Ketamine has received a Hollywood makeover. It used to be known as a rave drug (street name special K) and cat anesthetic. However, in recent years, some doctors have prescribed ketamine to treat conditions from post-traumatic stress disorder to depression. “The practice is not without controversy,” notes Cold Spring Harbor Laboratory (CSHL) Professor Hiro Furukawa.

‘Should we give a hallucinogen to patients in compromised mental states?’ wonder ketamine’s skeptics. The controversy came to a head in 2024 following the death of Matthew Perry. The popular TV actor, best known as Chandler on NBC’s Friends, died from a ketamine overdose. One person charged in connection with Perry’s death was the doctor who’d prescribed him ketamine for depression and anxiety.

This 3D animation illustrates the tension-and-release mechanism that controls how brain receptor GluN1-2B-2D opens and closes its ion channel pore.

“Even putting this aside, many questions remain regarding how ketamine affects the brain,” says Furukawa. “It’s been suggested for over a decade that the drug blocks a specific kind of NMDA receptor (NMDAR), called GluN1-2B-2D.” There was one big problem with this theory. Scientists weren’t quite sure that GluN1-2B-2D existed. A new study from the Furukawa lab shines much-needed light on the situation.

In a paper published in the journal Neuron, Furukawa and postdoc Hyunook Kang prove that GluN1-2B-2D does exist in the mammal brain. They then reconstruct a human version of GluN1-2B-2D. They don’t stop there. Using electron cryo-microscopy (cryo-EM), they capture GluN1-2B-2D in action. The neuroscientists identify the tension-and-release mechanism that controls GluN1-2B-2D movements. They can now see how this mysterious NMDAR opens and closes its ion channel pore. And they go another step further. They reveal several ways ketamine may bind to GluN1-2B-2D.

A series of stunningly detailed visualizations show ketamine molecules becoming attached to specific parts of GluN1-2B-2D. “It’s like a mesh,” explains Furukawa. “Over tiny fractions of a second, ketamine can latch onto these sections and close off the channel.” Furukawa and his colleagues captured four binding patterns. However, they believe there are many other ways ketamine can take hold.

It’s thought that ketamine may ease symptoms of depression and anxiety by affecting GluN1-2B-2D movement. But for how long should the channel remain open or closed? “This likely varies per patient,” Furukawa says. Likewise, side effects of ketamine therapy can range from mild hallucinations to full-on psychosis. However, if scientists can determine how GluN1-2B-2D movements affect the brain, they may be able to synthesize new versions of the drug with fewer harmful side effects. That could offer hope for millions of people living with depression and anxiety. So, that’s where Furukawa and his colleagues at CSHL will set their sights next.

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Every year on February 11, we celebrate International Day of Women and Girls in Science, honoring women and girls’ contributions to a field long dominated by men. Among these trailblazers is Nobel laureate Barbara McClintock, whose groundbreaking work at Cold Spring Harbor Laboratory (CSHL) reshaped our understanding of genetics.

For the filmmaking competition Symbiosis, CSHL postdoc Penelope Lindsay teamed with filmmaker Nora Long to create a short film in one week. In homage to McClintock’s free spirit and deep connection with nature, the pair composed No Two Plants. The film celebrates the curiosity and wonder that fueled McClintock’s discovery of “jumping” genes—those that move within chromosomes, sometimes altering physical traits. Initially met with skepticism, this groundbreaking finding in maize crops earned McClintock the Nobel Prize over 30 years later.

A journey across time, space, and along the history of the maize plant, No Two Plants explores resilience and different ways of knowing.

McClintock’s path to scientific superstardom was far from straightforward. In fact, her theories were seen as so controversial for their time that she stopped submitting her research to academic journals altogether. Rather than listen to her detractors, McClintock listened to what nature was telling her. No Two Plants follows McClintock as she carves out a path for herself and her revolutionary ideas, forever changing the fields of genetics and plant biology. “The film explores the resilience, creativity, and challenges of women in science, using the story of Barbara McClintock as a lens to examine representation and innovation across generations,” says Lindsay, a plant biologist in CSHL Professor David Jackson’s lab.

It’s an experimental film about an experimental pioneer and her enduring legacy. We think McClintock would be proud.

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Public support of science is an investment in the future health, well-being, and security of our nation, in addition to being a driver of U.S. economic development and innovation. The new Supplemental Guidance from the administration of President Trump via the National Institutes of Health (NIH) aims to severely reduce the Indirect Cost Rate for research in our nation’s universities and research institutes. It has abruptly lowered the Indirect Cost Rate to 15%—a huge reduction in support of research. This will have a major negative impact on Cold Spring Harbor Laboratory (CSHL), but even more profound is the overall detrimental impact this Guidance will have on the entire infrastructure of bioscience, impeding future medical breakthroughs and slowing economic growth and affecting thousands of jobs in bioscience.

The impact to Cold Spring Harbor Laboratory and other academic scientific research institutions is unsustainable. CSHL is a 501(c)(3) nonprofit research and education institution that has shaped contemporary biomedical research and education with programs in cancer, neuroscience, plant biology, and quantitative biology for 134 years. Our researchers work on diseases from Alzheimer’s and autism to rare childhood cancers and cancers that impact millions worldwide. Discoveries at CSHL have resulted in the development of one of the most impactful treatments for breast cancer and a lifesaving treatment for spinal muscular atrophy (SMA), a neurodegenerative disease, which was the leading genetic cause of infant death. These are just a couple of the many incredible scientific advancements researchers are making here.

CSHL received roughly $21 million of NIH indirect cost reimbursement last year. Had the 15% Indirect Cost Rate been in effect it would have resulted in a loss of approximately $16 million of NIH funding toward our critical research infrastructure. To understand the true impact of the NIH Supplemental Guidance, it is important to identify the full scope of what is included in the NIH definition of indirect costs (also known as Facilities and Administration/F&A costs). This useful infographic (pdf), developed by a variety of bioscience associations, explains the breakout.

Direct and indirect costs are both necessary expenditures for conducting cutting-edge scientific research. Direct costs cover expenses such as researchers’ salaries and benefits and project-specific supplies and equipment. On the other hand, indirect costs, as defined by the NIH, support the true costs of research operations. While indirect costs cover a portion of general administrative expenses, such as human resources, finance, etc. (commonly referred to as business overhead), the vast majority of indirect costs are comprised of research operations costs, including expenditures on scientific computing resources, research journal access, grant reporting, medical and chemical waste management, maintenance of laboratories and special laboratory mechanical, electrical and plumbing systems, growing regulatory compliance with federal and state regulatory guidelines, and much more. Research requires an incredible amount of supplemental support that is simply not captured in direct research costs.

The U.S. has long been the leader in scientific research. If this NIH guidance stands, the country will see a loss of discovery, innovation, and competitiveness, and ultimately a loss of well-being in the nation’s health and economy. To preserve and strengthen the United States’ competitive research advantage, we should be looking for ways to provide more, not less, public support for scientific research.

—Bruce Stillman, Ph.D.
President & CEO

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At the 18th annual Angel’s Wish Gala on January 25, the Christina Renna Foundation (CRF) presented $41,700 to Cold Spring Harbor Laboratory (CSHL). Driven by its goal to see a cancer-free world, CRF raises funds to combat rhabdomyosarcoma (RMS), the rare and often fatal pediatric cancer that claimed the life of Christina Renna nearly two decades ago. Since its founding, CRF has donated over $550,000 to CSHL, where this year’s honoree, Professor and Cancer Center Deputy Director Chris Vakoc, leads research on RMS and other pediatric cancers.

Philip Renna, CRF’s director and Christina’s father, spoke about the foundation’s impact. “You are the driving force keeping Christina’s wish alive,” he said. “Our efforts have already shed light and hope into the darkness that cancer brings.” Just last year, Vakoc’s lab uncovered a new drug target for RMS that may also apply to some of the most common forms of cancer.

Vakoc joined Renna at the podium as he reflected on the evening’s significance. “As we enter 2025 and celebrate our 18th Angel’s Wish Gala, I realized that Christina has been gone for longer than she was with us,” Renna said. “But her dream continues.”

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The domestication of maize is one of the greatest examples of humankind’s impact on evolution. Early farmers’ pre-industrial plant breeding choices turned corn from a nearly inedible crop into the major global food source it is today.

Now, Cold Spring Harbor Laboratory Professors Rob Martienssen and Thomas Gingeras are uncovering the genetics behind choices farmers made 9,000 years ago. They aim to better understand how evolution works and to help today’s farmers update corn so it can grow in harsh conditions. To get there, they’ve launched a new genomic encyclopedia called MaizeCODE. The research project is based on the Encyclopedia of DNA Elements (ENCODE). ENCODE aimed to identify functional elements in the human genome. Gingeras was one of its principal investigators. He explains:

“The original purpose—and it’s copied in the MaizeCODE effort—is to find all the domains of the genome that encode operational and coding information that the cell uses to reproduce and carry out the functions the cell serves.”

In a new study, the Gingeras and Martienssen labs analyzed regulatory sequences across five different tissue types from three strains of maize and its ancestor teosinte. They found hundreds of thousands of regulatory regions, called enhancers, that help turn genes on and off in plants.

CSHL Professor & HHMI Investigator Rob Martienssen tells corn’s curious origin story.

