell culture, which he had never done before. He contaminated nearly all the cultures for about a month.

While Tjian described the lab as a “competitive place,” he felt like his colleagues “helped each other.”

When he wasn’t conducting his experiments or contaminating cultures, he spent time on the tennis court, playing regularly with Watson. Watson wasn’t “exactly the most coordinated athlete in the world,” although Tjian respected his “remarkably good, natural forehand.” He was also one of the few people who was able to use the lab boat, which he used to fish for striped bass and bluefish early in the morning. “I would try to drag all kinds of people out there,” he said. 

While his CSHL experience was “the best thing” for him, Tjian explained that the lab might not be the ideal fit for everyone, in part because it’s considerably smaller than larger universities. At Berkeley, he has 40 to 55 PhD students in molecular biology and he can interact with 40,000 undergraduates, which is a “very different scale.”

Tjian has returned many times to CSHL and is planning to visit the lab at the end of August for a meeting he’s organizing on single molecule microscopy.

Each time he comes back, he “always felt like I was coming home,” he said.