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Cold Spring Harbor Laboratory

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

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

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From left, Mikala Egeblad and Xue-Yan He. Photo from Constance Brukin

By Daniel Dunaief

They both have left Cold Spring Harbor Laboratory, but the innovative research they did on Long Island and that they continue to do, is leaving its mark.

From left, Mikala Egeblad and Xue-Yan He at the American Association for Cancer Research (AACR) annual meeting in New Orleans, Louisiana in 2022. Photo from Xue-Yan He

When Xue-Yan He was a postdoctoral researcher in the lab of Mikala Egeblad, who was Associate Professor at CSHL, the tandem, along with collaborators, performed innovative research on mice to examine how stress affected the recurrence and spread of cancer in a mouse model.

In a paper published in late February in the journal Cancer Cell, He, who is currently Assistant Professor of Cell Biology & Physiology at Washington University School of Medicine in St. Louis, discovered that stress-induced neutrophil extracellular traps (NETs), which typically trap and kill bacteria, trigger the spread of cancer.

“The purpose of our study is to find out what stress does to the body” of an animal model of cancer, said He.

The data in mice demonstrated that targeting NETs in stressed animals significantly reduced the risk for metastases, He explained, suggesting that reducing stress should help cancer treatment and prevention. The researchers speculate that drugs preventing NET formation can be developed and used as new treatments to slow or stop cancer’s spread.

To be sure, this finding, which is encouraging and has generated interest among cancer scientists and neurobiologists, involved a mouse model. Any potential application of this research to the diagnosis and treatment of people will take considerably more effort.

“I want to stress that the evidence for the link between stress, NETs, and cancer is from mouse studies,” Egeblad explained. “We will need to design human studies to know for sure whether the link also exists for humans.”

Still, Egeblad hopes that eventually reducing stress or targeting NETs could be options to prevent metastatic recurrence in cancer survivors. “One major challenge is that a cancer diagnosis by itself is incredibly stressful,” she explained. The results of these experiments have attracted considerable attention in the scientific community, where “there is a lot more to learn!” 

Three part confirmation

When she was a postdoctoral researcher, He removed neutrophils from the mice using antibodies. Neutrophils, which are cells in the immune system, produce the NETs when they are triggered by the glucocorticoid stress hormone.

She also injected an enzyme called DNAse to destroy NETs in the test mice. The former CSHL postdoctoral researcher also used genetically engineered mice that didn’t respond to glucocorticoids.

With these approaches, the test mice developed metastasis at a much lower rate than those that had intact NETs. In addition, chronically stressed mice who didn’t have cancer had NETs that modified their lung tissue.

“Stress is doing something to prepare the organs for metastasis,” said He.

Linda Van Aelst, CSHL Professor and a collaborator on the study, suggested that this work validates efforts to approach mental health in the context of cancer.

“Reducing stress should be a component of cancer treatment and prevention,” Van Aelst said in a statement.

After He removed the primary tumor in the mouse models, the stressed mice developed metastatic cancer at a four-fold higher rate than the mice who weren’t stressed but who also previously had cancer.

The CSHL scientists primarily studied breast cancer for this work.

He appreciated the help and support from her colleagues at CSHL. “To really understand the mechanism” involved in the connection between stress and cancer, “you need a mouse model in the lab, an expert in neuroscience and an expert in the cancer field,” she said.

As a neuroscientist, Van Aelst offered suggestions and comments and helped He conduct behavioral tests to determine a mouse’s stress level. The work for this project formed the focus ofHe’s postdoctoral research, which started in 2016 and ended in 2023.

The link between stress and cancer is receiving increasing attention in the scientific community and has attracted attention on social media, He said.

CSHL “provided a great environment to perform all these experiments,” said He. The numerous meetings CSHL hosts and the willingness of principal investigators across departments made the lab “one of the best places” for a postdoctoral scientist.

“If you need anything from a neural perspective or a technical perspective, you can always find a collaborator” at CSHL, He added.

