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Dr. John Inglis Photo from CSHL

By Daniel Dunaief

Evolution doesn’t just favor species that have adaptive advantages in a changing environment. It’s also relevant for businesses, as they move into new markets, and even to scientific publishing.

A preprint scientific publishing effort that started in 2013 at Cold Spring Harbor Laboratory with bioRxiv and expanded in 2019 with medRxiv is making changes that its creators believe positions it to grow while continuing to serve the scientific community.

BioRxiv and medRxiv are becoming an independent nonprofit, called openRxiv. The new format, which takes the preprint offerings outside the home of Cold Spring Harbor Laboratory, will create a product that is outside the realm of a single institution and that has transparent governance.

“We had an independent needs assessment done by a consulting company,” said Dr. John Inglis, Chair of the openRxiv Scientific and Medical Advisory Board. The governance needed to be “more community-oriented, with not just funders, but committees of working scientists.”

The Chan Zuckerberg Initiative, which has been the major funder for the preprint services, understood the benefits of transitioning to an independent non profit. They also wanted to “see a diversification of funding” from other sources and contributors, Inglis said.

Up until co-founders Inglis and Dr. Richard Sever, Chief Science and Strategy Officer at openRxiv created these two preprint services, most biological and medical scientific discoveries progressed through the slower pace of peer review publishing that helps them advance their fields while sharing their results.

Preprints, however, greatly accelerated that process by allowing researchers to display their work before peer review. While scientists might need to amend their findings by adding further studies, these preprints enable researchers to do the equivalent of presenting their research to a worldwide audience, the way scientists do at meetings.

The preprint servers are “like the biggest conference you’ve ever seen, with millions of people,” said Inglis.

A growing market 

In each month of the last quarter of 2024, bioRxiv recorded between 8 million and 9.7 million page views, with between 4.7 million and 6.8 million downloads, Inglis said. MedRxiv, meanwhile, had between 1.8 million and 1.9 million page views with a million downloads per month.

With more than 110 new articles per day last year, bioRxiv added 11 percent more original preprints last year. MedRxiv grew by 12 percent, adding 12,863 preprints last year, or about 35 new articles per day.

MedRxiv launched the year before the pandemic and quickly became the major channel of communication for pandemic-related preprints.

In 2020, when pandemic related coverage accounted for 80 percent of everything posted, medRxiv shared a total of 14,070 research pieces.

At this point, contributing authors have come from 190 countries. The most prolific contributors are the United States and the United Kingdom. With readers coming from around the world, openRxiv’s primary task is to convert some of the readers from other countries into contributors, Inglis said.

Search for a CEO

OpenRxiv creates opportunities for several executives.

Sever, who had been CSHL Press Assistant Director, will leave the lab to become the chief scientific and strategy officer for openRxiv.

At the same time, openRxiv, which has an annual budget of $3 million, has hired a recruiting firm to lead the search for its first Chief Executive Officer.

The new CEO will need to “believe in the mission, promise, potential and ambition of openRxiv,” said Inglis, as the CEO will be the “principal ambassador” for the effort.

The new leader will also need experience running a complex organization with various stakeholders and that has community engagement.

Inglis described the current employees, which includes eight full time staff, as “fantastically motivated.” He anticipates the new leader could be announced as soon as three or four months from now.

Expanded opportunities

The preprint servers has appealed to academic institutions directly for ongoing repeated support, through a membership model.

Indeed, preprint managers reached out on the 10th anniversary of bioRxiv and received backing from institutions that are listed on every bioRxiv and medRxiv preprint.

“We want to build on that, to reach out to more institutions,” said Inglis. He wants to have a “real dialog with them about what these servers mean to their faculty and how we can be useful in terms of their operations.”

Some academic institutions don’t always know which research studies are appearing on these servers.

OpenRxiv can give universities information for researchers who are posting their studies.

Additionally, these servers have been offering authors the chance to transfer their manuscripts to particular journals. At this point, openRxiv has connections with 45 publishers who oversee 380 journals.

Inglis said they charge a small fee to set that up and described this effort as the “germ” of a business model. He anticipates that openRxiv could provide more of these connections.