They also saw that maize has a few thousand “super enhancers.” Each controls several genes at once. Incredibly, these super enhancers were very strongly selected when maize was domesticated 9,000 years ago. Martienssen explains:

“We can now say that maize domestication was really focused—unwittingly perhaps —by selection on this rather narrow set of super enhancers in maize ears.”

In addition to expanding our understanding of evolution, these findings could help point the way to new strains of maize. Martienssen and Gingeras have received a grant from the National Science Foundation to work on creating crops that can grow in soil with high levels of aluminum. Such conditions are common in South America. The scientists will use MaizeCODE “to find all the regulatory regions that are responsible for endowing both maize and sorghum with aluminum resistance,” Martienssen says.

But that’s not MaizeCODE’s only use. The genome database may one day help farmers further improve their maize crops. Imagine plants that are more resistant to disease or tolerant to droughts. Better still, imagine crops with higher yields that can feed more people. MaizeCODE may help make all of this possible. And because the data is publicly available, it can be accessed by plant biologists and breeders across the globe. “We’re only touching the tip of the iceberg,” Martienssen says.

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“Nature is trying to tell you something.” Taken by itself, this quote from Nobel laureate and former Cold Spring Harbor Laboratory (CSHL) scientist Richard Roberts suggests that the solutions to any number of problems may be within earshot. If only things were so simple. The fact is, scientific experiments go awry all the time. When trying to answer complex questions, researchers often guess wrong—and keep guessing wrong—in hopes that every once in a while, something goes right.

In the 1970s, Richard Roberts’ lab was working on adenovirus, a common virus that causes colds and sore throats. Postdoc Rich Gelinas kept expecting to see 15 or 20 spots in his test results. Instead, he kept finding just one. When he repeated the test over and over and kept seeing the same mistake, Roberts considered that it might not be an error after all. It turned out that this time, he was right.

The ‘mistake’ ended up being the discovery of RNA splicing, a naturally occurring process whereby the parts of messenger RNA (mRNA) that contain cell instructions are kept and the non-coding sections are removed. In a monumental paper published in 1977, Roberts showed through adenovirus that one gene doesn’t necessarily contain the instructions for only one protein, as previously thought. Instead, pieces of information in a single gene can be arranged, or spliced, in different combinations to produce a variety of proteins.

Want to know more about how RNA splicing works? Watch this animated video. If only nature would speak so clearly!

Not only did RNA splicing help account for the genome’s tremendous complexity. It also pointed to the root cause of numerous diseases. The discovery set the stage for the creation of RNA splicing modifiers called antisense oligonucleotides, which have been used to treat spinal muscular atrophy (SMA), the leading genetic cause of death among infants. SMA is one of more than 200 diseases caused by errors in RNA splicing. In fact, Professor Adrian Krainer, who developed the first FDA-approved drug for SMA, was recruited to CSHL by Roberts himself. (But that’s a story for another day.)

In 1993, Roberts was awarded the Nobel Prize in Physiology or Medicine, along with Philip Sharp of MIT.

Years later, reflecting on his discovery, Roberts said, “Failure is a great thing. It [means] one of two things. Either you screwed up, or maybe nature is trying to tell you something. So, don’t ever be disheartened by failure.” Those are wise words for anyone. They also get at the heart of fundamental biology research. To turn science into medicine and technology, one must first know the ‘language’ that nature speaks. Uncovering that knowledge is the role of fundamental biology.

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Despite being entirely metallic, these sculptures evoke the biological machinery studied in labs across CSHL. Reminiscent of plant and animal cells, these industrial fusions of chains, nuts, bolts, and machine parts were a centerpiece of CSHL’s Nothing but Steel art exhibition. Conceived and curated by local artist Christopher Solbert, the show ran from June 1 to October 31, 1987. Alongside Malpass’ two evocative sculptures, the public exhibition featured 22 other works by 19 artists.

Science and art have long been intertwined at CSHL. Since its inception, the Laboratory has acquired a vast and varied collection of paintings, sculptures, and other works. Many of these are available for public viewing. They’re routinely encountered on campus tours, and longer events like the CSHL Center for Humanities and History of Modern Biology’s 2024 Science Meets Art Festival.

When Nothing but Steel ended in 1988, most of the exhibit’s metal artwork left CSHL. Malpass’ “Nuts & Bolts” and “Midnight Fair” remained. That year, Richardson Pratt Jr., then-president of Brooklyn’s Pratt Institute, donated the black metal spheres to CSHL for permanent display. Since then, they have stood between Hooper and Jones—protected from the elements by a fresh coat of paint every few years.

Malpass would pass away in 1991, three years after Nothing but Steel’s conclusion. However, his artistic legacy continues to inspire at CSHL and beyond. In fact, “Nuts & Bolts” and “Midnight Fair” are two of more than a dozen metallic spheres the sculptor fashioned throughout his career.

In addition to CSHL, Malpass’ sculptures have been displayed at numerous other facilities across the region, including the General Electric research lab in Schenectady, NY. His work is also featured in several museums and collections throughout the United States, Poland, Bulgaria, and France.

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Kaboom! The first time most of us hear the sound of an explosion is in the movies. Encountering the sound in the real world—even at a distance—has a profoundly different effect. Why? It’s all about context. How we react to sounds and other sensory stimuli depends on how they’re presented. We often don’t know how we’ll respond to something until we experience it. And the sensation is sometimes quite different from what we expected. So, the brain has to adjust quickly.

Cold Spring Harbor Laboratory (CSHL) Professor Florin Albeanu explains:

“In nature, animals are faced with different rules of engagement. Sometimes, the same stimuli mean different things depending on context. Therefore, it’s not so unusual that you have to act on these different rules and assess what action you have to take. What are the associations that the stimulus has with certain outcomes?”

New research from Albeanu and postdoc Diego Hernandez Trejo helps explain how this works. Their findings point to never-before-seen fast-updating signals in a feedback loop between the brain’s olfactory cortex and olfactory bulb. These signals may help put odors and sounds into new contexts. The feedback loop may enable an animal’s brain to immediately adapt to changes and help the animal fine-tune its motor responses accordingly.

This short film shows how odor information might travel through your brain when you smell something.

Hernandez Trejo and colleagues ran a series of behavioral tests to measure mice’s reactions to different smells and sounds. The mice were trained to associate rewards with one stimulus but not the other—and only for a while. Importantly, the researchers switched the rules once the mice seemed to learn them. That presented little trouble for expert mice, Albeanu says.

“The animal is able to extract this change. Within a few seconds, it’s going to act in a way that is consistent with understanding. Interestingly, we observed that top-down signals, which originate in the olfactory cortex, convey information about the reward value of the stimulus to the olfactory bulb—irrespective of them being sound or odor.”

The olfactory cortex is the part of the brain that processes smell, yet it seems to take sound into account. This result tracks with another CSHL discovery, which shows how sensory cues become integrated with each other in the brain. It also raises some exciting questions.

How do reward signals emerge? Does this feedback loop also integrate sight and touch? “There’s a universe of possibilities,” Albeanu says. He’s eager to continue exploring that universe along with collaborators Andrei Ciuparu and Raul Muresan from TINS in Romania, knowing that each answer tells us more about the world we share and the perceptions that shape our understanding of it.

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Cold Spring Harbor Laboratory Associate Professor Tobias Janowitz has been elected to the American Society for Clinical Investigation (ASCI). Janowitz is recognized for his outstanding scholarly research, which approaches cancer from a whole-body perspective. He has led clinical trials and published authoritative studies on cancer cachexia, a debilitating condition that affects patients in the late stages of the disease.

“I am pleased to become a member of the ASCI,” says Janowitz. “It is humbling to join what is considered one of the most respected medical societies in the U.S. I most look forward to the knowledge exchange opportunities that membership promises, especially across medical specialties.”

Founded in 1908, the ASCI is one of the country’s oldest medical honor societies. Each year, the ASCI Council elects up to 100 physician-scientists nominated by members. The Society seeks to support the scientific efforts, educational needs, and clinical aspirations of physician-scientists to improve the health of all people.

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We regret to inform you that your manuscript has not been selected for publication.

That’s how Andrew Dillin’s relationship with Genes & Development (G&D) begins. The scientific journal, published by Cold Spring Harbor Laboratory (CSHL) Press, fields hundreds of article submissions each year. It’s considered one of the top publications in all of developmental and molecular biology. In 1997, Andrew Dillin, then a graduate student, submits a paper on transcriptional silencing to G&D. He hopes for acceptance, to have his discovery showcased alongside other breakthroughs. What he receives turns out to be even more valuable.

Looking back on the rejection letter, Dillin recalls, “The comments and support that [former] Editor Terri Grodzicker provided were crucial for helping me understand my findings within the larger field of our study.” Grodzicker’s words don’t just inspire Dillin to build on his research. They teach him the true value of the peer-review process. It’s not only about finding and sharing “the best” scientific research. It’s about helping scientists see their own research in a new light.

Now, Dillin is back at G&D. Only he’s not an author. He’s the journal’s new editor-in-chief. In the years since his rejection, Dillin has had an extremely successful career. An investigator with the Howard Hughes Medical Institute and a professor at the University of California, Berkeley, he is considered a leader in the field of aging research. His work focuses on how the aging process affects an organism’s whole-body physiology. It’s an area of growing interest at CSHL and labs around the world, and Dillin will lead G&D’s expansion into this exciting field.

