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.”
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.
Estrogen plays an important role in the developing mouse brain. By facilitating connections to other brain regions, estrogen turns on genes that affect how the brain of male and female rodents develops and, down the road, how mice behave.
Cold Spring Harbor Laboratory Associate Professor Jessica Tollkuhn this week, along withgraduate student Bruno Gegenhuber who recently earned his PhD, published research in the journal Nature that demonstrates how a specific region of the brain, called the bed nucleus of the stria terminalis, or BNST, responds to estrogen when the hormone receptor binds to DNA.
Male rodents convert a surge in testosterone into estrogen, which then triggers the development of more cells in the BNST than in female rodents. Later on in life, this can affect mating, parenting and aggression.
At this point, there is no data on how the BNST is masculinized in humans, although it is bigger in adult men than in women. Scientists also don’t know what the BNST does in humans. The BNST in humans is not much bigger than it is in mice.
On a broader scale, by understanding how estrogen shapes the developing brain differently in males and females, Tollkuhn hopes to discover the progression of behavioral disorders that are often more prevalent in one gender than the other. Boys have more neurodevelopmental disorders than girls, such as autism, language delays, dyslexia and attention deficit hyperactivity disorder, or ADHD. Girls, on the other hand, particularly after puberty, have twice the incidence of major depression compared to their contemporary male counterparts, Tollkuhn said.
Tollkuhn is part of a collaboration, funded by the Simons Foundation, to study autism. The CSHL researcher doesn’t believe autism originates in any particular brain region, describing it as a complex disorder with many causes.
“I do think that sex differences in brain regions such as the BNST can intersect with other genetic and environmental factors to increase vulnerability to developing certain symptoms in boys,” she explained.
In rodents, estrogen protects against programmed cell death. In the BNST and a few other brain regions, there are sex differences in cell death that are dependent on hormone exposure. A male mouse without exposure to estrogen would not have a larger BNST.
History of her research
Tollkuhn has been looking for estrogen receptor alpha in the brain since she started her post doctoral research at UCSF in 2007. The genome-wide targets of this receptor in breast cancer cells were first described in 2006.
Back then, the technology wasn’t good enough to capture estrogen receptor alpha binding in the small, sparse population of cells. These receptors, after all, aren’t in most brain cells.
The receptors for a hormone that plays such an important developmental role sit in the same place in males and females.
Tollkuhn’s assumption going into this study was that estrogen receptor alpha would have access to different genes in adult males and females, based on the different life histories of when the two sexes had prior estrogen exposure, which was transient in the developing male brain and fluctuated in females after puberty.
That, however, was not the case. Giving females and males the same hormones caused the genome to respond the same way.
“It’s really the differences of which hormones are present in the circulation that determines what genes are active,” she explained in an email.
Future studies
Tollkuhn is interested in the variation of hormones, receptors and gene responses between individuals within a single species and among various species.
She suggested that a spectrum of variability in sexual differentiation likely exists within and across species. The differences in the way these hormones and receptors shape individual development “is advantageous” because the plasticity in behaviors makes a species more resilient to subtle or dramatic changes in the environment, enabling an organism to alter its behaviors depending on internal states such as hunger, time of year, or place in a social hierarchy.
Tollkuhn would also like to know the genomic targets of androgen receptor, within the BNST and elsewhere. She would like to look at where estrogen receptors and androgen receptor are expressed in the developing human brain. She also plans to study estrogen receptor beta, which is “poorly understood even outside the brain.”
Studying these receptors and the genes they alter could enhance an understanding of cognition and mood, as well as measures of stress and anxiety.
Women with estrogen receptor positive breast cancer sometimes take a medication that blocks estrogen in the breast and in the brain. A side effect of this medicine, however, is that it causes women to have menopausal-type symptoms, such as disrupted sleep, thermoregulatory issues like “hot flashes,” and mood disorders.
Tollkuhn and Cassandra Greco, a graduate student at Stony Brook University, will investigate how different breast caner medications that target estrogen receptor alpha differentially affect its recruitment to the genome.