Professional pathways

Authors have the ability to correct or amend their work on these servers. The preprints encourage people to explain the changes, while discouraging too many corrections or changes for grammatical reasons. The record for revisions on bioRxiv or medRxiv is seven.

Inglis has heard from numerous researchers who are grateful to increase the visibility of their work and their careers in a timely way.

These non peer reviewed studies can help scientists move up the ladder, getting job offers from other institutions while they await publication in a journal.

Ongoing support

CSHL, BMJ Group and Yale School of Medicine remain key supporters of openRxiv.

“OpenRxiv is the natural evolution and progression of free and open access to scientific information,” Bruce Stillman, President and CEO of CSHL said in a statement. “BioRxiv and medRxiv have revolutionized the field of science and scientific publishing. The establishment of openRxiv will allow for continued innovation in how the latest scientific results are communicated.”

In the last few weeks, openRxiv had the first in a series of webinars they are mounting on their own behalf. They plan to offer them to institutions across the world and believe they are an effective way to engage with the world of international science.

OpenRxiv is in conversation with faculty at an institution in Japan about organizing a webinar and will reach out to institutions in India. Staff at openRxiv plan to expand the scope of this process by contacting authors in potential locations who have multiple articles on the servers.

The response from students is an “encouragement to do more,” said Inglis. “Having more people and more resources will allow us to ramp up educational development of what we’re doing.”

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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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Bruce Stillman, CEO of Cold Spring Harbor Laboratory. Photo courtesy of CSHL

By Daniel Dunaief

The Oscars could learn a thing or two from Cold Spring Harbor Laboratory. The facility, which conducts research in cancer, neuroscience, genomics, quantitative biology and plant biology, hosted its 19th annual Double Helix Award Dinner on Nov. 14.

Front row from left, 2024 Double Helix Medals honorees Dr. Katalin Karikó, Daniel and Alisa Doctoroff.
Back row, from left, CSHL Chair Marilyn Simons, President & CEO Bruce Stillman, and Grace Stillman. Photo courtesy of Patrick McMullan Company

Held at the American Museum of Natural History in New York City and emceed by CBS journalist Lesley Stahl, the dinner, so named for the twisting ladder structure of the genetic material DNA, raised $7 million while honoring Nobel Prize winner Katalin Karikó, and Daniel and Alisa Doctoroff, a husband and wife team who are leaders of Target ALS.

Bruce Stillman, CEO of Cold Spring Harbor Laboratory, recently discussed the awards dinner, an innovative and potentially revolutionary study on aging, science funding, and a host of other topics in an exclusive interview.

The honorees at this year’s dinner were “really fantastic,” Stillman said.

Originally from Hungary, Karikó thrived in work that helped lead to BioNTech and Pfizer’s work using messenger RNA to create a vaccine for COVID-19 despite setbacks including four demotions while a scientist at the University of Pennsylvania.

Her experience shows how “a scientist can do Nobel prize winning research despite adversity,” Stillman said. She had an “idea she wanted to stick with.”

Through Target ALS, the Doctoroffs have helped generate progress in research on amyotrophic lateral sclerosis, or Lou Gehrig’s disease.

Daniel Doctoroff, who has ALS, had been Deputy Mayor for Economic Development and Rebuilding and CEO and president of Bloomberg LP.

The dinner has raised over $67 million since its inception and has honored scientists and public figures, including the late boxer and inaugural winner Muhammad Ali, baseball Hall of Fame right fielder Reggie Jackson and Nobel Prize winner and co-discoverer of gene editing tool CRISPR Jennifer Doudna.

As a part of the celebration, the lab produces videos of the honorees, who have made significant contributions to philanthropy or to research or who have been advocates for health.

A week after the dinner, Stillman had written a letter to potential honorees for next year.

“It’s a lot of work to do this properly,” said Stillman. “We have a time limit on the evening. We want everyone out by 9:30 p.m. We timed this whole thing down to the minute and it worked out very well.”

An important aging discovery

While the lab produced a large volume of research studies that could have implications in a range of fields during the year, Stillman highlighted the work of Corina Amor Vegas as being “probably the most impactful down the road.”

Corina Amor Vegas. Photo ourtesy of CSHL

Amor Vegas used a technology developed to treat cancer to address the effects of aging.