Of course, Dillin brings more than this expertise to G&D. “My goal as editor-in-chief is to help G&D continue to be as streamlined and as transparent as possible in the review process,” he says. While acknowledging the difficulties that scientific journals face today, Dillin is optimistic about the future of G&D and science communication in general. In his eyes, it’s not only about establishing consensus but also building communities. It’s not just a competition. It’s a conversation. And Dillin looks forward to helping more of the world’s most gifted scientists find their voice—even in rejection.

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On January 10—Cut Your Energy Costs Day—PSEG Long Island recognized Cold Spring Harbor Laboratory’s (CSHL’s) ongoing sustainability initiatives with $279,000 in rebates. These efforts are part of CSHL’s Foundations for the Future expansion project. Recent improvements include the installation of new, energy-efficient heating and cooling systems, LED lighting, battery backups, and submeters throughout the Laboratory’s idyllic main campus.

“This initiative goes to the heart of our mission,” CSHL COO John Tuke says. “Science is becoming increasingly data-based. We need to store and analyze billions and billions of bits of data. It takes a lot of energy. Our sustainability projects are not only helping with the efficiency of our operations. They’re allowing for more scientific research.”

Energy efficiency is especially important for the Laboratory’s cutting-edge NeuroAI program. A single experiment has the potential to generate massive amounts of data, CSHL Assistant Professor David Klindt says.

“We’re using AI to understand how the brain and diseases work,” he explains. “This is an exciting mission, but it takes a lot of resources. It’s only sustainable if we think about where the resources are coming from and set them up in a way that’s reliable. This PSEG program is helping us achieve our sustainability goals while pushing the frontiers of science and building a better place for future generations.”

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Sometimes, scientific breakthroughs happen by accident. Penicillin was discovered when a British scientist left a petri dish uncovered while he was away on vacation. Other times, serendipity plays a role. Case in point: two chance meetings at Cold Spring Harbor Laboratory (CSHL) led to the development of a drug that has vastly improved patient outcomes for the most common form of breast cancer.

The first happened in 1988 at CSHL’s Banbury Center. In the mid-1980s, David Beach had been investigating cell cycle regulation at CSHL. During a Banbury meeting, another scientist in attendance encouraged Beach to think about proteins called cyclins in connection with regulatory enzymes called cell division cycle kinases. Beach listened. By 1990, he was ready to publish what would become a game-changing research paper.

At the same time, future CSHL Trustee Charles Sherr was struggling with his own research. He’d read up on Beach’s work. One night, he sat down on a bus on the way back from the Howard Hughes Medical Institute. When he looked over, he realized his seatmate was none other than Beach. “I suggested I had a gene we could work on together,” Sherr recalls. “It turned out he had isolated the same gene, although we didn’t know that [yet]. It was just fortuitous.”

Gregory Hannon, now at the Cambridge Institute, was interviewing at CSHL for a postdoctoral fellowship on the day Beach and Sherr realized they’d been working on the same thing. “I remember sitting outside David’s office, chatting with the other postdocs, as he and Chuck were faxing each other one amino acid at a time to see if they had the same gene,” he recalls. “And I thought, ‘If this place is this exciting every day, it’s going to be really cool to be here.’”

In this video from 2002, then-CSHL Trustee Charles Sherr reflects on his first meeting with David Beach in the early 1990s. By 2015, their collaboration would result in an FDA-approved treatment for the most common form of breast cancer. Video: CSHL Library & Archives

In 1991, Beach and Sherr published back-to-back papers on Cyclin D in Cell. Soon thereafter, Sherr identified the cyclin-dependent kinase CDK4, which forms a complex with Cyclin D. In 1993, Beach, Hannon, and colleagues found p16, a natural inhibitor of CDK4. “Collectively, these papers from our two labs provided the key genetic and biochemical evidence that set the stage for drug discovery,” Sherr says. In time, a new drug target would emerge.

In 2015, the FDA approved Ibrance (palbociclib) for the treatment of HR-positive, HER2-negative breast cancer. Taken in combination with hormone therapy, the drug has been shown to increase patient survival by more than two years and reduce tumor size by 50%. Other applications are in the works as well. Ibrance is in clinical trials testing its potential for treating head and neck cancers, non-small cell lung cancer, and other solid tumor types.

“What is poignant about the 2015 approval of Ibrance is the fact that it came a quarter-century after the fundamental discoveries by Beach and Sherr,” says CSHL President Bruce Stillman. “In the early 1990s, we simply did not know enough about cancer to convert their newly generated knowledge into an effective anticancer drug. Now we do.”

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Imagine you’re at a dinner party, but you can’t smell the food cooking or hear the dinner bell. Sounds like a dream, right? What if it wasn’t?

“When we experience the world and interact with people, we use all our senses,” Cold Spring Harbor Laboratory Professor Stephen Shea says. “That’s true for animals and humans.” However, that’s not always the case in developmental disorders like autism. These conditions can affect how the brain processes incoming information, making it difficult to interpret the social cues that drive conversations, dates, and other interpersonal activities.

Exactly how such signals mix and influence each other in the brain isn’t well understood. To shed light on the subject, Shea and graduate student Alexandra Nowlan traced how smell and hearing interact in mouse brains during a maternal behavior called pup retrieval. This activity isn’t limited to mothers. It can also be learned by surrogates. Think stepmoms and babysitters. Shea explains:

“Pup retrieval is one of the most important things for mothers or caregivers. 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. One interesting thing we found was a projection from a location called the basal amygdala (BA).”

In mice and humans, the BA is involved in learning and processing social and emotional signals. During pup retrieval, the team found that BA neurons carry smell signals to the brain’s hearing center, the auditory cortex (AC). There, they merge with incoming sound signals and influence the animal’s response to future sounds—like pups’ cries. Amazingly, when Shea’s team blocked maternal mice from accessing smell signals, their pup retrieval response almost completely broke down.

“We think what’s reaching the AC is being filtered through social-emotional signals from BA neurons,” Shea explains. “That processing can be impaired in autism and neurodegenerative conditions. We think many parts of the brain participate in this behavior and that it’s very richly controlled.”

Shea’s lab is now exploring how these brain regions connect and interact with one another. Their work may lead to a better understanding of how autism can affect a person’s ability to interpret social cues. But that’s just the beginning.

“The idea that we found a neural circuit that may allow emotional processes to directly interact with perception is very exciting to me,” Shea says. He’s not alone there. His research might yet provide answers to one of humanity’s oldest questions. How do our senses inform the ways we connect with one another and experience the world?

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Fighting cancer can seem like a deadly game of chance. While some patients may respond well to certain treatments, others might not be as fortunate. Doctors and scientists have long struggled to explain why. Now, Cold Spring Harbor Laboratory (CSHL) Assistant Professor Katherine Alexander and University of Pennsylvania Professor Shelley Berger have found a possible source of this variability in clear cell renal cell carcinoma (ccRCC)—the most common kidney cancer diagnosed in adults.

Alexander has identified two different patterns of cellular structures known as nuclear speckles in kidney tumors. Even more exciting, Alexander’s research, conducted in Berger’s lab at the University of Pennsylvania, shows a potential correlation between speckle patterns and patient outcomes. Alexander explains:

“We found that different therapies are more or less effective depending on how the speckles look. This means potentially if a patient comes in with a normal or aberrant speckle state, they might be more responsive to one drug or another. Of course, more research needs to be done.”

Discovered over 100 years ago, nuclear speckles are tiny cellular structures that reside in the nucleus. Here, they’re thought to intermingle with DNA and help regulate gene activity. Alexander’s research reveals that nuclear speckles have two different signatures in ccRCC: normal-like and aberrant. It’s a matter of positioning. Normal-like speckles tend to congregate toward the center of the nucleus. Aberrant speckles are more dispersed.

“How these signatures affect patient outcomes remains a mystery for now,” Berger says. “However, the search for answers may lead to more personalized treatments. This discovery offers a new starting point in ccRCC.” Alexander adds:

“It’s the first suggestion that this would be potentially applicable to giving someone [diagnosed with ccRCC] one drug or another. That’s huge because cancer therapy has a lot of horrible side effects. To be able to tell a patient, ‘Your tumor looks like this, so we think this drug will work better than this drug,’ is something we really need.”

The team didn’t just look at kidney cancer. They analyzed speckles in over 20 different types of cancers, from melanomas to breast cancer. However, only ccRCC showed a correlation between speckle patterns and patient outcomes. What makes this cancer special? Alexander’s findings point to HIF-2𝛼, a protein typically overactive in ccRCC. The Alexander lab aims to pursue this lead alongside other researchers at CSHL’s Cancer Center.

For now, Alexander continues to investigate the mystery of nuclear speckles’ role in cancer. Though she’s in uncharted territory, the object of her search is clear. Her work seeks to help stack the odds in cancer patients’ favor.

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The Cold Spring Harbor Laboratory (CSHL) Board of Trustees, faculty, and staff mourn the passing of Charles “Chuck” Dolan, Honorary Trustee of the Laboratory and enthusiastic supporter of science education at CSHL. Chuck was elected to the CSHL Board of Trustees in 1990 and served as chairman of the Finance & Investment Committee from 1990-1992. He and his late wife Helen were named honorary trustees in 2003 and were presented the Double Helix Medals in 2017 in recognition of their outstanding contributions to the Laboratory.