Born and raised in Nanjing, China, He enjoyed living on Long Island, visiting vineyards and trying to explore every state park. In the harbor, He caught blue crabs while her husband Chen Chen, who was a postdoctoral researcher at CSHL in the lab of Camila dos Santos, went fly fishing at Jones Beach.

In her current research, where she manages a lab that includes a senior scientist, a postdoctoral researcher and an undergraduate, He is extending the work she did at CSHL to colorectal cancer, where she is also analyzing how stress affects the spread of cancer.

“When you’re stressed, you can develop gastrointestinal problems, which is why I wanted to switch from breast cancer to colorectal cancer,” she said.

Extensions of the work

As for context for the research at CSHL, Egeblad wrote that doctors treating patients where the known risk of recurrence is high might use NETs in the blood as a biomarker.

The scientists think cancers that tend to metastasize to the liver, lung or spleen are the strongest candidates to determine the effect of NETs and stress on cancer.

“We have not seen any effects of targeting NETs for metastasis to the bone or the brain in our mouse model and similarly, the studies that have linked NETs to metastasis in human patients have mostly been cancer that has spread to the liver or the lung,” Egeblad said.

Egeblad appreciated the “fantastic job” He did on the work and described her former researcher as being “fearless.”

“She found that stress increased metastasis early in her project but it was a lot of work to discover it was the NETs that were responsible and to conduct studies to ensure that the results were applicable to different types of cancer,” Egeblad explained.

While the two researchers have gone to different institutions and are leading other lab efforts, Egeblad said she’d be happy to collaborate with her former student, who shares the same sense of humor.

Egeblad recalled how He ended her talks by telling the audience that her results showed that Egeblad should give her a “long vacation.”

“I think indeed that she has deserved one after all this work!” Egeblad offered.

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Cold Spring Harbor Laboratory neuroscientist Arkarup Banerjee is using singing mice, like the one shown here, to understand how our brains control timing and communication. Photo by Christopher Auger-Dominguez

By Daniel Dunaief

Animals don’t have clocks, telling them when and for how long to run on a treadmill, to eat whatever they catch or to call to each other from the tops of trees or the bottom of a forest.

Arkarup Banerjee

The Alston’s singing mouse, which lives in Costa Rica, has a distinctive call that people can hear and that, more importantly, conveys meaning to other members of the species.

Using equipment to monitor neurons when a mouse offers songs of different length, Cold Spring Harbor Assistant Professor Arkarup Banerjee showed that these unusual rodents exhibit a form a temporal scaling that is akin to stretching or relaxing a rubber band. This scaling suggests that their brains are bending their processing of time to produce songs of different lengths.

“People have shown this kind of time stretching phenomenon in monkeys,” said Banerjee. It was unexpected and surprising that the same algorithm was used in the rodent motor cortex to control the flexibility of a motor pattern and action during vocalization.

Using recordings of neuronal activity over many weeks, Banerjee focused on a part of the mouse brain called the orofacial motor cortex (or OMC). He searched for differences in songs with particular durations and tempo.

Banerjee had set up a system in which he played back the recordings of Alston’s singing mice to his test subjects, who then responded to those songs. Mice generally respond with songs that are variable durations compared to when they sing alone.

These mice can adjust duration and tempo of these 10-second long songs while engaged in social communication.

People “do that all the time,” said Banerjee. “We change the volume of how loud we are speaking and we can change the tempo.”

The mice showed some vocal flexibility similar to other animals, including people.

These mice are singing the same song, with varying rhythms over shorter or longer periods of time. It is as if the same person were to sing “Happy Birthday” in 10 seconds or in 15 seconds.

Banerjee would like to know what is it in the mouse’s brain that allows for such flexibility. He had previously shown that the motor cortex is involved in vocal behavior, which meant he knew of at least one region where he could look for clues about how these rodents were controlling the flexibility of their songs.

By tracking the firing pattern of neurons in the OMC, he was able to relate neural activity to what the mice were doing in real time.

Neural activity expands or contracts in time, almost as if time is running faster or slower. These animals are experiencing relative time when it comes to producing their songs as they change their songs through a wide range of durations.

