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

By Daniel Dunaief

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Vaccinations

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

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

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

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

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

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

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

Shorter term changes

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

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

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

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

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

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

English origins

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

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

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

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

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

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

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

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

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Pictured from left are David Lyons, Maggie Ramos and Michael Voltz of PSEG Long Island with John Tuke, Brandon King, Bruce Schadler and Steve Monez of Cold Spring Harbor Laboratory. Photo courtesy of PSEG LI

PSEG Long Island recently commended Cold Spring Harbor Laboratory (CSHL) for its commitment to the environment. The lab completed several projects that qualified for rebates of nearly $280,000 through PSEG Long Island’s energy efficiency programs. 

The renovations include replacing 5,700 lights with energy-saving LEDs, heating and cooling upgrades, and a sub-metering project, which will allow the lab to more effectively monitor and manage its energy usage. 

CSHL is expected to realize nearly $300,000 in annual savings with the 1.7 million kWh of electricity these projects will save per year. 

Pictured from left are David Lyons, Maggie Ramos and Michael Voltz of PSEG Long Island with John Tuke, Brandon King, Bruce Schadler and Steve Monez of Cold Spring Harbor Laboratory.

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Alexandra Nowlan

By Daniel Dunaief

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

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

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

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

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

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

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

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

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

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

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

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

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

Recent publication

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

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

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

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

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

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

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

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

Deficits in vocalizations also can affect this behavior.

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

A winding path

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

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

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

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

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

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

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

Postdoctoral transition

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

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

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

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

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

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

Born on the same day

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

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

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

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

Nowlan appreciated how Peacock-López connected with students.

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

Peacock-López has known Nowlan for decades.

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

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

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

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

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

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

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

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

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Cold Spring Harbor Laboratory. Photo courtesy Cold Sping Harbor Laboratory website

By Daniel Dunaief

A stock fund is taking a page out of the Newman’s Own playbook.

The food company which was started by the late actor Paul Newman and author A.E. Hotchner donates its after tax profits to charity through the Newman’s Own Foundation, enabling consumers to feel that they aren’t just covering their salad with tasty dressing but are helping the world through their consumer choices.

Range Cancer Therapeutics, an exchange-traded fund that purchases a broad basket of cancer therapeutic stocks, created a new partnership with Cold Spring Harbor Laboratory to contribute to cancer research.

The fund, which was started in 2015, plans to contribute 23 percent of its revenues, reflecting the 23 pairs of chromosomes in the human genome, each quarter to Cold Spring Harbor Laboratory.

“The contribution from Range will directly benefit the research efforts at CSHL, underscoring our commitment to advancing scientific innovation in oncology therapeutics,” Range ETF’s founder and CSHL Association Board Member Tim Rotolo, said in a statement. The ETF provides “exposure to nearly the entire lifecycle of drug development and distribution, and this new collaboration with CSHL provides an opportunity for investors to also see their money go toward the earliest stages of cancer breakthroughs.”

Revenues collected by the fund are likely to vary by quarter, depending on the amount of money the fund manages. With an estimated $12.1 million in assets under management as of the end of September and an expense ratio of 0.79%, the fund could contribute about $21,850.

“Hopefully, people will feel when they’re buying the ETF that they are in some ways supporting cancer research,” said Charles Prizzi, Senior Vice President for Advancement & Special Advisor to CSHL President Bruce Stillman.

Prizzi anticipates that the funding could support the lab’s efforts to conduct a broad range of research as CSHL’s staff, who come to the site from all over the world, seek to address the kinds of questions that can lead to advancements in a basic understanding of processes as well as to translational breakthroughs that can help in the prevention, diagnosis and treatment of various diseases.

Prizzi hopes this partnership will attract attention and inspire other fund managers or businesses to contribute to the lab, particularly amid periods when the budgets for federal funding agencies that support research rise and fall.

Borrowing from the language of genetics, Prizzi hoped that this kind of arrangement will be “replicated” by others.

 NASDAQ event

The NASDAQ stock market, which is where the Range Cancer Therapeutics Fund trades under the ticker CNCR, will celebrate the partnership on November 14th in New York City.

The Nasdaq tower will feature a visual display, while Range ETFs and CSHL leadership and guests come together at the Nasdaq podium to mark the ongoing contribution.