As a giant and pioneer in the world of cable TV, Chuck understood better than anyone the power of connection. One of the Dolans’ first major contributions to CSHL helped establish a much-needed residence hall on campus. Dolan Hall has enabled thousands of visiting students and scientists to stay at the Laboratory while participating in the CSHL Meetings & Courses Program and collaborating with researchers here. The Dolan Family Foundation funded a significant expansion of CSHL’s DNA Learning Center, providing tens of thousands of elementary, middle, and high school students the opportunity to conduct hands-on experiments here in Cold Spring Harbor. Today, the Dolan DNA Learning Center is a model for public genetics education worldwide.

In establishing the Dolan Family Foundation and the Dolan Children’s Foundation, Chuck and Helen created a philanthropic legacy that supports numerous New York institutions. Chuck was co-founder and Chairman Emeritus of the Lustgarten Foundation, the largest private funder of pancreatic cancer research today, which continues to be an important partner with CSHL.

While Chuck was a distinguished businessman and philanthropist, he will be remembered at CSHL for his incredible vision in supporting both the programs and places necessary for research and education to thrive. In addition to providing crucial financial support for Laboratory programs, he was generous with his time and counsel. Chuck and Helen were also wonderful community leaders, hosting events at their Oyster Bay Cove estate and supporting many organizations that benefited Long Island.

The Laboratory expresses its deepest sympathy to the Dolan family.

— Bruce Stillman, Cold Spring Harbor Laboratory President & CEO, and Marilyn Simons, Cold Spring Harbor Laboratory Board of Trustees Chair

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In the winter of 1930, when it wasn’t fighting fires, the Cold Spring Harbor Fire Department was raising money for a new fire station. But what to do with the old one? Built in 1906, it was only 24 years old. Demolishing it may have seemed like a waste. During the early days of the Great Depression, the idea may have simply been unaffordable. The obvious solution then was to sell it. But to whom?

It turns out a potential buyer wasn’t far away.

Just across the harbor, one of Cold Spring Harbor Laboratory’s (CSHL’s) early predecessors—the Long Island Biological Laboratory—sought to expand its student housing. In that economy, new construction was likely out of the question. The old summer tents were gone, unsuitable for year-round residence. A solution might not have been found were it not for the Long Island Biological Association (LIBA), known today as the Cold Spring Harbor Laboratory Association (CSHLA).

The LIBA Women’s Auxiliary spearheaded the purchase of the old fire station. This group included several prominent women in the community, most notably Auxiliary President Elizabeth Nichols. Only two years prior, Elizabeth and Acosta Nichols’ $20,000 donation funded the construction of CSHL’s George Lane Nichols Building, named in honor of their late son who’d taken a nature studies class on the grounds.

If the Nichols Building was that expensive—about $368,997 today—how much would the Firehouse cost? Not much, it turns out. For the bargain basement price of $50, the building was theirs. Now, they just had to get it across the harbor to its new home. Follow the journey with the image carousel below, courtesy of the CSHL Library & Archives.

Once across the harbor, the Firehouse was brought to a foundation waiting near what is now Delbruck Laboratory. When the dust settled, the LIBA Women’s Auxiliary invested an additional $3,000 to transform the Firehouse into an 11-room summer dormitory. In 1972, further renovations replaced these with three year-round apartments. Past residents include 1993 Nobel laureate Richard Roberts and immunofluorescence microscopy inventors Mary Osborn and Klaus Weber.

Fourteen years later, the Firehouse was on the move again. To make room for the construction of CSHL’s Page Laboratory, the building was moved 50 yards down the road. This time, it traveled by land, not by sea. Movers hoisted the building onto a temporary steel foundation and winched it along a track of greased steel rails to its current harborside location. Today, the Firehouse continues to provide housing for members of the CSHL community.

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Evelyn and Arlindo Jorge believed in philanthropy. The couple wanted to instill in their young family a commitment to giving back. So, every year around the holidays, they asked each of their grandchildren to submit a “proposal” to support something important to them. As a young girl, Stephanie Gibbons suggested her grandparents fund graphing calculators for classrooms and meals for senior citizens. These “grant submissions” were formative experiences for Gibbons.

Now a Cold Spring Harbor Laboratory (CSHL) Association Director, Gibbons continues her family’s tradition of community support. The loss of her mother, Nancy Jorge Torcivia, to breast cancer in 1995 sharpened Gibbons’ philanthropic focus. At the time, there was little research on links between pregnancy and cancer risk. However, thanks in large part to CSHL, a body of knowledge has emerged in recent years. That information now points to new breast cancer prevention strategies and helps women advocate for their health.

Judy Jorge and Camila dos Santos unveil a plaque outside the newly renovated breast cancer research laboratory in CSHL’s McClintock building.

The research of breast cancer specialist and CSHL Associate Professor Camila dos Santos inspired Gibbons and her family in the Arlindo and Evelyn Jorge Family Foundation to make a generous $1 million donation to support this vital work.

On November 20, dos Santos, Gibbons, and the rest of the Jorge family presided over a dedication ceremony in memory of Nancy Jorge Torcivia. CSHL’s McClintock Laboratory, named after pioneering woman scientist Barbara McClintock, was in dire need of updates. Thanks to the Jorge family, CSHL was able to completely renovate the dos Santos lab, which operates inside the building. This revitalization ensures that the lab’s crucial research efforts will continue to thrive for years to come.

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Not everything inside us is, strictly speaking, us. The closer we look at the genome, the more we appreciate the role of small RNAs in what we call epigenetic inheritance. That’s when traits get passed down without altering our basic DNA sequence. We now know that small RNAs guide epigenetic modifications in both plants and animals. We also know that a molecule called pseudouridine (Ψ) is the most common RNA modification. What we haven’t been able to do is connect these two important bits of knowledge. How does Ψ work in small RNAs? Could it guide epigenetic inheritance?

Cold Spring Harbor Laboratory (CSHL) now has answers to both questions. These new explanations could help us solve one of biology’s greatest mysteries—how do our bodies distinguish “self” from “nonself”—and point to new ways of fighting off viruses in plants and animals.

To get answers, CSHL Professor and HHMI Investigator Rob Martienssen’s lab collaborated with molecular biologist Tony Kouzarides at the University of Cambridge. Together, they developed a series of screens to scan for Ψ in small RNAs. They found that Ψ does in fact guide epigenetic inheritance. It does so by helping to transport small RNAs into reproductive cells. Amazingly, they found this holds true in plants and mammals. They saw that sperm cells in mice are loaded with Ψ. So too is pollen from the mustard plant Arabidopsis.

Furthermore, the team discovered that Ψ enables a process called the triploid block, whereby plants produce only sterile offspring. Discovered at CSHL nearly 100 years ago, triploid blocks are now found in produce aisles worldwide. Martienssen explains:

“Seedless cucumbers, seedless melons, seedless fruits—they’re all made this way.”

This process is one example of what geneticists call selfish inheritance. Martienssen recently showed that another kind of selfish inheritance, known as gene drive, may have been behind corn’s rapid spread across the Americas. “The same class of small RNAs is responsible for both forms of selfish inheritance,” Martienssen adds.

The question now becomes why are these small RNAs so heavily modified in both plants and animals? One possibility is that these modifications block the immune system from detecting the small RNAs, so they’re recognized as “self” rather than “nonself.” If proven, this hypothesis could help usher in a new generation of RNA therapeutics. Martienssen says:

“It would add to our understanding of how RNA vaccines are tolerated by patients.”

The more we understand how our bodies distinguish what’s “us” from what isn’t, the better we can fight back against the viruses that threaten humans today as well as those that may do so in the future.

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She helped save millions of lives. So, how does it feel? With humility and wit, 2023 Nobel laureate Katalin Karikó shared insights on her life’s work during a free public event at the CUNY Graduate Center on November 15. CUNY’s recital hall was filled to capacity as guests took their seats for an up-close and personal look at Dr. Karikó’s brilliant career, including firsthand accounts of research that laid the foundation for the COVID-19 vaccines and hundreds of other therapies now in clinical trials.

Dr. Karikó’s studies changed science’s understanding of how mRNA interacts with our immune system. Interviewed by New York Times columnist and popular science writer Carl Zimmer, Dr. Karikó spoke for nearly an hour about her journey of discovery, her love for science, and staying positive in the face of adversity. She referenced several excerpts from her autobiography Breaking Through, which speak to a philosophy of focusing on what you can control and treating “failure” as a learning opportunity. She also reminded the audience of a simple truth. Science is fun.

Carl Zimmer is the acclaimed author of more than a dozen popular science books. Katalin Karikó is the winner of the 2023 Nobel Prize in Physiology or Medicine. Watch Zimmer interview Karikó about a range of topics.

The City of Science event was presented in partnership between the CUNY Graduate Center and Cold Spring Harbor Laboratory Center for Humanities & History of Modern Biology. It was made possible through the generous support of the BGI Nobel Laureates Archives Program.

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Research is itself an educational activity. With the laws of science and nature for teachers, researchers conduct experiments to learn how life and the world work. Cold Spring Harbor Laboratory (CSHL) is world-renowned for breakthrough bioscience research. What many outside the scientific community might not realize is that the Laboratory was founded as an educational institute. That was all the way back in 1890. Over the following century, CSHL’s Meetings & Courses Program, Cold Spring Harbor Laboratory Press, and DNA Learning Center helped to cement the Laboratory’s reputation as a leader in sharing scientific knowledge.