Tollkuhn plans to test the three most commonly prescribed treatments to see how they are affecting the brain and what they are doing to the estrogen receptor regulated genes in the brain.
She hopes one day to help develop a therapy with more specific targets that doesn’t have the same side effects.
Science origin story
When she was young, Tollkuhn liked reading books about biology, but didn’t discover her interest in research until she attended Mills College in Oakland, CA.
She got her first research experience working at biotech companies during her undergraduate studies. At that point, she learned that she was capable of doing challenging experiments.
In addition to continuing to read about a range of other research experiments, Tollkuhn enjoys the challenge of research.
“The joy of this job is that I get paid to ask questions that are interesting,” she said.
Attendees at a conference at CSHL, an in-person tradition started in 1933. These conferences were suspended from 1943 to 1945 during WWII and were virtual during the pandemic in 2020 and for most of 2021. Photo by Miriam Chuai/CSHL
By Daniel Dunaief
For scientists, meetings and conferences aren’t just a chance to catch up on the latest research, gossip and see old friends: they can also provide an intellectual spark that enhances their careers and leads to new collaborations.
Amid the pandemic, almost all of those in-person conferences stopped, including the annual courses and meetings that Cold Spring Harbor Laboratory hosts. The internationally renowned lab has run meetings since 1933, with a few years off between 1943 and 1945 during World War II.
CSHL’s David Stewart. Photo by Gina Motisi/CSHL
While scientists made progress on everything from basic to translational research, including in laboratories that pivoted towards work on the SARS-CoV-2 virus, which causes COVID-19, they missed out on the kinds of opportunities that come from in-person interactions.
Assuming COVID infection rates are low enough this fall, CSHL is hoping to restart in-person conferences and courses, with the first conference that will address fifty years of the enzyme reverse transcriptase scheduled for Oct. 20th through the 23rd. That event was originally scheduled for October of 2020.
One of the planned guest speakers for that conference, David Baltimore, who discovered the enzyme that enables RNA to transfer information to DNA and is involved in retroviruses like HIV, won the Nobel Prize.
“I am hoping that there will be significant participation by many eminent scientists, so that is in itself somewhat [of] a ceremonial start,” wrote David Stewart, Executive Director of meetings and courses at Cold Spring Harbor Laboratory.
To attend any of the seven in-person meetings on the calendar before the end of the year, participants need to have vaccinations from either Pfizer, Moderna, Johnson & Johnson or AstraZeneca.
Attendees will have to complete an online form and bring a vaccination card or certificate. Scientists who don’t provide that information “will not be admitted and will not get a key to their room or be able to attend the event,” Stewart said.
CSHL also plans to maintain the thorough and deep cleaning procedures the lab developed.
Stewart hopes that 75 to 80 percent or more of the talks presented will be live, with a virtual audience that could be larger than the in-person attendance.
“It is important to have a critical mass of presenters and audience in-person, but there’s no real limit on how large the virtual audience could be,” he explained.
Typically, the courses attract participants from over 50 countries. Even this year, especially with travel restrictions for some countries still in place, Stewart expects that the majority of participants will travel from locations within the United States.
The Executive Director explained that CSHL was planning to introduce a carbon offset program for all travel to conferences and courses that the facility reimburses starting in 2020. After evaluating several options, they plan to purchase carbon offsets from Cool Effect and will encourage participants paying their own way to do the same or through a similar program.
The courses, meanwhile, will begin on October 4th, with macromolecular crystallography and programming for biology. CSHL hopes to run six of these courses before the end of the year, including a scientific writing retreat.
“We are looking to 100 percent enrollment for our courses, so likely this year that will largely be domestic,” Stewart explained.
The courses, which normally have 16 participants, may have 12 students, as the lab tries to run these training opportunities safely without masks or social distancing.
From March of 2020 through the end of last year, the lab had planned 25 meetings and 25 courses. As the pandemic spread, the lab pivoted to virtual meetings. “I felt like a car salesman trying to sell virtual conferences,” Stewart recalled. For the most part, the lab was able to keep to its original schedule of conferences, albeit through a virtual format.