She produced chimeric antigen receptors on the surface of the immune system’s T cells to attack senescent cells, which have aged and are not functional but could otherwise cause aging related problems such as diseases.

In a mouse model, Amor Vegas found that treating these aging mice with modified forms of their own T cells, through car-T immunotherapy, improved metabolic dysfunction and exercise capacity. Indeed, even a single treatment was enough to provide long term benefits for these mice.

The work attracted considerable venture capital interest and the lab is in discussions about how to pursue a business approach that taps into the potential use of this discovery.

As for businesses, the lab has a number of companies that are “under the radar screen” but that will have an impact in their fields.

Professor Partha Mitra started a company called Clarapath that will make “a major splash” with its automatic slides for pathology, Stillman said. A machine can do the work automatically that is otherwise labor intensive.

Down the road, scientists could apply artificial intelligence to analyze the samples. The laboratory has several faculty that are doing machine learning or AI in their research in areas such as neuroscience or genetics.

Through a neuro-AI scholars program, CSHL brings in people who have had a high level of training in computer science related to machine learning. The scholars come to CSHL for one or two years, where they work in a neuroscience lab.

Meetings

Stillman was pleased with the meetings on site this year, including one on epigenetics and CRISPR.

At the end of May in 2025, CSHL plans to have a symposium called Senescence and Aging.

The lab has invited scientists to speak from Germany, Israel, Japan and the United Kingdom as well as from Harvard, Brown and Yale. Locally, Amor Vegas, Assistant Professor Semir Beyaz and Professor Lloyd Trotman have also received invitations to share their work.

Stillman anticipates the publication of compelling findings from CSHL next year, including in autism.

At the same time, the lab is building a new Neuroscience Research Complex that should be finished in 2026. The 36,347 square-foot facility will include three modern buildings that focus on neurodegenerative diseases, brain-body physiology and quantitative biology and NeuroAI.

The construction has been going “very well,” Stillman said.

Science and politics

Amid talk of a rationalization of the research budget next year when the former and future president Donald Trump takes office, Stillman cautioned against a heightened focus on translational studies.

“If we knew what basic science would be translational, we would be doing it,” Stillman said. “If you go back and look at fundamental discoveries of how a disease can be cured, like Spinraza, people would have said, ‘Don’t study this or that.’”

Professor Adrian Krainer developed the drug Spinraza at CSHL, which is an effective treatment for an otherwise debilitating childhood disease called spinal muscular atrophy.

The development of CRISPR came from a study of bacteria that grow in a marine environment.

If Trump’s administrators think they can predict that every dollar will be productive, “they are nuts,” Stillman said. “We should have a discussion before they start pronouncing what should be done.”

Converting the National Institutes of Health into a directed translational research institute will push down American competitiveness.

China is planning to spend large sums of money in basic research. If the United States cuts back in these areas, this is a “recipe for the country to become a second class citizen to those that are “investing in basic science.”

The Human Genome Project cost $3 billion over 25 years. The returns exceed $1 trillion, Stillman said.

“That’s an enormous payoff,” he added. 

Despite concerns and a watchful eye on research funding, Stillman shared a positive outlook.

“I’m not pessimistic about the future,” he said. “The United States economy is very strong.”

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Olaf Kleingbeil at the Pezcoller24 Symposium in Italy in June, 2024. Photo by Claudia Tonelli

By Daniel Dunaief

The wreck-and-check method sometimes works, providing the kind of clues that lead to cures.

In the case of cancer, however, taking out one gene or one protein may not be enough, particularly when a combination contributes to cancer growth or to inactivating the body’s defenses against the disease.

Olaf Klingbeil. Photo courtesy of CSHL

Over the course of seven years, first developing a technique, then searching for possible clues about what the work might reveal, Olaf Klingbeil, a postdoctoral researcher in the lab of Professor Chris Vakoc at Cold Spring Harbor Laboratory, discovered two proteins that work together to do cancer’s bidding.

Called Mark 1 and Mark 2, these two proteins in combination keep a tumor suppressor called Hippo from doing its job, enabling a wide range of cancers from continuing to grow.

The Hippo pathway is one of the most dysfunctional in all human cancer biology.

The journey to this discovery is as compelling as the finding itself.

Klingbeil honed a technique that took out a series of genes, hoping to find out how more than one protein might be involved in the kind of on-off switch geneticists are often seeking to slow or squelch cancer.