In 1999, CSHL made it official with the launch of an innovative graduate school program, the CSHL School of Biological Sciences (SBS). The program immerses students in the labs of CSHL faculty members, where they conduct cutting-edge experiments and interact with visiting scientists and collaborators from around the world. Today, SBS graduates are leaders in research, academia, and industry. Some run basic biology labs of their own. Others help bring new medicines to doctors and patients. Their accomplishments reflect the wide range of experiences and opportunities available to SBS students. To celebrate the School’s 25th anniversary, we spoke with five graduates about their time at CSHL and what they’ve been up to in the years since. Here are their stories.

Seeding excellence: Plant biologist Michelle Heck

Michelle Heck first caught the biology bug as a high schooler in New Hyde Park, NY. It happened during a visit to CSHL’s Dolan DNA Learning Center. Even decades later, Heck recalls the hands-on experiment she conducted to cut and separate viral DNA. “When I saw that we could actually look at DNA, there was a part of me that became hooked,” she says.

After earning her bachelor’s degree at Boston University, Heck returned to Long Island to complete her Ph.D. at the SBS. Here, she joined Professor David Jackson’s lab, which studies genes and signals in cells that regulate plant growth and shape. She looks back on her homecoming with fond memories:

“I was excited to come back and be a part of the Cold Spring Harbor environment. If you go there, the place is like one extended science camp. It’s heaven on Earth for people who love to do science.”

For her thesis, Heck conducted the first-ever genetic screen to uncover genes that regulate how plant cells communicate. “It was so thrilling to be a part of that discovery and to have that knowledge that no one else on Earth knew,” she says.

Heck became interested in disease when Jackson introduced her to a plant virologist. She was fascinated by how viral proteins hijack the pathways plant cells normally use to communicate. Today, she works to expand our knowledge of plant viruses and bacterial diseases spread by insects, and she uses this information to help farmers develop new agricultural management tools. For one, she is the co-inventor of a new biotechnology called Symbiont, which allows therapeutic molecules to be delivered directly into trees.

The fatal citrus greening disease has decimated groves across Florida. Heck is carving out new solutions at the USDA. “Interestingly,” she says, “we’re now using the discovery that I made as a grad student—this particular gene that I discovered in my screen—to help optimize the Symbiont technology we developed.”

Heck’s lab is located at Cornell University, so she also has an appointment as an adjunct professor of plant pathology and plant-microbe biology. “Through my role at Cornell, I am able to mentor graduate students, undergraduates, and postdocs,” she says. Many of the lessons she passes along were informed by her time at CSHL:

“Cold Spring Harbor scientists are pushing the boundaries of their fields, and that has shaped the scientist I’ve become. I am not afraid to think big. I’m not afraid to fail. I want my science to push the boundaries of knowledge. And it helps me develop a rigorous research program where people know that we strive for excellence.”

Sharing knowledge: Journal editor Darren Burgess

Rigor and a commitment to excellence are qualities that all universities look for in students. Of course, that doesn’t mean these qualities only translate to academic success.

After finishing his master’s studies at the University of Oxford in England, Darren Burgess found himself at a crossroads. He knew he wanted to pursue a Ph.D. but wasn’t quite sure where. The choice came down to whether he would stay in the U.K. or move to the U.S. to enroll at CSHL.

He recalls his thought process at the time:

“In terms of the atmosphere, I really felt Cold Spring Harbor had an edge. Everyone was very welcoming, very smart. But they’re also very keen to be the best right now.”

In their first year at the SBS, students rotate through laboratories before deciding which one to join. Burgess landed in then-CSHL Professor Scott Lowe’s lab. His research focused on developing new screens to better understand chemotherapy resistance in cancer. However, once he received his Ph.D. in 2007, Burgess stepped out of the lab and into the world of science communication.

Burgess joined the Nature staff in 2010, initially working for Nature Reviews Genetics and Nature Reviews Cancer. In 2023, he became a senior editor at Nature, handling manuscripts in biotechnology, genomics, and clinical research. He now reviews about 20 new manuscripts per week. He then arranges for those articles to be peer-reviewed by other scientists and oversees the manuscripts as they go through multiple rounds of revisions before they are officially accepted for publication. In addition to reviewing manuscripts, he does “quite a lot of outreach” to ensure the best research is submitted.

Academic researchers often find that their careers are measured by how many papers they’ve published and in which journals. So, emotions can run high during the publication process. Interacting with researchers requires tact, diplomacy, and the certainty that one’s decisions are based on “solid science,” Burgess says. “Our decisions have a big impact on people’s careers, so we need to make sure we’re thoroughly professional, robust, and consistent in the way we make those decisions.”

Even decades later, Burgess says he still benefits from the skills and “approach to life” he learned while enrolled in CSHL’s Ph.D. program:

“Cold Spring Harbor is the sort of environment where you learn not to be intimidated by people’s job titles, success, stature, or influence, because everyone is a scientist, everyone’s interested, and everyone’s human. It’s also taught me very high standards. At Cold Spring Harbor, they don’t settle for second best. They want everything to be the best. And that’s very similar to what we strive for.”

Bridging bench to bedside: Pharma leader Cathy Seiler

Over the course of her career, Cathy Seiler has jumped between several industries. She’s worked in academia, managed a biobank in a hospital, and led groups at biotech businesses. Now, she supports translational medicine and cancer research at one of the world’s largest pharmaceutical companies.

Seiler and Burgess were classmates at the SBS. And like him, she remembers feeling drawn to CSHL’s unique intellectual atmosphere where everyone is excited about the latest cutting-edge science. Seiler recalls:

“It really is all-encompassing and all-consuming. I loved the idea of the program. I loved the idea that you were going to learn how to think. You were going to learn how to question. You were going to learn how to learn.”

Seiler joined the SBS in 2001 and conducted her thesis research in then-CSHL Professor Yuri Lazebnik’s laboratory, which studied how cancer cells evolve and can be selectively killed. Seiler focused on how certain enzymes are activated during programmed cell death. However, throughout the course of the program, she began to think about pursuing other avenues. Along with a thesis advisor, SBS students are paired with an academic mentor who provides additional support. Seiler’s was David Stewart, the executive director of CSHL’s Meetings & Courses Program. Seiler says the pairing was “really well-placed,” as it allowed her to visualize a career path that didn’t end in a lab.

During the program, students share their research with other scientists and learn how to evaluate studies outside their areas of expertise. Seiler sought out more opportunities to further hone her communication skills, like writing for CSHL’s Harbor Transcript magazine and conducting interviews at the Cold Spring Harbor Symposia on Quantitative Biology. Today, sharing research findings with the public is a big part of her job, but it’s not just about communication. It’s about improving people’s lives.

Seiler joined AstraZeneca in 2022 as director of operational excellence in translational medicine in oncology research and development. AstraZeneca researches, develops, and manufactures prescription drugs for cancer and rare diseases, among other conditions. The company produces nearly 40 medications available to patients in the U.S.

Earlier this year, Seiler began a new role as business planning and operations lead supporting translational medicine in oncology. Working in translational medicine, she helps the company bridge the gap between basic research and patient treatments. One of her main duties is helping manage a multimillion-dollar budget for a department of over 160 people. Seiler credits CSHL with teaching her how to quickly pick up new skills, like overseeing large budgets or using new technologies:

“I know that I can go in there, and I can learn it. I think that’s allowed me to be more confident in taking risks in my career.”

Championing research: Preclinical powerhouse Rebecca Bish

One thing students learn quickly at CSHL is the importance of private funding. Private grants and fellowships are major sources of funding not only for the labs in which the students work but also for Ph.D. student salaries. CSHL is a private nonprofit institution. And while Becky Bish might not have known it when she graduated, she would eventually bring her extensive cancer research experience back to the nonprofit world.

Today, Bish is the head of discovery and preclinical research at The Mark Foundation for Cancer Research, a nonprofit that funds basic and translational cancer research. In this role, she identifies research that could have a big impact on patients yet is difficult to fund through traditional sources. She explains:

“Maybe it’s a little bit too out there and needs some more preliminary data before the government would be willing to fund it. Or it’s too far away from direct clinical impact for a pharma company to fund it. So, we try to identify those gaps, step in, accelerate the findings that scientists make in the lab, and get them to cancer patients faster.”

After graduating from MIT with a bachelor’s degree in biology, Bish joined then-Professor Michael Myers’ lab at CSHL. Her thesis focused on studying proteins in a cell, seeing how they interact in different disease states, and identifying findings that could be applied to diagnosing or treating cancer. Bish went on to conduct research at New York University and Memorial Sloan Kettering Cancer Center. During this time, she also founded a company that offered scientific editing for life sciences research. She then worked with a computational biochemistry research company before joining the Mark Foundation in 2017.

In her role at the Mark Foundation, Bish reads through hundreds of researchers’ grant proposals each year and helps decide which scientists should receive funding. In the seven years Bish has been with the foundation, it has awarded $230 million in grants and funded eight different startups. The nonprofit currently funds research at more than 100 institutions in 16 countries.

Bish says she uses the skills she learned at CSHL daily, especially “the ability to quickly and rigorously evaluate scientific output.” She says CSHL’s atmosphere of open collaboration helped her learn to take criticism well and communicate her own criticism clearly to others:

“You have to be flexible and willing to say, ‘No, I was wrong. I have to go in a completely different direction now.’ And it doesn’t matter who points that out to you. The data are what they are, and that sort of humility and flexibility is key to being a good scientist.”