In addition to the scheduled meetings, CSHL decided to add meetings to discuss the latest scientific information related to COVID research.
Stewart approached Hung Fan, a retired virologist at the University of California at Irvine, to help put together these COVID exchanges. Those meetings occurred in June, July, August, October, and January. The sixth one recently concluded.
The meetings addressed “everything around the science of the virus,” Stewart said, which included the biology, the origin, the genomics, the immune response, vaccines, therapeutics and diagnostics, among other scientific issues.
“There was a lot of excellent work being done around SARS-CoV-2,” Stewart said. “We were trying to identify that early on. It was helpful to have people who knew the field well.”
Fan said he combed through preprints like the CSHL-based bioRxiv and related medRxiv every day for important updates on the disease.
Fan described the scientific focus and effort of the research community as being akin to the Manhattan Project which built the atomic bomb during World War II, where “everybody said, ‘We have a common enemy and we want to apply all our capabilities to combating that.”
While Fan is pleased with the productive and valuable exchanges that occurred amid the virtual conferences, he recognized the benefit of sharing a room and a drink with scientific colleagues.
“A lot of the productive interactions at meetings take place in a social setting, at the bar, over dinner” and in other unstructured gatherings, he said. “People are relaxed and can share their scientific thoughts.”
After presentations, Fan described how researchers discuss the work presented and compare that to their own efforts. It’s easier to talk with people in person “as opposed to making a formalized approach through letters and emails.”
Cold Spring Harbor Laboratory’s DNA Learning Center and the Red Cloud Indian School recently launched a program called Students Talk Science in which high school students could ask questions from several senior scientists about the vaccine for COVID-19 and healthcare disparities in minority communities.
Dr. Eliseo Pérez-Stable
The talks are a component of a program called STARS, for Science, Technology & Research Scholars, an effort the group started in 2019 to build interest and experience in STEM for minority students. The Students Talk Science program engaged the STARS participants and students from the Red Cloud Indian School on the Pine Ridge Indian Reservation.
Jason Williams, Assistant Director of Inclusion and Research Readiness at the DNA Learning at CSHL; Brittany Johnson, an educator at the DNA Learning Center; Katie Montez, a teacher at the Red Cloud Indian School ;and Carol Carter, Professor in the Department of Microbiology and Immunology at the Renaissance School of Medicine at Stony Brook University, wanted to connect minority students with practicing physicians and scientists in leadership positions at the National Institutes of Health to allow them to ask questions of concern regarding the vaccines.
Dr. Monica Webb-Hooper
“We did this to empower them to function as trusted resources for their families, friends and network,” Carter, who participated as an individual rather than as a formal representative of Stony Brook University, explained in an email.
The conversations included interactions with Dr. Eliseo Pérez-Stable, Director of the National Institute on Minority Health and Health Disparities, or NIMHD at the National Institutes of Health; Dr. Monica Webb Hooper, Deputy Director of the NIMHD; Dr. Gary Gibbons, Director of the National Heat, Lung and Blood Institute; and Dr. Eugenia South, Assistant Professor in Emergency Medicine at the Hospital of the University of Pennsylvania and the Presbyterian Medical Center of Philadelphia.
The high school students prepared informed questions.
Dr. Gary Gibbons
“The students were encouraged to do their own research” on the interview subjects, Williams explained. “We asked students not to look just at [each] interviewee’s science work, but also any personal background/ biography they could find. Students had multiple opportunities for follow up and were largely independent on their choices of questions.”
Samantha Gonzalez, a student at Walter G. O’Connell Copiague High School, asked South about her initial skepticism for the vaccine.
South acknowledged that she had no interest in taking the vaccine when she first learned she was eligible. “I almost surprised myself with the fierceness with which I said, ‘No,’” South said. “I had to step back and say, ‘Why did I have this reaction?’”
Some of the reasons had to do with mistrust, which includes her own experiences and the experiences of her patients, whom she said have had to confront racism in health care. In addition, she was unsure of the speed at which the vaccine was developed. She had never heard of the mRNA technology that made the vaccines from Moderna and Pfizer/ BioNTech possible.