Pre-song activity

Even before an animal sings, Banerjee speculates its brain could be preparing for the sounds it’s going to make, much as we think of the words we want to say in a conversation or our response to a question before we move our mouths to reply or type on a keyboard to respond.

Songs also track with intruder status. An animal in a home cage sings a shorter song than an animal brought into a new cage.

Vocalizations may scale with social rank, which might help attract mates or serve other social purposes.

Females in the lab, which presumably reflect similar trends in the wild, tend to prefer the male that produces a longer song with a higher tempo, which could reflect their physical fitness and their position in the social hierarchy, according to research from Steve Phelps, Professor at the University of Texas at Austin in the Department of Integrative Biology.

Applications

While it’s a long way from the research he’s conducting to any potential human application, Banerjee could envision ways for these studies to shed light on communication processes and disorders.

The motor cortex in humans and primate is a larger region. Problems in these areas, from strokes or injuries, can result in aphasia, or the inability to articulate words properly. Banerjee plans to look at stroke models to see if the Alston’s singing mouse might provide clues about potential diagnostic or therapeutic clues.

“There are ways we can use this particular system to study cognitive deficits that show up” during articulation deficits such as those caused by strokes, said Banerjee.  While he said scientists know the parts list of the brain regions involved in speaking, they don’t yet know how they all interact.

“If we did, we’d have a much better chance of knowing where it fails,” Banerjee  explained. A challenge along this long process is learning how to generalize any finding in mice to humans. While difficult, this is not an impossible extrapolation, he suggested.

An effective model

Banerjee built a model prior to these experiments to connect neural activity with behavior.

“We had an extremely clear hypothesis about what should happen in the neural domain,” he said. “It was pretty gratifying to see that neurons change the way we predicted given the modeling.”

When the paper first came out about eight months ago in the scientific preprint bioRxiv, it received considerable attention from Banerjee’s colleagues working in similar fields. He went to India to give three talks and gave a recent talk at Emory University.

Outside of the lab, Banerjee and his wife Sanchari Ghosh, who live in Mineola, are enjoying watching the growth and development of their son Ahir, who was born a year and a half ago.

“It’s fascinating as a neuroscientist to watch his development and to see how a tiny human being learns about the world,” Banerjee said.

As for his work with this compelling mouse, Banerjee credited Phelps and his post doctoral advisor at New York University, Michael Long for doing important work on this mouse and for encouraging him to pursue research with this species. Long is a co-corresponding author on the paper. “It’s very gratifying to see that the expectation of what we can do with this species is starting to get fulfilled,” said Banerjee. “We can do these interesting and complex experiments and learn something about vocal interactions. I’m excited about the future.”

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SCIENCE ON SCREEN

The Cinema Arts Centre, 423 Park Ave., Huntington continues its Science on Screen series with a mind-expanding exploration of the mysteries of language and communication, featuring a lecture and Q&A with neuroscientist Arkarup Banerjee, of Cold Spring Harbor Laboratory, and a rare big-screen showing of Denis Villeneuve’s profound 2016 drama ARRIVAL on Tuesday, March 26 at 7 p.m..

Dr. Banerjee’s work explores the theme of decoding messages and touches on the fundamental assumptions of reality which are unpacked in the film. Discover how every species and culture’s unique symbols and codes shape our understanding of the world around us, and uncover the intriguing ways in which our brains navigate the limits and possibilities of language.

Tickets are $16, $10 members. To purchase in advance, visit www.cinemaartscentre.org. 

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Bruce Stillman. Photo from CSHL

The toxic talk and policies towards immigrants in the United States is hurting American science and could threaten the country’s ability to compete in technology, an important economic driver.

That’s one of several messages Bruce Stillman, Cold Spring Harbor Laboratory President and Chief Executive Officer, shared in an exclusive interview.