Inspiring innovation: Entrepreneur Yaniv Erlich

The ability to go off in new directions is also invaluable when changing careers, like when CSHL graduate Yaniv Erlich left academia to pursue his dream of starting his own company. He’s now the CEO and co-founder of multimillion-dollar biotechnology startup Eleven Therapeutics. The company uses “next generation” RNA molecules called xRNA to silence disease-causing genes.

Erlich was drawn to the SBS in part because of its small community, where, as an international student, he felt he would be well taken care of. He completed his thesis in then-CSHL Professor ​​Greg Hannon’s lab, which focused on developing tools and strategies for manipulating gene expression. There, Erlich devised a method that allows researchers to sequence thousands of DNA samples at once. “We call it DNA Sudoku because it’s like solving a puzzle,” he explains. “You have a few sets of cells that are assigned, and then you can go and complete everything.”

After completing his Ph.D., Erlich moved to the Whitehead Institute at MIT, where he started his own lab. During his time there, he published several high-profile studies, including a paper in Science suggesting the identities of anonymous participants in research studies could be recovered by analyzing Y chromosomes. However, after authoring over 50 peer-reviewed papers and patents, Erlich was ready to try something else. He worked for three years as chief science officer for the genealogy company MyHeritage before deciding to set out on his own.

In 2020, Erlich founded Eleven Therapeutics with his mentor, Greg Hannon. The company uses artificial intelligence and biochemistry to create new, specially modified messenger RNA (mRNA) molecules. In recent years, mRNA vaccines have become extremely popular, but the technology has built-in limitations, Erlich says:

“If you want to create drugs for chronic treatments, you want to have long-lasting expression of your therapeutic protein or peptide. An RNA molecule is pretty bad for that because it enters into the cells and breaks quite rapidly. We developed chemical strategies that make these molecules much more stable by introducing chemical modifications to the molecule.”

In the company’s early stages, Erlich did much of the science himself. He even coded its first website. Now, his role has switched to managing a team and considering the company’s future.

Erlich says his time at Cold Spring Harbor taught him “so many things” he still uses in his career today, including how to recover from failure and communicate with other scientists. Moreover, it taught him to be both bold and humble:

“You can try new things. You can do something crazy and inspiring and take high risks. And it will reward you. Greg used to ideate this type of approach, and I think I learned that as well.”

25 years of insight and innovation

The five stories above offer a glimpse at the many different paths SBS graduates may take after leaving Cold Spring Harbor. They also illustrate some of the things that set the SBS apart from other graduate schools. However, it’s important to keep in mind that these are the stories of just five of 156 students who have received a Ph.D. from the SBS since 1999.

A current list of graduates includes professors at Yale and Cambridge University. Others have positions at leading technology companies Amazon and Meta. Others still have found their way back to Cold Spring Harbor. Arkarup Banerjee (class of 2016) is an assistant professor studying neuroscience at CSHL. Zachary Lippman (class of 2005) is a professor and HHMI investigator studying plant biology. As CSHL Director of Graduate Studies, he’s also the head of the SBS.

No two students’ stories are the same. However, in each case, the CSHL School of Biological Sciences has offered its graduates the experiences needed to help them better understand life and the world. They pay these opportunities forward every day, improving lives around the planet and making the world a better place for all of us.

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Scientific progress isn’t always a straight line. Discovery demands flexibility—a willingness to go off the beaten path. Oftentimes, that means leaving one’s comfort zone. And that’s exactly what Cold Spring Harbor Laboratory (CSHL) Associate Professor Saket Navlakha has in mind.

Navlakha has received a 2024 Simons Foundation Pivot Fellowship. Launched in 2022, the fellowship supports scientists working to expand their research into new disciplines. Through the year-long program, Navlakha will team up with mentor and CSHL Assistant Professor Hannah Meyer to explore how the adaptive immune system, like the brain, solves the kinds of complex problems that are also common in machine learning.

“This is a classic CSHL story—two people in complementary areas of research collaborating on problems that we would not necessarily be able to tackle on our own,” Navlakha says. “It’s a very natural collaboration borne out of random conversations. We’re going to have fun.”

As an immunologist, Meyer is excited about the work’s potential applications in science and medicine. “In computational research, it can be difficult to find the questions that are most impactful and relevant,” she says. “I look forward to offering that biological insight. And in Saket, I have a ‘mentee’ with very high expertise whom I can learn from as well.”

Navlakha is one of eight scientists awarded the fellowship in 2024. Pivot fellows receive one year’s salary and $10,000 toward research, travel, and professional development. Mentors receive an additional $50,000 to support their fellow’s training.

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It’s a big year for microRNAs. The 2024 Nobel Prize in Physiology or Medicine went to Victor Ambros and Gary Ruvkun, who discovered the first microRNA in 1993. Today, we know that humans make more than 1,000 different microRNAS. These molecules are critical for building and maintaining healthy bodies, so it’s crucial that they’re made the right way. Errors in microRNA manufacture can put us at risk for developmental disorders, cancer, or neurodegenerative disease.

To learn how cells accurately generate a mind-boggling array of microRNAs, Cold Spring Harbor Laboratory (CSHL) Professor and HHMI Investigator Leemor Joshua-Tor focuses her attention on a molecular machine called Microprocessor (MP). MP kicks off microRNA production by trimming down longer molecules called primary microRNAs (pri-miRNAs). MP is responsible for finding and processing every pri-miRNA in the cell. That seems like a tall order, as each pri-miRNA is shaped a little differently. At the same time, MP must avoid cutting other kinds of RNA that resemble pri-miRNAs.

Joshua-Tor says pri-miRNAs all share a characteristic hairpin loop. However, that doesn’t fully explain how MP knows which molecules to cut or how it manages to cut them correctly.

For structural biologists like Joshua-Tor, seeing is understanding. So, Ankur Garg, a postdoc in Joshua-Tor’s lab, uses cryo-electron microscopy to capture extraordinarily detailed freeze frames of MP in action. “The images show MP wrapping itself around five different pri-miRNAs, each with a distinct shape,” Garg says.

See the Microprocessor (MP) intertwined with three of the five primary microRNAs (pri-miRNAs) that the Joshua-Tor lab captured. The pri-miRNAs are labeled at the top, and MP components at the bottom.

In each image, a loop of RNA nestles within the same grooves of MP. Amazingly, the shape of MP differs depending on which pri-miRNA is in its grasp. Joshua-Tor says this surprising variability prompted her team to think of MP as an octopus armed with tentacle-like proteins:

“The body of the octopus is sitting on the bottom of the hairpin, and the tentacles can go and kind of read the RNA. So, they make the same kind of interactions with the RNA. But they can move with the RNA. The RNA basically dictates to the protein where it’s going to sit.”

That flexibility explains how MP can process so many different pri-miRNAs. Still, MP is choosy, leaving many hairpin-containing RNAs untouched. By seeing exactly how it interacts with different structures, the team is able to define key features that determine which RNAs MP will cut.

Researchers can now use this knowledge to better predict which of a cell’s many strands of RNA are destined to become microRNAs. Those predictions will help paint a clearer picture of the impact these influential molecules have on health and disease.

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It’s called Frog Pond. And while its namesake is often easy to find there, frogs aren’t the pond’s only inhabitants. On any given day, passersby may encounter dragonflies, geese, ducks, turtles, toads, and more. Duckweed and other aquatic plants blanket the pond’s muddy waters. Trees left over from the 1986 construction of Grace Auditorium stand tall near the water’s edge. It might come as a surprise to learn that Frog Pond has another thing in common with the auditorium. Both are man-made.

Before 1988, there was no Frog Pond. That year, CSHL finished a project to restore some of Bungtown Road’s mid-century aesthetic by replacing its telephone poles with underground wiring.

“In the summer of 1948, this then-sylvan path had a rural quality that reflected what Long Island must have been like in the 19th century,” CSHL’s 1988 Annual Report (pdf) states.

Frog Pond’s native species aren’t the only amphibians you’ll find at CSHL. Since 1993, Xenopus, the African clawed frog, has helped countless scientists learn about the origins and mechanics of life through CSHL’s Cell & Developmental Biology of Xenopus: Gene Discovery & Disease Course.

For over three decades, Frog Pond has served as a retention basin to manage stormwater runoff and help prevent flooding. These days, it is also a key source of duckweed for the Martienssen lab’s biofuel research happening across the street. But the pond is still perhaps best known in the CSHL community as a place to relax and catch a glimpse of the frogs and turtles that frequent the area.

CSHL Horticulturist Riley McKenna agrees. “The biggest feature of the pond is its wildlife,” he says. “Most mornings I see some kind of action happening from some kind of bird, groundhog, or turtle.”

Frog Pond is fed from above by a small stream and several lesser ponds before continuing underground into Cold Spring Harbor. The surrounding willow oaks, dogwoods, and winterberry bushes provide shade and a source of food for any animals that may stop by.

“I visit it nearly weekly throughout the year to search for whatever reptiles and amphibians might be hanging out, but also to admire the change in seasons,” says CSHL Professor Zachary Lippman, who took most of the photos in this story. “The arrival of spring especially brings all these great animals out again, and we get to enjoy the pollywogs going from tadpoles to frogs before our eyes.”