Dave Tuveson, head of the Cancer Center, Professor Adrian Krainer, who developed an effective treatment for spinal muscular atrophy using antisense oligonucleotide to affect gene splicing, Vice Chair Howard Morgan, and Goldman Sachs’s Roy Zuckerberg, and others will attend the event.

d Spring Harbor Laboratory President Bruce Stillman. File photo

“Cold Spring Harbor Laboratory is one of only seven national basic biological research cancer centers designated by the National Cancer Institute in Washington, DC,” Bruce Stillman, CEO of the lab said in a statement. “The institution is investing heavily in the growth of our cancer program, specifically in multidisciplinary, collaborative ventures as part of our new brain-body physiology initiative.”

Prizzi is often searching for novel ways to support research and was pleased with the contribution and hopeful that it would spur other creative donations and support.

“I hope people will learn from it and copy it,” Prizzi said. “It will benefit the lab for many years to come.”

Rotolo joined the board at CSHL earlier this year and has supported the lab for about a decade.

Rotolo had approached the lab to establish this financial commitment.

The laboratory is a 501c3 nonprofit institution, which means that donations to the lab are tax deductible.

Prizzi suggested that interested donors often reach out to him towards the end of December.

“We would love to have more people support what we’re doing,” said Prizzi.

CSHL is home to eight Nobel Prize winners and employs 1,000 people, including 600 scientists, students and technicians.

The Meetings & Courses Program bring in more than 12,000 scientists from around the world each year, offering opportunities for researchers to meet and establish collaborations and to learn about the latest scientific breakthroughs.

CSHL is in the first phase of a Foundations for the Future project, which is a seven-acre expansion effort that will tackle research in neuroscience, neuro-AI and the brain-body. Scientists will pursue better patient outcomes by exploring cancer’s whole-body impacts.

In the second phase of the project, the lab will create a new conference center and collaborative research center.

As for the connection with Range, Prizzi added that CSHL is a “lab, we like experiments. This is like an experiment. I hope it goes well and other people build off of it.”

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Shushan Toneyan and Peter Koo at Cold Spring Harbor Laboratory. Photo by Gina Motisi/CSHL

By Daniel Dunaief

The real and virtual world are filled with so-called “black boxes,” which are often impenetrable to light and contain mysteries, secrets, and information that is not available to the outside world.

Sometimes, people design these black boxes to keep concepts, ideas or tools outside the public realm. Other times, they are a part of a process, such as the thinking behind why we do certain things even when they cause us harm, that would benefit from an opening or a better understanding.

In the world of artificial intelligence, programs learn from a collection of information, often compiling and comparing enormous collections of data, to make a host of predictions.

Companies and programmers have written numerous types of code to analyze genetic data, trying to determine which specific mutations or genetic alterations might lead to conditions or diseases.

Left on their own, these programs develop associations and correlations in the data, without providing any insights into what they may have learned.

That’s where Peter Koo, Assistant Professor at Cold Spring Harbor Laboratory, and his former graduate student Shushan Toneyan come in.

The duo recently published a paper in Nature Genetics in which they explain a new AI-powered tool they designed called CREME, which explored the genetic analysis tool Enformer.

A collaboration between Deep Mind and Calico, which is a unit of Google owner Alphabet, Enformer takes DNA sequences and predicts gene expression, without explaining what and how it’s learning.

CREME is “a tool that performs like large-scale experiments in silico [through computer modeling] on a neural network model that’s already been trained,” said Koo. 

“There are a lot of these models already in existence, but it’s a mystery why they are making their predictions. CREME is bridging that gap.”

Award winning research

Indeed, for her work in Koo’s lab, including developing CREME, Toneyan recently was named a recipient of the International Birnstiel Award for Doctoral Research in Molecular Life Sciences.

“I was genuinely surprised and happy that they selected my thesis and I would get to represent CSHL and the Koo lab at the ceremony in Vienna,” Toneyan, who graduated from the School of Biological Sciences, explained. 

Toneyan, who grew up in Yerevan, Armenia, is currently a researcher in The Roche Postdoctoral Fellowship Programme in Zurich, Switzerland.

She said that the most challenging parts of designing this tool was to focus on the “interesting and impactful experiments and not getting sidetracked by more minor points more likely to lead to a dead end.”