The attitude of some Americans towards immigrants, particularly amid the southern border issue, is “scaring a lot of people off, thinking about working in the United States,” said Stillman. Some of these talented immigrants are wondering why they would come to America. “The perception is that the US is not as welcoming as it used to be,” even for the immigration of highly skilled people, he added.

This hostility could have a detrimental top-down effect on science.

Indeed, immigrants have distinguished themselves, earning top prizes in science and accounting for 38 percent of the Nobel Prizes in physics, 34 percent in medicine and 37 percent in chemistry since 1901, according to Forbes.

“This is a very important economic and competitiveness issue,” said Stillman, who grew up in Australia.

It is increasingly difficult to recruit people from certain countries, particularly amid challenges getting visas, Stillman said.

Cold Spring Harbor Laboratory has an offer out to a “very talented scientist” who has been waiting for almost a year to receive a visa, he said.

Many people have an opinion on the way things ought to be, Stillman explained, including issues related to diversity, equity and inclusion.

“The dialog in the US is no longer civil, but now people are emboldened to attack those in leadership positions,” he explained in an email. “It is part of the wider adversarial dialog going on in America.”

Policies in some states like Florida create the impression, even to accomplished and dedicated workers, that the country does not want them to work here.

CSHL embraces “talented scientists who want to work in the US to come to CSHL,” he explained.

Major scientific recession

Apart from immigration policies that exclude a broad swath of people who might otherwise ensure American technological competitiveness, Stillman is also worried about how political logjams in Washington could limit future funding for science.

“The moderates on both sides of Congress need to come together to override those on the left wing of the Democratic party and those on the right wing in the Republican party,” he explained.

Stillman does not understand why most members of Congress don’t vote out the extremes. If everyone in the middle stood up, “they would be lauded by the general public,” Stillman wrote in an email.

Listening to the fringes of science on both sides who attack science raises the risk of maintaining a leadership position.

Still, he maintains that he is optimistic that the general public and the moderate majority will prevail.

Learning from history

As the leader of Cold Spring Harbor Laboratory for 29 years, Stillman recognizes his institution’s role in a dubious chapter in American history.

Indeed, a century ago, the United States passed the Johnson-Reed Act, or the Immigration Act of 1924, which provided a quota that limited the number of immigrants to two percent of the people of each nationality in the country as of the 1890 census. The law excluded immigrants from Asia.

After that law, Cold Spring Harbor Laboratory played a role in this policy by creating a eugenics record office.

CSHL put up a web site 18 years ago to chronicle the lab’s involvement in a period when science was used to justify discriminatory policies.

“We have highlighted on our web site about the eugenics movement so as to educate children and adults about how misunderstanding science, in this case genetics, can lead to dangerous public policy,” he explained in an email.

This year, on the 100th anniversary of the immigration law, the lab plans to highlight the 1924 Immigration Act as something that led to policies that are “not compatible with what the US is about,” he said.

Building for the future

Like other labs, CSHL is competing to earn federal grants from the National Institutes of Health and the National Science Foundation.

The lab needs to raise “considerable amounts of money each year to eep cutting edge science moving forward,” he wrote.

Indeed, CSHL recently started a major expansion on seven acres of land at the top of the campus to build four research buildings. The lab plans to hire about 14 to 16 new faculty to join the current staff of 56 investigators.

These buildings will expand on programs that explore brain-body physiology, which describes how organs such as the stomach and others interact with the brain.

Many diseases, including cancer, upset the normal brain body interactions, he added. Intervening in these circuits can lead to new therapeutics for cancer and for many neurological disorders.

Researchers at CSHL will publish several discoveries in the next few years in this field that represent “important breakthroughs,” Stillman said.

At the end of May and early June, CSHL will host an annual symposium on brain body physiology, which will include a lecture for the general public.

CSHL is pursuing the most ambitious capital campaign in the lab’s history, raising funds to support the construction of new research and education buildings and to increase the endowment to support the science.

The lab is also building another center called NeuroAI that integrates neuroscience, artificial intelligence and computer science. The computational AI effort has “taken on a life of its own,” he explained. “We plan a major effort to understand how our brain does normal computation and then use this knowledge to improve computer programs.”