Indeed, disrupting either of the proteins on its own would not have been enough, as the disease would have progressed with a singular inhibitor.

“When you manipulate A or B individually” you don’t see much difference in the cancer cells, Vakoc said. “When you manipulate A plus B, you get a massive effect.”

Vakoc suggested that his lab developed a new technology to find cancer targets, enabling them to search for processes and contributors that were otherwise invisible. Klingbeil used lentiviruses to introduce CRISPR gene editing into cancer cells.

“What [Klingbeil] developed, a method where you can introduce two [changes] at the same time, can be engineered to target combinations of genes,” Vakoc said. “It took years to figure out how to do this.”

Klingbeil explored the effect of making these double knockouts through many perturbations.

“It was the largest project in my lab to this point,” said Vakoc.

A eureka moment

Klingbeil examined several potential leads that might provide clues about how to attack cancer cells. He published 1,719 single gene knockouts and 2,529 paralog double knockouts and expected to find a few jewels. 

Christopher Vakoc. Photo courtesy of CSHL

He likens the process to panning for gold at a creek, which involves getting rid of numerous stones before discovering that gold nugget, which, in this case came in the form of two kinases, which add phosphate labels to macromolecules.

When Klingbeil honed in on Mark 2 and Mark 3, he couldn’t immediately understand why inhibiting these enzymes affected some forms of cancer, but not all of them. 

The postdoctoral researcher read a study in which the researchers looked at the tumor suppressive function of Yap/Taz in leukemia and neuroendocrine cancers and realized that these were the cancer types that didn’t show a reaction to inhibiting these kinases.

This was the first hint that Marks 2 and 3 and Yap/Taz might work together, Klingbeil explained.

The affected cancers include liver, lung, colorectal, ovarian, triple negative breast cancer, pancreatic cancer and prostate cancer. That list also includes rhabdomyosarcoma, a rare form of pediatric cancer for which Vakoc, in particular, is eager to develop new treatments.

While numerous scientists are seeking ways to block this pathway directly, the focus on Mark 2 and Mark 3 presents a new potential opportunity.

Marks are “totally overlooked in the community” and are “not a known target,” said Vakoc. “This is the first paper that announces these as cancer targets in a compelling way.”

An existing drug

Once he discovered this link, Klingbeil searched for existing drugs that might target Marks 2 and 3. Fortunately, he found one that Merck had tried to develop for Alzheimer’s disease.

While that didn’t work as well as the pharmaceutical company had hoped, the CSHL researchers are looking to use it as a starting point for a future therapy.

“We are excited that there’s a chemical matter” that might help treat cancer, Vakoc said, adding that such a treatment will likely require “a lot of love by chemists to give them the ideal attributes” for any therapeutic approach.

The drug Merck produced inhibited Marks 1 and 4 as well as 2 and 3, which provides opportunities to tailor it for the most relevant enzymes. By increasing the specificity of the drug for two of the four proteins, researchers and pharmaceutical companies could reduce the side effects of inhibition.

To be sure, Vakoc and Klingbeil cautioned that this discovery, while encouraging, wouldn’t likely provide a magic bullet for cancer, which has a way of becoming resistant to treatments and to tapping into other unknown or unseen pathways to continue to cause harm.

Effective future treatments that involve inhibiting Marks 2 and 3 could require the use of a combination of therapies, which might outmaneuver or slow the progression of cancer.

A personal message

Earlier this year, Klingbeil learned that the journal Cancer Discovery had accepted the paper for publication in an unusual way. He was attending a dinner one night at a conference in Italy when Elizabeth McKenna, the Executive Editor of the journal, approached him.

“She told me she was about to send an email” to Vakoc that the paper was accepted, Klingbeil said. “I was very excited. I’m happy to publish it and that I could convince the most critical reviewers about the value of the work.”

After a productive and rewarding collaboration with Vakoc, Klingbeil is preparing for the next steps in his career. He is speaking with various institutions, particularly in Europe, where he can be closer to his family and his native Berlin, Germany while continuing to advance his scientific career. He plans to continue to work with Vakoc after he leaves.

“The discovery was big enough to carve out a piece for him and me,” Klingbeil said and suggested he would study Mark function in pancreatic cancer in more detail.