She credits Koo with providing insights into the bigger picture.

New knowledge

Without taking DNA, running samples in a wet lab, or looking at the combination of base pairs that make up a genetic code from a live sample, CREME can serve as a way to uncover new biological knowledge.

CREME interrogates AI models that predict gene expression levels from DNA sequences.

“It essentially replicates biological or genetic experiments in silico through the lens of the model to answer targeted questions about genetic mechanisms,” Toneyan explained. “We mainly focused on analyzing the changes in models outputs depending on various perturbations to the input.”

By using computers, scientists can save considerable time and effort in the lab, enabling those who conduct these experiments to focus on the areas of the genome that are involved in various processes and, when corrupted, diseases.

If scientists conducted these experiments one mutation at a time, even a smaller length sequence would require many experiments to analyze.

The tool Koo and Toneyan created can deduce precise claims of what the model has learned.

CREME perturbs large chunks of input sequence to see how model predictions change. It interrogates the model by measuring how changes in the input affect model outputs.

“We need to interpret AI models to trust their deployment,” Toneyan said. “In the context of biological applications, we are also very interested in why they make a certain prediction so that we learn about the underlying biology.”

Using ineffective and untested predictive models will cause “more harm than good,” added Koo.  “You need to interpret [the AI model’s] programs to trust them for their reliable deployment” in the context of genetic studies

Enhancers

Named for Cis Regulatory Element Model Explanations, CREME can find on and off switches near genetic codes called enhancers or silencers, respectively.

It is not clear where these switches are, how many there are per gene and how they interact. CREME can help explore these questions, Toneyan suggested.

Cis regulatory elements are parts of non-coding DNA that regulate the transcription of nearby genes, altering whether these genes manufacture or stop producing proteins.

By combining an AI powered model such as Enformer with CREME, researchers can narrow down the possible list of enhancers that might play an important genetic role.

Additionally, a series of enhancers can sometimes contribute to transcription. A wet lab experiment that only knocked one out might not reveal the potential role of this genetic code if other nearby areas can rescue the genetic behavior.

Ideally, these models would mimic the processes in a cell. At this point, they are still going through improvements and are not in perfect agreement with each other or with live cells, Toneyan added.

Scientists can use the AI model to aid in the search for enhancers, but they can’t blindly trust them because of their black box nature.

Still, tools like CREME help design genetic perturbation experiments for more efficient discovery.

At this point, the program doesn’t have a graphical user interface. Researchers could use python scripts released as packages for different models.

In the longer term, Koo is hoping to build on the work he and Toneyan did to develop CREME.

“This is just opening the initial doors,” he said. “One could do it more efficiently in the future. We’re working on those methods.”

Koo is pleased with the contribution Toneyan made to his lab. The first graduate student who worked with him after he came to Cold Spring Harbor Laboratory, Koo suggested that Toneyan “shaped my lab into what it is.”

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Qingtao Sun, postdoctoral researcher at CSHL, presents a poster of the cachexia research taken at a Society for Neuroscience meeting in 2023 in Washington, DC. Photo by Dr. Wenqiang Zheng

By Daniel Dunaief

Cancer acts as a thief, robbing people of time, energy, and quality of life. In the end, cancer can trigger the painful wasting condition known as cachexia, in which a beloved relative, friend or neighbor loses far too much weight, leaving them in an emaciated, weakened condition.

A team of researchers at Cold Spring Harbor Laboratory has been studying various triggers and mechanisms involved in cachexia, hoping to find the signals that enable this process.

Recently, CSHL scientists collaborated on a discovery published in the journal Nature Communications that connected a molecule called interleukin-6, or IL-6, to the area postrema in the brain, triggering cachexia.

By deleting the receptors in this part of the brain for IL-6, “we can prevent animals from developing cachexia,” said Qingtao Sun, a postdoctoral researcher in the laboratory of Professor Bo Li.

Through additional experiments, scientists hope to build on this discovery to develop new therapeutic treatments when doctors have no current remedy for a condition that is often the cause of death for people who develop cancer.

To be sure, the promising research results at this point have been in an animal model. Any new treatment for people would not only require additional research, but would also need to minimize the potential side effects of reducing IL-6.