In the realm of artificial intelligence, CSHL has used a program called alpha fold, which a unit of Google called Deep Mind developed.

This program predicts protein-protein interactions and protein-drug interactions, which helps “transform the way biology is done,” he said.

While the work “accelerates” the science, it doesn’t “replace doing real experiments,” he added.

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Zhe Qian

By Daniel Dunaief

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

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

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

Nicholas Tonks. Photo courtesy of CSHL

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

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

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

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

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

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

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

Blocking the receptor

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

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

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

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

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

Limited presence

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

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

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

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

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

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

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

Eureka moment

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

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

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

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

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

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

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

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

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

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The 2023 Double Helix Medals Dinner was once again held under the American Museum of Natural History's iconic blue whale model. Photo from CSHL

By Nick Wurm

On November 15, Cold Spring Harbor Laboratory (CSHL) held its 18th annual Double Helix Medals dinner (DHMD) at the American Museum of Natural History in New York City. CBS journalist Lesley Stahl returned to emcee the awards dinner, which honored Neri Oxman & William Ackman and 2018 Nobel laureate Jim Allison. Thanks to the event chairs and donors, the event raised more than $10 million. After receiving the Double Helix Medal, Oxman and Ackman announced an extraordinary gift, further breaking the event’s fundraising record to support scientific research and education at CSHL.

William Ackman & Neri Oxman

Neri Oxman & William Ackman are co-trustees of the Pershing Square Foundation. The organization empowers scientists to take on important social causes, including the environment, cancer, and cognitive health. Ackman is also the CEO of Pershing Square Capital Management and chairman of the Howard Hughes Corporation. Oxman is an innovative designer whose fusions of technology and biology have been featured in museums around the world. Her work has yielded over 150 scientific publications and inventions.

“Something we continue to this day is backing young, talented entrepreneurs who are on a mission to solve an important societal problem,” Ackman says. “We believe in taking risks with incredible scientists who have the ability to tackle these complex problems,” Oxman adds.

Dr. Jim Allison

Dr. Jim Allison is regental professor and chair of the MD Anderson Cancer Center’s Department of Immunology. He won the 2018 Nobel Prize in Physiology or Medicine for pioneering the field of cancer immunotherapy. Since then, his research has led to the development of ipilimumab, an FDA-approved therapy for metastatic melanoma, renal cell carcinoma, and lung cancer.

“The perception of immunology has shifted,” Dr. Allison says. “People used to say, ‘Will immunotherapy ever work?’ We now know it works. Immunotherapy is going to be a part of all cancer therapies for almost every kind of cancer.”

The 2023 DHMD was chaired by Ms. Jamie Nicholls and Mr. O. Francis Biondi, Ms. Barbara Amonson and Dr. Vincent Della Pietra, Drs. Pamela Hurst-Della Pietra and Stephen Della Pietra, Mr. and Mrs. John M. Desmarais, Mr. and Mrs. Jonathan Gray, 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, Drs. Marilyn and James Simons, and Mr. and Mrs. Paul J. Taubman.

Since the inaugural gala in 2006 honoring Muhammed Ali, the DHMD has raised over $60 million to support CSHL’s biological research and education programs.

Author Nick Wurm is a Communications Specialist at Cold Spring Harbor Laboratory.

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Christopher Vakoc with graduate student Junwei Shi. Photo by Gina Motisi/ CSHL.

By Daniel Dunaief

It is the type of miraculous conversion that doesn’t involve religion, and yet it may one day lead to the answer to passionate prayers from a group of people on a mission to help sick children.

Researchers in the lab of Professor Christopher Vakoc at Cold Spring Harbor Laboratory have been working tirelessly to understand the fundamental biology of Rhabdomyosarcoma, or RMS, which is a type of connective tissue cancer that afflicts between 400 and 500 people each year in the United States, with more than half receiving the diagnosis before they turn 10 years old.

As a part of her PhD research, Martyna Sroka searched for a way to convert the processes involved in this cancer into something benign.