For McKenna, the pond and its surroundings also offer a sense of peace and serenity. “A landscape would be nothing without its environment,” he says. “I think that’s what makes the lab, the lab—the environment around us. Long Island is an island like no other.”

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In a sense, each of us begins life ready for action. Many animals perform amazing feats soon after they’re born. Spiders spin webs. Whales swim. But where do these innate abilities come from? Obviously, the brain plays a key role as it contains the trillions of neural connections needed to control complex behaviors. However, the genome has space for only a small fraction of that information. This paradox has stumped scientists for decades. Now, Cold Spring Harbor Laboratory (CSHL) Professors Anthony Zador and Alexei Koulakov have devised a potential solution using artificial intelligence.

When Zador first encounters this problem, he puts a new spin on it. “What if the genome’s limited capacity is the very thing that makes us so smart?” he wonders. “What if it’s a feature, not a bug?” In other words, maybe we can act intelligently and learn quickly because the genome’s limits force us to adapt. This is a big, bold idea—tough to demonstrate. After all, we can’t stretch lab experiments across billions of years of evolution. That’s where the idea of the genomic bottleneck algorithm emerges.

In AI, generations don’t span decades. New models are born with the push of a button. Zador, Koulakov, and CSHL postdocs Divyansha Lachi and Sergey Shuvaev set out to develop a computer algorithm that folds heaps of data into a neat package—much like our genome might compress the information needed to form functional brain circuits. They then test this algorithm against AI networks that undergo multiple training rounds. Amazingly, they find the new, untrained algorithm performs tasks like image recognition almost as effectively as state-of-the-art AI. Their algorithm even holds its own in video games like Space Invaders. It’s as if it innately understands how to play.

An AI-simulated cheetah cannot move forward on its own without training. Press play to see how it does with the genomic bottleneck algorithm.

Does this mean AI will soon replicate our natural abilities? “We haven’t reached that level,” says Koulakov. “The brain’s cortical architecture can fit about 280 terabytes of information—32 years of high-definition video. Our genomes accommodate about one hour. This implies a 400,000-fold compression technology cannot yet match.”

Nevertheless, the algorithm allows for compression levels thus far unseen in AI. That feature could have impressive uses in tech. Shuvaev, the study’s lead author, explains:

“For example, if you wanted to run a large language model on a cell phone, one way [the algorithm] could be used is to unfold your model layer by layer on the hardware.”

Such applications could mean more evolved AI with faster runtimes. And to think, it only took 3.5 billion years of evolution to get here.

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More than two million new cases of cancer will be diagnosed in the United States in 2024, according to the National Cancer Institute. Range Cancer Therapeutics ETF (Nasdaq: CNCR) is partnering with Cold Spring Harbor Laboratory (CSHL) to highlight CSHL’s pioneering role in advancing cancer research. Through the partnership, 23% of revenues generated by fees from CNCR will be donated to CSHL quarterly.

Bringing together the powers of philanthropy and investing, Range ETFs and CSHL announced this unique affiliation with a historic event at the Nasdaq stock market on November 14, 2024. The event featured a powerful visual display on the Nasdaq tower, and Range ETFs and CSHL leadership and guests gathered on the iconic Nasdaq podium to mark this momentous occasion.

“Cold Spring Harbor Laboratory is one of only seven national basic biological research cancer centers designated by the National Cancer Institute in Washington DC. Cancer research is fundamental to our discovery efforts,” said CSHL President and CEO Bruce Stillman. “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.”

Range ETFs CNCR ETF focuses on companies dedicated to cancer research, treatment, and therapeutics, offering investors targeted exposure in this vital sector. It is purpose-built to provide exposure to a wide range of cancer therapeutic modalities.

“The contribution from Range will directly benefit the research efforts at CSHL, underscoring our commitment to advancing scientific innovation in oncology therapeutics,” said Range ETFs founder and CSHL Association Board Member, Tim Rotolo. “CNCR 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.”

Stillman added that unique partnerships like this provide opportunities to engage with people who are already committed to scientific advancement and maximize efforts to support cancer research in unique ways.

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The opportunity to turn curiosity into discoveries that impact the human condition is at the core of Cold Spring Harbor Laboratory’s mission. Our scientists are empowered to ask big questions and search for solutions to biology’s most challenging problems. Doing that requires interdisciplinary study, and the Laboratory’s brain-body physiology program encourages our scientists to confront today’s toughest health challenges from multiple fronts collectively. Understanding the connections between our minds and our bodies and their effect on physiological homeostasis has the potential to lead to revolutionary medical interventions that will enable us to remain healthy as we age.

In this issue of Harbor Transcript, we share CSHL’s latest research into brain-body connections relevant to aging, breast cancer, menopause, pregnancy, and more. Our cover story sheds light on important topics that remain understudied. It is well known that historical underrepresentation of research on women’s health has resulted in a limited understanding of how women experience disease and respond to treatment. Associate Professors Camila dos Santos and Jessica Tollkuhn exemplify researchers at Cold Spring Harbor working to change this dynamic.

Another highly misunderstood condition is autism spectrum disorder. With generous support from the Simons Foundation, Professors Michael Wigler and Ivan Iossifov have combined their expertise in molecular biology and computer science to explore large datasets of genetic variants associated with autism. By pinpointing and cataloging these variants, they’ve given medical professionals the tools to diagnose autism and provide potentially life-altering interventions sooner.

While CSHL scientists work diligently to understand complex brain-body interactions, we also function as a global hub for cutting-edge science, which is why our Meetings and Courses Program, Banbury Center, DNA Learning Center, and Center for Humanities are critical to the future of science. Education and discovery go hand in hand. Indeed, we have added new scientific meetings that focus on brain-body interactions, whole-organism physiology, and the aging processes.

No one better understood that connection than Jim Simons, honorary trustee, longtime supporter of the Laboratory, and husband to our Board of Trustees Chair, Marilyn Simons. Though we lost a dear friend this year, his life was a testament to the power of living in service to the community, and his legacy will live on through the programs and people he and Marilyn have touched. We are forever grateful for Jim’s transformational commitment.

We appreciate all those who have joined Cold Spring Harbor throughout the year at events, meetings, tours, or simply by visiting our website. Cold Spring Harbor is a unique place that brings together people who want to leave the world a little better than we found it, and we appreciate you taking this journey with us.

—Bruce Stillman, Ph.D.
“President’s Message”
Harbor Transcript, Volume 44, Issue 2

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On November 14, Cold Spring Harbor Laboratory (CSHL) held its 19th annual Double Helix Medals dinner (DHMD) at the American Museum of Natural History in New York City. The event, emceed by CBS journalist Lesley Stahl, honored Alisa and Daniel Doctoroff and 2023 Nobel laureate Dr. Katalin Karikó. With the support of the event chairs and donors, the gala raised $7 million for biology research and education at CSHL.

Alisa and Daniel Doctoroff are leaders of Target ALS, an innovative nonprofit that has sparked dramatic progress in research on amyotrophic lateral sclerosis (ALS). Before being diagnosed with this neurodegenerative disease, Mr. Doctoroff served as New York City Deputy Mayor for Economic Development and Rebuilding and as CEO and president of Bloomberg L.P. He is the founder and board chair of Target ALS.

“My goal for Target ALS is our mission statement, ‘Everyone lives.’ We are in sight of that goal,” says Mr. Doctoroff. “We can see the day coming, and there are smaller goals that will get us there,” adds Mrs. Doctoroff. “We are, one by one, achieving and attacking those goals and getting to the point where everyone lives with ALS.”

Dr. Katalin Karikó is a winner of the 2023 Nobel Prize in Physiology or Medicine and a professor at the University of Szeged in Hungary. Her revolutionary biomedical advancements at the University of Pennsylvania and later at the pharmaceutical company BioNTech created the blueprint for mRNA vaccines, saving millions of lives. Despite this success, she remains humble as ever.

“Getting a Nobel Prize, I realized that attention is on the science and the scientist,” Dr. Karikó says. “I receive a lot of awards, but every time, I emphasize that a lot of scientists contributed. I want to be remembered as an honest, cheerful, happy scientist. That’s it.”

The 2024 DHMD was chaired by Dr. Neri Oxman and Mr. William Ackman, Ms. Jamie Nicholls and Mr. O. Francis Biondi, Mr. and Mrs. David Boies, Dr. Albert Bourla and Pfizer, Inc., Ms. Barbara Amonson and Dr. Vincent Della Pietra, Drs. Pamela Hurst-Della Pietra and Stephen Della Pietra, Mr. and Mrs. John Desmarais, Mr. and Mrs. Jeffrey E. Kelter, Dr. and Mrs. Tomislav Kundic, Mr. and Mrs. Robert D. Lindsay, Ms. Ivana Stolnik-Lourie and Dr. Robert Lourie, Dr. Marcia Kramer Mayer, Dr. and Mrs. Howard L. Morgan, Mr. and Mrs. Tom Secunda, Dr. Marilyn H. Simons, and Mr. and Mrs. Paul J. Taubman.

Since 2006, the DHMD has raised over $67 million to support CSHL’s research and education programs.

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How do you turn a small but influential science education outpost into one of the world’s leading destinations for breakthrough bioscience? It takes a village.

This year marks the centennial anniversary of the formation of the Cold Spring Harbor Laboratory Association (CSHLA). Formerly known as the Long Island Biological Association (LIBA), the CSHLA is a remarkable group with a remarkable history. Though founded in 1924, its origins lie in the 19th century.