On the personal front, fate lent a hand when Klingbeil first arrived on Long Island.

He started his life here in the middle of the winter, without a car or a driver’s license. The lab provided temporary housing on campus. He had a choice to share an apartment with either a French or an Italian postdoctoral researcher.

He chose to live with postdoctoral researcher Claudia Tonelli, who works in the lab of Cancer Center Director David Tuveson and is now his partner. The two researchers, who started dating a few months after living together, have a daughter Lily.

As for his work, he is cautiously optimistic that this discovery may one day help with new and effective therapies.

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Bottom row, from left, Andrew Whitely, VP Business Development and Technology Transfer at CSHL; Dr Susan Poser, President of Hofstra University; students Dimitri Dumontier; Charlie Chung, Yong Lin, Stephen Staklinski and Javier Anduaga; Dr. Janet A. Lenaghan, Dean of the Frank G. Zarb School of Business at Hofstra University; and Erick Hunt, Director of the Institute of Innovation and Entrepreneurship at Hofstra University Top row, from left, students Zifei Wang, Viet Hang Lee, Yujia Li, Jed de Ruiter-Swain, and Eva Lentsch. Photo courtesy of Hofstra University

By Daniel Dunaief

Ten graduate students and postdoctoral researchers stepped outside their familiar surroundings at Cold Spring Harbor Laboratory into a different campus and discipline recently.

As a part of the inaugural Bioscience Business Innovation Program, these developing scientists spent a week working with a collection of business professors at the Frank G. Zarb School of Business at Hofstra University, where they learned a range of subjects such as financial planning, intellectual property, leadership and project management.

The program, which will include a second week of training in March, is designed to teach developing scientists about market validation, Food and Drug Administration processes, and the creation of business models. The program also teaches leadership, team building and communications, which could help researchers who enter the pharmaceutical or biotechnology fields after they leave CSHL.

The goal is to “familiarize these new researchers on several aspects of business, marketing, finance, and management” which will help them consider the potential commercial application of their work, said Anoop Rai, Finance Professor at Zarb and one of the instructors in the Bioscience Business effort.

Indeed, in applying for some grants for startups from agencies like the National Science Foundation, researchers need to answer questions relating to growth, profitability and a target market.

“A knowledge of business is probably very important in that sense,” added Rai.

Scientists often have an interest in developing an innovation that could be useful for society, whether that’s a drug to treat a disease, a test to monitor health, or a new product. Such efforts need to “be marketed to become successful,” Rai said. “This group may, at some point, try and make [their findings] into a successful venture.”

Scientists would benefit from knowing about business in case they move to the next stage in their research or business development. To be sure, a two-week course offers an opportunity to learn and to develop an awareness of the business world, but doesn’t provide a comprehensive formula for success. The students will “get a feel more on the venture funding side, not so much on the complete running of a business,” said Rai.

Still, at the end of the program, the CSHL researchers will have an opportunity to make a pitch alongside a law student and a MBA candidate that a group of experts will evaluate. These pitches will require a basic understanding of business.

Student experience

Some of the students, who put most of their research aside for a week to immerse themselves in intensive training from a host of lecturers and experts, felt they have already benefited from such instruction.

Stephen Staklinski

One of the biggest take-home messages for PhD candidate Stephen Staklinski, who works in the lab of Professor Adam Siepel, involved understanding the consumers of any future product.

In research, Staklinski reads papers and looks for information that’s missing in the field. He rarely communicates directly with people who might be affected by any future discovery until a project is well under way. With a business viewpoint, he gained a new perspective he feels he can integrate effectively into his research.

Staklinski recognized the value of talking to physicians and cancer patients about some of their biggest issues. He sees the benefit of these open communications about how to serve patients who are battling various conditions.

In his current research, Staklinski builds statistical probabilistic models around the human genome. Specifically, he’s looking at molecular sites in RNA and is searching for targets that lead to metastatic processes. In working with experimental collaborator, Staklinski said he can “think about therapeutics to block this.”

Viet Hang Le, a postdoctoral researchers in the lab of Professor Linda Van Aelst, felt she received an introduction on how to develop fundamental research findings towards making new therapies.