Using a gene editing tool enhanced by another former member of Vakoc’s lab, Sroka disrupted a signal she had spent years trying to find in a protein called NF-Y, causing cancerous cells in a dish to differentiate into normal muscle cells, a conversion that offers future promise for treatment.

Sroka, who is now working as a scientist in a biotechnology company focused on the development of oncology drugs, described how RMS cells look small and round in a microscope. After disrupting this protein, the “differentiated cells become elongated and spindle-like, forming those long tubular structures,” she explained.

She often grew cells on plastic dishes and the differentiated RMS cells spanned the entire diameter of a 15 centimeter plate, providing a striking visual change that highlighted that conversion.

While this research represents an important step and has created considerable excitement in the scientific community and among families whose philanthropic and fundraising efforts made such a discovery possible, this finding is a long way from creating a new treatment.

Other research has indicated that disrupting NF-Y could harm normal cells. A potential therapeutic alteration in NF-Y could be transient and would likely include follow ups such as a surgical, radiation or biological approach to remove the converted RMS cells, Vakoc explained.

Nonetheless, the research, which was published in August in the prestigious Proceedings of the National Academy of Sciences, offers a potential roadmap for future discoveries.

“It was a long journey and being able to put the pieces of the puzzle together into a satisfying mechanism, which might have broader implications not only for our basic understanding of the biology of the disease but also for potential novel therapeutic approaches, was extremely exciting and rewarding,” said Sroka.

“It’s great to see so much excitement in the pediatric cancer field, and I am hoping that with time it will translate to much-needed novel therapeutic options for pediatric patients.”

The search

Cancer signals typically involve rewiring a cell’s genetic material, turning it into a factory that creates numerous, unchecked copies of itself.

Sroka and Vakoc were searching for the kind of signal that might force those cells down what they hope is a one-way differentiation path, turning those otherwise dangerous cells into more normal muscle cells that contract.

To find this NF-Y gene and the protein it creates, Sroka, who started working in Vakoc’s lab in the summer of 2017, screened over a 1,000 genes, which Vakoc described as a “heroic effort.”

Encouraged by this discovery and as eager to find new clinical solutions as the families who helped support his research, Vakoc recognizes he needs to strike a balance between trumpeting this development and managing expectations.

Interactions with the public, including families who have or are confronting this health threat, “comes with a lot of responsibility to make sure we’re being as clear as possible about what we’ve done and what have yet to do,” said Vakoc. “It’s going to be a long and uncertain road” to come up with new approaches to this cancer.

Funding families

Some of the families who provided the necessary funding for this work shared their appreciation for the commitment that Vakoc, Sroka and others have made.

“We are very excited about the newest paper [Vakoc and Sroka] published,” said Phil Renna, the Senior Director of Communications at CSHL and Director of the Christina Renna Foundation, which he and his wife Rene formed when their daughter Christina, who passed away at the age of 16, battled the disease. The Christina Renna Foundation has contributed $478,300 to Vakoc’s lab since 2007.

“In just a few short years, he has made a major leap forward. This lights the path of hope for us and our cause,” said Renna.

Renna explained that the lab has had numerous inquiries about this research. He and others recognize that the search for a cure or treatment involves “tough, grinding work” and that considerable basic research is necessary before the research can lead to clinical trials or new therapeutics.

Paul Paternoster, whose wife Michelle succumbed to the disease and who has raised funds, called Vakoc and Sroka “brilliant and incredibly hard working,” and suggested the exciting results “came as no surprise.”

He is “extremely pleased” with the discovery from the “standpoint of what it can lead to, and how quickly it was discovered.”

Paternoster, President of Selectrode Industries Inc., which manufactures welding products and has two factories in Pittsburgh, suggested that this strategy can have implications for other soft tissue sarcomas as well.

The next steps

To build on the discoveries Sroka made in his lab, Vakoc plans to continue to use a technique Junwei Shi, another former member of his lab, developed after he left CSHL and joined the University of Pennsylvania, where he is now a tenured professor.