“I had to do my own research to understand that this wasn’t a new technology,” she said.
Dr. Eugenia South
South went through a learning process, in which she read information and talked to experts. After she received answers to her questions and with the urging of her mother, she decided to get the vaccine.
“I’m so thankful that I was able to do that,” South said.
The team behind Students Talk Science not only wanted to empower students to make informed decisions, but also wanted to give them the opportunity to interact with scientists who might serve as personal and professional role models, providing a pathway of information and access that developed amid an extraordinary period.
“We wanted to engage high school students in something unique going on in their lifetime,” Carter said.
To be sure, Carter and Williams said the scientific interactions weren’t designed to convince students to take the vaccine or to urge their parents or families to get a shot. Rather, they wanted to provide an opportunity for students to ask questions and gather information.
“We purposely did not participate in the discussions because our goal was not to convince or ‘preach,’ but to enable students and their networks to make informed decisions,” Carter said.
Parents had to read and sign off on the process for students to participate. The organizers didn’t want a situation where they were doing something that conflicts with a parents’ decisions or views.
Williams added that the purpose of the conversations was never to say, “you must get the vaccine. Our purpose is to talk about information.”
The objective of these interactions is to help minority students find a track for a productive career in ten years.
In addition to questions about hesitancy, Williams said some of the high school students expressed concerns about access to vaccines. He is pleased with the result of this effort to connect students with scientists and doctors.
The group was “able to get some of the most important scientists in the country to sit with high school students,” he said. “It was very powerful to give students access to these role models.”
The goal is to stay with these students, mentor them and stay in touch with them until they graduate from college and, perhaps, return as research scientists.
Even for students who do not return, this type of interaction could provide an “impactful experience that prepares them for other opportunities,” Williams explained, adding that the STARS program would incorporate the Students Talk Science Series into the program more formally in the future, with new students and topics most likely during the school year.
The interviews are available at the following website: https://dnalc.cshl.edu/resources/students-talk-science/.
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.”
Heather Johnson has been at the helm of The Northport Historical Society for the past five years. Photo by Alex Petroski
The Northport Historical Society is searching for a new director, as Heather Johnson, who has held the position for five years, is moving on to a new job with Cold Spring Harbor Laboratory.
“Her enthusiasm for her job radiates from her and has enabled the Northport community to become much more supportive,” society board of trustees President Steven King said about Johnson in an interview Tuesday. “All of our events that involve social interaction have improved because she enjoys doing things for people, helping people, takes pride in Northport community and that’s been very helpful over the past five years to make the historical society a more successful institution in the village.”
Johnson, whose last day is Feb. 11, arrived in January 2011 with nearly two decades of experience in various departments at Hofstra University. She spent time in their public relations department and in the office of international admissions, taught art history and even spent time working in their on-campus museum.
Johnson also had a unique upbringing, spending years living in New York City, Jacksonville, Florida, and England while her mother pursued an opera career. She returned to Long Island in 1989 and currently lives in Smithtown.
Above, the Northport Historical Society. Photo from Heather Johnson
Her journey prior to landing in Northport, coupled with some of her own personal interests, made the position at the historical society a fit too perfect to pass up.
“I’m a history buff,” Johnson said in an interview Tuesday. “I’ve always loved history, since I was a little kid.” She laughed and added, “There are not many little girls who are interested in history.”
Johnson saw a 20 percent increase in membership in her first year alone, bringing the society’s total membership to more than 400. She maintained that number during the rest of her five-year tenure. The group also has a new website.
The outgoing director was adamant that she accomplished nothing on her own.
“I’m not going to take credit for anything that’s happened around here,” Johnson said. “It really is a team. What we have is people who are really dedicated and who really love Northport, and are very interested in the historical society, or history in general.”
During her time, Johnson was responsible for scheduling programs and exhibits for the museum, recruiting members and creating events. Some of her favorites that she mentioned were a Civil War cooking class and an educational and social tour of Northport Harbor.
“My mantra has been to educate and to entertain,” Johnson said. “When you can put those two things together, it’s a beautiful thing.”
King was not as dismissive of Johnson’s impact and accomplishments as she was.