“We got to learn about the laws and policies involved” in creating a new company, said Le. On the clinical safety side, she also learned how new products maneuver through health care and reach patients.

Her original curiosity was to see how research findings could lead to real-life treatments. Understanding business fundamentals opens more career options.

Indeed, even if Le and her colleagues continue to conduct research, she feels she can communicate more effectively with industry partners. It also whet her appetite for more business learning.

“It really bridges the gap between our background in fundamental science and the requirement for an MBA course,” Le explained. 

She is working on two projects in Van Aelst’s lab. In the first, she is studying early onset epilepsy, which is a symptom of an X-linked intellectual disability in patients carrying a mutation in the gene Oligophrenin 1.

In the second, she is exploring how the nervous system influences the progression of cancer in main tumors and metastatic tumors.

“We built a hypothesis on how different branches of nerves might increase the growth of cancer,” said Le. In Van Aelst’s lab, they are working with primary breast cancer and liver metastasis.

Originally from Dan Nang, Vietnam, Le spent a number of weeks during several summers as a part of the US Navy Pacific Partnership delivering medical treatment to medically underdeveloped areas in the country.

Through her lab work and any budding business interest, she would like to figure out how to deliver medical care to patients who might struggle with the financial or logistical challenge of affording care.

By connecting with experts who’ve negotiated various obstacles, “I’m gaining a clearer sense of how to streamline the path from discovery to patient care, cutting down unnecessary costs and time without compromising safety,” she said.

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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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By Daniel Dunaief

A male mouse embryo surrounded by a group of female embryos during development in some cases is protected against developmental delays caused by a viral infection of their mother.

That’s one of a host of intriguing observations and findings from a recent set of experiments conducted by postdoctoral researcher Irene Sanchez Martin, who works in the lab of Assistant Professor Lucas Cheadle at Cold Spring Harbor Laboratory.

Irene Sanchez Martin and Lucas Cheadle at Cold Spring Harbor Laboratory. Photo by Justin Park

Sanchez Martin is studying how maternal exposure to viruses triggers immune responses, particularly inflammation, which can contribute to developmental delays characteristic of autism. 

In mice as in humans, males are much more susceptible to the onset of the kinds of neurological developmental behaviors that are characteristic of autism than their female counterparts.

“The advantage of our model is that it helps us understand why this happens, providing insights into the underlying mechanisms driving this increased vulnerability in males,” Sanchez Martin explained.

Researchers have been studying viral exposure and developmental disorders for a while. The new element in Sanchez Martin’s research is that she can observe phenotypic changes as early as 24 hours after a pregnant mouse is exposed to a virus, providing a much earlier window into how maternal immune activation affects development.

At an early stage of gestation, when sensory organs, the head, spine and other organs are starting to develop, the male mice demonstrate disruptions in normal development, which affects these structures in different ways. Sanchez Martin hopes these kinds of studies help uncover the pathways through which environmental factors contribute to the development of some cases of autism.

Sanchez Martin’s work is part of a broader effort in Cheadle’s research.

“My lab is interested in understanding how interactions between the nervous system and the immune system shape the development and plasticity of the brain,” Cheadle explained. One goal is to understand how systemic inflammation during prenatal stages leads to heightened risk of autism in offspring.

To be sure, the genetic component suggests that inflammation is not necessary for the development of autism. Nevertheless, exposure to prenatal inflammation can increase autism risk by about three times, making inflammation a likely “key contributor to the development of autism in some, but not all, individuals,” said Cheadle.

Sanchez Martin found that female mice did not develop the same changes as males. She believes this is one of the most valuable applications of the model she’s working on with Cheadle, as it can reveal the biological and developmental differences that contribute to this gender disparity.

Timing

Sanchez Martin studied mice that were exposed to a virus between 12 to 13 days after fertilization, which is similar to the end of the first trimester in a human embryo. Mice develop more rapidly, so the process doesn’t track exactly the same as it would in humans.

About a day after the maternal exposure, some males looked different through ultrasound than they would during typical development. The differences are subtle and it is still too early to assume these changes could serve as a diagnostic marker for autism spectrum disorder.

A host of disruptions could affect the growth of the embryo. The placenta serves as a bridge between the mother and the developing embryo, allowing communication, filtering substances, and protecting the embryo during development. Each mouse embryo has its own placenta and its own amniotic fluid in its amniotic sac, creating a unique microenvironment.