Shi, whom Vakoc called a “legend” at CSHL for honing the gene editing technique called CRISPR for just this kind of study, is also a co author in this paper.

In future research, Vakoc’s lab plans to take the screens Sroka used to find NF-Y to search to the entire human genome.

“That’s how the family tree of science operates,” said Vakoc. Shi “made a big discovery of CRISPR and has since continued to create new technology and that he is now sharing back” with his lab and applying it to RMS. Additionally, Vakoc plans to expand the testing of this cellular conversion from plastic dishes to animal models

Shi, who worked in Vakoc’s lab from 2009 to 2016 while he earned his PhD at Stony Brook University, expressed satisfaction that his work is paying dividends for Vakoc and others.

“It just feels great that [Vakoc] is still using a tool that I developed,” said Shi in an interview. Many scientists in the field are using it, he added.

For Shi, who was born and raised in southern China, working at Cold Spring Harbor Laboratory fulfilled a lifelong dream.

He recalled how he retrieved data one Saturday morning that indicated an interesting pattern that might reveal the power of a new methodology to improve CRISPR screening.

When Vakoc came to the lab that morning, Shi shared the data, which was a “whole turning point,” Shi said. 

Shi said he appreciates how CSHL has been “a home for me,” where he learned modern molecular biology and genetics.

When he encounters a problem in his lab, he often thinks about how Vakoc would approach it. Similarly, Vakoc suggested he also reflects on how his mentor Gerd Blobel, who is a co-author on the recent paper and is at the Children’s Hospital of Philadelphia, would respond to challenges.

As for the family members of those eager to support Vakoc, these kinds of scientific advances offer hope.

When he started this journey, Renna suggested he would feel satisfied if researchers developed a cure in his lifetime. This paper is the “next step in a marathon, but it makes us very excited,” he said.

To share the encouraging results from Vakoc’s lab with his daughter, Renna tacked up the PNAS paper to the wall in Christina’s bedroom.

 

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A Jamaican fruit bat, one of two bat species Scheben studied as a part of his comparative genomic work. Photo by Brock & Sherri Fenton

By Daniel Dunaief

Popular in late October as Halloween props and the answer to trivia questions about the only flying mammals, bats may also provide clues about something far more significant.

Despite their long lives and a lifestyle that includes living in close social groups, bats tend to be resistant to viruses and cancer, which is a disease that can and does affect other mammals with a longer life span.

Armin Scheben

In recent work published in the journal Genome Biology and Evolution, scientists including postdoctoral researcher at Cold Spring Harbor Laboratory and first author Armin Scheben, CSHL Professor and Chair of the Simons Center for Quantitative Biology Adam Siepel, and CSHL Professor W. Richard McCombie explored the genetics of the Jamaican fruit bat and the Mesoamerican mustached bat.

By comparing the complete genomes for these bats and 13 others to other mammals, including mice, dogs, horses, pigs and humans, these scientists discovered key differences in several genes.

The lower copy number of interferon alpha and higher number of interferon omega, which are inflammatory protein-coding genes, may explain a bat’s resistance to viruses. As for cancer, they discovered that bat genomes have six DNA repair and 33 tumor suppressor genes that show signs of genetic changes.

These differences offer potential future targets for research and, down the road, therapeutic work.

“In the case of bats, we were really interested in the immune system and cancer resistance traits,” said Scheben. “We lined up those genomes with other mammals that didn’t have these traits” to compare them.

Scheben described the work as a “jumping off point for experimental validation that can test whether what we think is true: that having more omega than alpha will develop a more potent anti-viral response.”

Follow up studies

This study provides valuable potential targets that could help explain a bat’s immunological superpowers that will require further studies.

“This work gives us strong hints as to which genes are involved, but fully understanding the molecular biology will require more work” explained Siepel.

In Siepel’s lab, where Scheben has been conducting his postdoctoral research since 2019, he is using human cell lines to see whether adding genetic bat elements makes them more effective in fighting off viral infections and cancer. He plans to do more of this work with mice, testing whether these bat variants help convey the same advantages in live mice.