The early years

In 1890, the Brooklyn Institute of Arts and Sciences (BIAS) established the Biological Laboratory at Cold Spring Harbor as a summer school for training biology teachers and students. Early courses covered topics such as zoology, variation and inheritance, embryology, bacteriology, and ecology. Initially housed in the New York State Fish Hatchery, the Laboratory moved across the road to land provided by the Jones family, which later set up a nonprofit corporation called the Wawepex Society to hold a title for the property. New Yorkers will recognize the name ‘Jones’ for its connection to Jones Beach. The phrase “keeping up with the Joneses” also refers to this family.

Through the beginning of the 20th century, the Laboratory’s relationship with BIAS became increasingly fraught. Things came to a head in 1914 when the director of the Laboratory threatened to resign. In response, the Laboratory was made a department of BIAS. Then, in 1917, efforts were renewed to create an endowment for the Laboratory. Through the generosity of a small number of local supporters—including Louis Comfort Tiffany, William John Matheson, Walter Jennings, August Heckscher, and Cornelia Prime—the remarkable sum of $27,000 was raised in just eight months. To put that in context, $27,000 in 1917 equals about $700,000 in 2024.

At this point, the Laboratory’s director was also running two additional institutes on the Cold Spring Harbor campus. In 1921, he resigned from his post, citing these other responsibilities. However, he suggested various measures to mitigate such conflicts moving forward. In particular, he advocated for BIAS to hand over control of the Biological Laboratory at Cold Spring Harbor to an association of neighbors. The group would include those local residents who’d so generously contributed to the 1917 endowment. There would be a new director and a scientific advisory board to offer guidance. BIAS raised no objections to this proposal, and a charter was drawn up for the Long Island Biological Association.

In August 1923, a local organization of neighbors voted to form the Association. On February 18, 1924, LIBA was incorporated. One week later, the first meeting of the Board of Directors was held. The group adopted bylaws and appointed Dr. Reginald Harris as its founding director. On March 12, the Brooklyn Institute formally turned over its buildings along with its endowment and scholarship funds. The Wawepex Society transferred ownership of Jones Laboratory and drafted a 50-year lease for the grounds.

The 1924 Biological Laboratory Annual Report (pdf) listed LIBA’s first members. There were six “Founding Members” and 19 “Patrons” who each contributed $5,000 and $500, respectively. There were also more than 170 “Sustaining Members” whose combined contributions totaled $1,700. The membership list includes such illustrious names as J.P. Morgan, W.K. Vanderbilt, Marshall Field III, Henry De Forest, Charles Frick, Walter James, Mrs. Otto Kahn (Addie Wolff), August Heckscher, and Louis Tiffany.

LIBA’s importance to the Biological Laboratory became immediately apparent. In 1926, LIBA members raised the funds needed to purchase 32.5 acres of land adjacent to the Laboratory. The following year, Mr. and Mrs. Acosta Nichols donated $12,000 for the construction of a lab in memory of their son George, who had taken part in a nature studies class held on campus.

LIBA also became known across the region for its impressive “Gold Coast” galas. One example took place in 1932. It was during this year that the Field family held a grand fundraising event at Caumsett, their estate in Lloyd Harbor, NY. Attended by celebrities such as Fred Astaire, the gala included activities like dancing and china breaking. (“China breaking” is exactly what it sounds like. The activity was overseen by prominent businessman Vincent Astor.) All told, the event raised over $4,500—i.e., $99,000 in 2024 dollars. Through the 1940s and 1950s, LIBA members contributed between 7% and 10% of the Biological Laboratory’s income.

The modern era

LIBA’s modern era began in 1962 when the institute we now know as Cold Spring Harbor Laboratory first took the name of its neighboring community. It was during this year that the Carnegie Institution closed the Department of Genetics. Its land and buildings were combined with those of the Biological Laboratory to create the Cold Spring Harbor Laboratory of Quantitative Biology. (The name would be shortened to Cold Spring Harbor Laboratory in 1970.) LIBA did not have any direct responsibility for governing the new institute. However, the Association did retain two places on the new Board of Trustees. It now fully devoted itself to ambassadorship and fundraising. And it accomplished these goals with great success.

For example, in 1972, LIBA Chairman Edward Pulling led a campaign that raised $250,000 for a new addition to Jones Laboratory. A few years later, he helped raise $225,000 to build a new Williams House and another $200,000 to purchase land still owned by the Carnegie Institution.

In one historic gift, LIBA contributed $600,000 toward the cost of the Oliver and Lorraine Grace Auditorium. Grace is the primary venue for CSHL’s world-renowned Meetings & Courses Program. This program has brought hundreds of thousands of leading scientists to Cold Spring Harbor. Here, they’ve discussed their latest research, shared ideas with potential collaborators, and planted the seeds of countless breakthroughs. So, while $600,000 may sound like a lot, there’s really no way to quantify the return on this investment.

In 1992, LIBA officially became the Cold Spring Harbor Laboratory Association (CSHLA). The Association has since furthered its mission to provide CSHL with much-needed philanthropic support. Over the past 10 years, CSHLA members have helped raise an extraordinary $80 million in unrestricted funding for the Laboratory. Indeed, many of the labs and other facilities found across campus today owe their existence to CSHLA members.

Of course, a lot has changed since the early days. After all, today’s Association gatherings are unlikely to break out in spontaneous bouts of china breaking. Nevertheless, CSHLA continues to bring some of Long Island’s best and brightest together for a worthy cause. Current Association Directors include acclaimed actress Susan Lucci and the late best-selling novelist Nelson DeMille, among many other prominent community members.

For over 100 years, LIBA and CSHLA have played an essential role in supporting the advancement of science at Cold Spring Harbor. Its members and their community have transformed a small summer school into one of the world’s most renowned institutes for cutting-edge science research and education. This is a proud legacy, to say the least—one that holds great promise and potential for the next 100 years.

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If there’s one thing cancer knows, it’s growth. Over the last two decades, scientists have observed that many cancers progress by activating a set of proteins called YAP and TAZ, which control cell growth and organ size. When left uncontrolled, YAP/TAZ can lead to tumor formation. So, if you’re looking for new drug targets, why not start there? Targeting them directly, while possible, remains a challenge. Now, Cold Spring Harbor Laboratory Professor Christopher Vakoc and postdoc Olaf Klingbeil have found a workaround. They’ve successfully tested their new approach in the lab against some of the most common and deadly cancers.

Previous research aimed to target YAP/TAZ molecular interactions and directly inhibit their tumor-promoting function. Vakoc’s team wanted to find another way to go after them. Using a CRISPR screening strategy, they discovered that YAP and TAZ rely heavily on a second set of proteins called MARK 2 and MARK 3. Rather than interfering with the functions of YAP/TAZ directly, targeting MARK 2/3 reactivates their natural ‘off’ switch, called the Hippo signaling pathway.

“We found a way to engage YAP/TAZ earlier,” Klingbeil says. “MARK 2/3 inhibition can reactivate a suppressor pathway normally used by healthy cells, thereby preventing them from going to the nucleus and being active.”

Last year, Vakoc’s team transformed rhabdomyosarcoma cells into healthy muscle cells—a major advancement. However, this treatment strategy, known as differentiation therapy, is still a long way from the clinic. MARK 2 and MARK 3, on the other hand, are druggable targets, and their activity in a wider range of tumors will hopefully generate interest among pharmaceutical companies. Vakoc explains:

“This is a target for rare pediatric sarcomas that we’re very passionate about trying to solve. It’s also relevant in breast cancer. It’s relevant in lung cancer. It’s relevant in pancreatic cancer. Some of the most common human cancers and uncommon human cancers share this addiction to YAP/TAZ.”

Vakoc and Klingbeil found that by reactivating YAP/TAZ’s off switch, tumors don’t just stop growing. They actually shrink, and the cancer begins to disappear. The Vakoc lab now has a new drug target in its sights. In time, that could mean more effective treatments for thousands of patients and new hope for parents who want only to see their kids grow up healthy and cancer-free.

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Diseases can spread rapidly, but now, so can the knowledge needed to stop them. A new information-sharing platform seeks to help slow the spread of infectious diseases. It’s called the Pathogen Data Network (PDN). And it just might help stop the next pandemic before it can start.

Cold Spring Harbor Laboratory’s DNA Learning Center (DNALC) is part of a global consortium of research institutions that have received $2.7 million from the National Institute of Allergy and Infectious Diseases to build the PDN. Their mission: improve pandemic response worldwide by providing open access to shared resources and data on all pathogens affecting humans.

One key component is a new outreach and training program from the DNALC. The program will train undergraduate educators in disease-tracking techniques that could help prevent future pandemics. Importantly, it will focus on institutions in those communities often hit hardest by public health crises.

“This partnership is a natural fit for us,” says DNALC Assistant Director of Diversity and Research Readiness Jason Williams. “We bring the latest technologies and teaching approaches for working with DNA into classrooms around the world. Sharing scientific knowledge and resources worldwide will empower future generations to respond to potential outbreaks sooner, thereby saving lives.”

The PDN builds upon and expands the successful European COVID-19 Data Platform. Led by the Swiss Institute of Bioinformatics and the UK’s European Bioinformatics Institute, the PDN also includes organizations in South Africa and throughout Europe.

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