In her lab work, Sanchez Martin is collaborating with Dr. Brian Kalish at Boston Children’s Hospital, who is helping to analyze molecular changes in the placentas of affected and unaffected embryos. Sanchez Martin has data indicating differences between the placentas of affected and healthy individuals, as well as in the amniotic fluid.

“This suggests a dysfunction in the placenta in affected cases” indicating it is not adequately performing its protective and filtering function, she explained.

Female mouse embryos may be more protected in part because of their more active immune response. Other studies have shown that female immune systems, as early as the developmental stage, express higher levels of interferon-stimulated genes and have stronger responses to infections, which may offer better protection than males.

While male mice in some cases benefit from the protection provided by their nearby sisters, Sanchez Martin and Cheadle are “still working to fully understand the underlying mechanism,” she explained.

Epidemiology

By looking at the prevalence of conditions such as autism in the aftermath of larger viral infections, researchers have demonstrated that these illnesses can and do have impacts on the incidence of autism and schizophrenia, among other conditions. It’s not only the pathogen that is responsible, but also the immune response triggered by the infection, as well as the timing of the infection during pregnancy.

Covid, which infected over 100 million Americans, may cause an increase in the number of children born with autism.

“There is precedent from studies of other viral infections during pregnancy, which suggest that maternal immune activation can contribute to altered neurodevelopment in offspring,” Sanchez Martin said. “There is some evidence that male children exposed to SARS-CoV-2 during pregnancy might have a slightly elevated risk of other neurodevelopmental disorders.”

Additional research with longer-term follow up is necessary to confirm these findings. The timing and the immune response during pregnancy could be key factors in determining the outcomes​​.

Cheadle appreciated the effort and dedication of Sanchez Martin, whom he described as being “bright, talented, motivated and an excellent experimentalist. Her work is among the most important projects in the lab.”

From Madrid to CSHL

Born and raised in Madrid, Spain, Sanchez Martin has been a master of motion. During her final years of her Veterinary Medicine studies at Universidad Alfonso X El Sabio in Madrid, she moved to the University of Helsinki to complete her clinical rotations.

She later earned her PhD at the Centre National de la Recherche Scientifique in Marseille, France and defended her thesis at the Aix- Marseille University. During her PhD, she was a visiting student at Biocenter Oulu in Finland.

Her first job was at Laboklin in Bad Kissingen, Germany, where she worked in a clinical laboratory.

She did her first postdoctoral research in the Microbiology Department at Mount Sinai. During the pandemic, she was involved in studying innate and adaptive immune responses in different in vitro models, focusing on vaccine candidates for Covid-19 and influenza.

A resident of Manhattan, Sanchez Martin has contributed to Cheadle’s lab for two years.

She enjoys listening to classical music, reading, and swimming, which she likes to do several times a week as she has some of her best ideas when she’s in the water.

As for her work, Sanchez Martin appreciates the opportunity to conduct her research as a part of Cheadle’s team that is hoping to identify the molecular mechanisms that contribute to autism in mice.

“It’s an ongoing effort and we hope that with time and collaboration, we can gain more insight,” she explained.

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Kate Alexander. Photo courtesy of CSHL

By Daniel Dunaief

In the nucleus of the cell, researchers often focus on the genetic machinery, as the double-helical DNA sends signals that enable the creation of everything from my fingers that are typing these words to your brain that is processing what you’ve read.

But DNA, which occupies most of the nucleus, is not alone. Scattered through the nucleus are protein and RNA filled structures that have an influence on their important gene-bearing nuclear cohabitants, including speckles.

One of the newest members of the Cold Spring Harbor Laboratory team, Assistant Professor Kate Alexander, who joined the lab in August, is focused on a range of questions about these speckles, which represent about 10 to 30 percent of the nuclear volume.

Preliminary data from Alexander’s lab support the idea that speckles can signal how a person responds to various types of therapy, although careful extensive follow up studies are needed, Alexander explained. She would like to know how the speckles are affecting the genetic machinery.

While speckles have been known since 1910, the ways they affect healthy cells and diseased cells remains a mystery. In some cases, normal or aberrant speckles can signal how a person responds to various types of therapy.