“I don’t think that there’s any way to replace personality traits that Heather has,” King said. “We hope to settle on a final candidate who has some of what Heather has brought to us, but perhaps a different set of capabilities that will enhance our mission in the future.”
“There are not many little girls who are interested in history.”
— Heather Johnson
Johnson shared an emailed letter from a community member that she received when news of her imminent departure got out. The sender preferred to remain anonymous.
“We have learnt a lot about the village, its history and its people — and always in a welcoming and congenial setting,” the email reads.
Johnson plans to maintain a relationship with the historical society as a member of the fundraising committee and their gallery committee. She also insists that she’s not leaving the community that has become such a large part of her life, mainly due to the close bond she feels.
“This village, and Northport in general, they just really know how to come together for each other,” she said. “I plan to eat, play and shop in Northport for the rest of my life. It’s just a really, really incredible place.”
Suffolk County Executive Steve Bellone, center, along with regional leaders, announced a new regional plan on Tuesday. Photo from the county executive’s office
As the percentage of youth on Long Island declines, regional leaders are determined to entice young people to move in and stay, but their plan comes with a price.
On Tuesday, County Executive Steve Bellone (D) and several regional leaders, including Brookhaven Town Supervisor Ed Romaine (R), announced they are seeking $350 million to fund the Long Island Innovation Zone, I-Zone, plan. I-Zone aims to connect Long Island’s transit-oriented downtown areas, like New Village in Patchogue, the Meadows at Yaphank and the planned Ronkonkoma Hub, to institutions like Stony Brook University, Brookhaven National Laboratory and Cold Spring Harbor Laboratory.
The I-Zone plan emphasizes the use of a bus rapid transit, or BRT, system that runs north to south and would connect Stony Brook University and Patchogue. There will also be a paralleling hiking and biking trail, and the system will serve as a connection between the Port Jefferson, Ronkonkoma and Montauk Long Island Rail Road lines.
The goal is to make Long Island more appealing to the younger demographic and avoid local economic downturns.
According to the Long Island Index, from 2000 to 2009, the percentage of people aged 25-34 decreased by 15 percent. The majority of these individuals are moving to major cities or places where transportation is readily accessible.
“We must challenge ourselves because if we don’t, we have an Island at risk,” Romaine said. Government officials acknowledged that without younger people living on Long Island the population will be unable to sustain the local economy. Fewer millennials means there are less people who will purchase property and contribute to the success of businesses in the area.
The proposal comes after Governor Andrew Cuomo’s (D) call for regional planning.
The plan also builds upon the Ronkonkoma Hub plan, with the installation of sewers and a new parking area. The I-Zone proposal claims to improve Long Island’s water quality, as funding will help connect sewers through Islip downtown areas to the Southwest Sewer District.
Additionally, the plan calls for the construction of a new airport terminal on the north side of Long Island MacArthur Airport in Islip and for the relocation of the Yaphank train station in closer proximity to Brookhaven National Laboratory.
“We have all that stuff [access to recreational activities, education center and downtown areas] here but we don’t have a connection. We don’t have any linked together,” said Justin Meyers, Suffolk’s assistant deputy county executive for communications.
Bellone and Romaine, as well as Stony Brook University President Samuel Stanley, Islip Town Supervisor Angie Carpenter (R), Suffolk County Legislator Kara Hahn (D-Setauket), Long Island Regional Planning Council Chairman John Cameron, Patchogue Mayor Paul Pontieri, Vice President of Development and Community Relations at CSHL Charles Prizzi, Chief Planning Officer of the Long Island Rail Road Elisa Picca, Director of BNL Doon Gibbs, and founder of Suburban Millennial Institute Jeff Guillot, were involved with the I-Zone proposal.
If funding for the project is received, construction could begin in approximately two years, Meyers said, adding that constructing the BRT and the hiking and biking trial would take as few as five years.
Bellone said that without younger people moving in, the trend could lead to the Island’s economic stagnation.
“We are aging faster than any other region in our country,” he said. “The inevitable result of that will be an ever-growing population that naturally is pulling more social services infrastructure.”