Like so many other molecules in the body, IL-6 plays an important role in a healthy system, promoting anti- and pro-inflammatory responses among immune cells, which can help fight off infections and even prevent cancer.

“Our study suggests we need to specifically target IL-6 or its receptors only in the area prostrema,” explained Li in an email.

Tobias Janowitz, Associate Professor at CSHL and a collaborator on this project, recognized that balancing therapeutic effects with potential side effects is a “big challenge in general and also is here.”

Additionally, Li added that it is possible that the progression of cachexia could involve other mechanistic steps in humans, which could mean reducing IL-6 alone might not be sufficient to slow or stop this process.

“Cachexia is the consequence of multi-organ interactions and progressive changes, so the underlying mechanisms have to be multifactorial, too,” Miriam Ferrer Gonzalez, a co-first author and former PhD student in Janowitz’s lab, explained in an email.

Nonetheless, this research result offers a promising potential target to develop future stand alone or cocktail treatments.

The power of collaborations

Working in a neuroscience lab, Sun explained that this discovery depended on several collaborations throughout Cold Spring Harbor Laboratory. 

“This progress wouldn’t be possible if it’s only done in our own lab,” said Sun. “We are a neuroscience lab. Before this study, we mainly focused on how the brain works. We have no experience in studying cachexia.”

This paper is the first in Li’s lab that studied cachexia. Before Li’s postdoc started this project, Sun had focused on how the brain works and had no experience with cachexia.

When Sun first joined Li’s lab three years ago, Li asked his postdoctoral researcher to conduct an experiment to see whether circulating IL-6 could enter the brain and, if so where.

Sun discovered that it could only enter one area, which took Li’s research “in an exciting direction,” Li said.

CSHL Collaborators included Janowitz, Ferrer Gonzalez, Associate Professor Jessica Tolkhun, and Cancer Center Director David Tuveson and former CSHL Professor and current Principal Investigator in Neurobiology at Duke University School of Medicine Z. Josh Huang.

Tollkuhn’s lab provided the genetic tool to help delete the IL-6 receptor.

The combination of expertise is “what made this collaboration a success,” Ferrer Gonzalez, who is now Program Manager for the Weill Cornell Medicine partnership with the Parker Institute for Cancer Immunotherapy, explained in an email.

Tuveson added that pancreatic cancer is often accompanied by severe cachexia.

“Identifying a specific area in the brain that participates in sensing IL-6 levels is fascinating as it suggests new ways to understand physiological responses to elevated inflammation and to intervene to blunt this response,” Tuveson explained. “Work in the field supports the concept that slowing or reversing cachexia would improve the fitness of cancer patients to thereby improve the quality and quantity of life and enable therapeutic interventions to proceed.”

Tuveson described his lab’s role as “modest” in promoting this research program by providing cancer model systems and advising senior authors Li and Janowitz.

Co-leading an effort to develop new treatments for cachexia that received a $25 million grant from the Cancer Grand Challenge, Janowitz helped Sun understand the processes involved in the wasting disease. 

Connecting the tumor biology to the brain is an “important step” for cachexia research, Janowitz added. He believes this step is likely not the only causative process for cachexia.

Cutting the signal

After discovering that IL-6 affected the brain in the area postrema, Sun sought to determine its relevance in the context of cachexia.

After he deleted receptors for this molecule, the survival period for the test animals was double that for those who had interleukin 6 receptors in this part of the brain. Some of the test animals still died of cachexia, which Sun suggested may be due to technical issues. The virus they used may not have affected enough neurons in the area postrema.

In the Nature Communications research, Sun studied cachexia for colon cancer, lung cancer and pancreatic cancer.

Sun expects that he will look at cancer models for other types of the disease as well.

“In the future, we will probably focus on different types” of cancer, he added.

Long journey

Born and raised in Henan province in the town of Weihui, China, Sun currently lives in Syosset. When he’s not in the lab, he enjoyed playing basketball and fishing for flounder.

When he was growing up, he showed a particular interest in science.

As for the next steps in the research, Sun is collaborating with other labs to develop new strategies to treat cancer cachexia.

He is eager to contribute to efforts that will lead to future remedies for cachexia.

“We are trying to develop some therapeutic treatment,” Sun said.

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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.”

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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.”

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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.

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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.

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