Normal speckles are in the center of the cell nucleus, while aberrant speckles are more scattered. Aberrant speckles can activate some of the surrounding DNA.

At this point, Alexander and her colleagues have “found that normal or aberrant speckle states correlate with survival of clear cell renal cell carcinoma. This accounts for over 80 percent of all kidney cancers.”

Medical choices

After a patient with clear cell renal cell carcinoma receives a cancer diagnosis, the first line of treatment is usually surgery to remove the tumor in the kidney. In addition, doctors could treat the tumor with a systematic anti-cancer therapy. The treatments themselves can and often do cause difficult side effects, as therapies can harm healthy cells and can disrupt normal biological functioning.

Normal speckles look something like the face of the man on the moon and are more centrally located.

Alexander is hoping speckles will help predict the state of the tumor, offering clues about how it might respond to different types of treatments. She could envision how aberrant speckles could correlate with better responses to one drug, while normal speckles might correlate with better responses to another treatment.

In her research, Alexander is exploring how DNA is organized around speckles, as well as how the speckles affect DNA.

“Speckles can change and impact what’s happening to all the DNA that’s surrounding them,” she said. 

Over 20 tumor types show evidence for both normal and aberrant speckles. Aberrant tumors can occur in many types of cancer.

“The consequence of [speckles] becoming normal or aberrant are starting to become more clear,” she said, although there is “still a lot to learn.”

Alexander is trying to figure out how to alter the conformation of these speckles. During cancer, she suspects these speckles may get trapped in a particular state.

In one of the first experiments in her lab, she’s culturing cells in an incubator and is trying to predict what cues may cause speckles in those cells to switch states. 

‘Speckle club’ leader

Alexander previously did postdoctoral research at the University of Pennsylvania in the laboratory of Shelley Berger, where she was also a Research Associate. She led a subgroup in the lab known as the “speckle club.”

Charly Good, who is now Senior Research Investigator in Berger’s lab, worked with Alexander at Penn from 2017 until this summer.

Aberrant speckles are scattered throughout the nucleus.

Alexander “helped recruit me to the postdoc I ended up doing,” said Good who appreciated Alexander’s computational skills in analyzing big data sets. Speckles represent an “up and coming area” for research, which Alexander and Berger are helping lead, Good suggested.

Alexander’s quick thinking meant she would go to a talk and would email the speaker as soon as she got back to her desk. “Her brain is always spinning,” said Good.

Alexander is building her lab at CSHL. Sana Mir is working as a technician and is helping manage the lab. Recently, Hiroe Namba joined the group as a postdoctoral researcher. In the next few years, Alexander would like to add a few graduate students and, within five years, have about eight people.

Originally from Tigard, Oregon, Alexander attended Carleton College in Northfield, Minnesota. In her freshman year, she tried to get into a physics class that was full and wound up taking a biology class. She was concerned that biology classes were mostly memorization. When she started the course, she appreciated how the science involved searching for missing pieces of information.

Cold Spring Harbor Laboratory appealed to her because she could go in whatever direction the research took her.

For Alexander, scientific questions are like a layer of cloth with a few threads sticking out.

“You see one sticking out and you start to pull,” Alexander said. “You don’t necessarily know what’s going to come out, but you keep getting the urge to pull at that thread. You realize that it is connected to all these other things and you can look at those, too.”

She is excited to cross numerous disciplines in her work and is eager to think about how her research might “interplay across those fields and boundaries.”

Speckle origins

As for speckles, Alexander observed during her postdoctoral research how one factor seemed to influence a neighborhood of genes.

For that to occur, she realized that something had to affect those genes at the same time in the physical space. She hadn’t known about speckles before. A few of her colleagues, including Good, came across speckles in their analysis. That made Alexander curious about what these speckles might be doing.

She saw an opening to pursue connections between changes in these potential gene activators and illnesses.

Researchers know that viruses can use speckles to help them copy themselves.

If they are used by viruses “they must be important” and they “probably go wrong in a lot of diseases,” Alexander said. There are a series of neurodevelopmental disorders called “speckleopathies” that involve mutations in proteins found inside speckles.

“We have the computational and experimental tools to start investigating them across a wide variety of conditions,” she said.

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