Armin Scheben won the German Academic International Network Science Slam competition with his presentation on bat genomics.

Siepel and Scheben have discussed improving the comparative analysis by collecting information across bats and other mammals of tissue-specific gene expression and epigenetic marks which would help reveal changes not only in the content of DNA, but also in how genes are being turned on and off in different cell types and tissues. That could allow them to focus more directly on key genes to test in mice or other systems.

Scheben has been collaborating with CSHL Professor Alea Mills, whose lab has “excellent capabilities for doing genome editing in mice,” Scheben said.

Scheben’s PhD thesis advisor at the University of Western Australia, Dave Edwards described his former lab member’s work as “exciting.”

Edwards, who is Director of the UWA Centre for Applied Bioinformatics in the School of Biological Sciences, suggested that Scheben stood out for his “ability to strike up successful collaborations” as well as his willingness to mentor other trainees.

Other possible explanations

While these genetic differences could reveal a molecular biological mechanism that explains the bat’s enviable ability to stave off infections and cancer, researchers have proposed other ways the bat might have developed these virus and cancer fighting assets.

When a bat flies, it raises its body temperature. Viruses likely prefer a normal body temperature to operate optimally. 

Bats are “getting fevers without getting infections,” Scheben said.

Additionally, flight increases the creation of reactive oxygen species, which the bat needs to control on an ongoing basis.

At the same time, bats produce fewer inflammatory cytokines, which helps prevent them from having a runaway immune reaction. Some researchers have hypothesized that bats clear reactive oxygen species more effectively than humans.

A ‘eureka’ moment

The process of puzzling together all the pieces of DNA into individual chromosomes took considerable time and effort.

A Mesoamerican mustached bat, one of two bat species Scheben studied as a part of his comparative genomic work. Photo by Brock & Sherri Fenton

Scheben spent over 280,000 CPU hours chewing through thousands of genes in dozens of species on the CSHL supercomputer called Elzar, named for the chef from the cartoon “Futurama.” Such an effort would have taken eight years on a modern day personal computer.

During this effort, Scheben saw this “stark effect,” he said. “We had known that bats had lost some interferon alpha. What astounded me was that some bats had lost all alpha” while they had also raised interferon omega. That was the moment when he realized he found something novel and bat specific.

Scheben recognized that this finding could be one of many that lead to a better understanding of the processes that lead to cancer.

“We know that it’s unlikely that a single set of genes or a small set of genes such as we identified can fully explain the diversity of outcomes when it comes to a complex disease like cancer,” said Scheben.

A long journey

A resident of Northport, Scheben grew up in Frankfurt, Germany. He moved to London for several years, which explains his use of words like “chuffed” to describe the excitement he felt when he received a postdoctoral research offer at Cold Spring Harbor Laboratory.

When he was young, Scheben was interested in science despite the fact that classes were challenging for him.

“I was pretty poor in math and biology, but I liked doing it,” he said.

Outside of work, Scheben enjoys baking dense, whole wheat German-style bread, which he consumes with cheese or with apple, pear and nuts, and also hiking.

As for his work, which includes collaborating with CSHL Professor Rob Martienssen to study the genomes of plants like maize that make them resilient amid challenging environmental conditions, Scheben suggested it was the “best time to be alive and be a biologist” because of the combination of new data and the computational ability to study and analyze it.

Scheben recognized that graduate students in the future may scoff at this study, as they might be able to compare a wider range of mammalian genomes in a shorter amount of time.

Such a study could include mammals like naked mole rats, whales and elephants, which also have low cancer incidence and long lifespans.

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A scene from 'Oppenheimer'

By Daniel Dunaief

Researchers at Brookhaven National Laboratory, Cold Spring Harbor Laboratory and Stony Brook University joined the chorus of moviegoers who enjoyed and appreciated the Universal film Oppenheimer.

“I thought the movie was excellent,” said Leemor Joshua-Tor, Professor and HHMI Investigator at Cold Spring Harbor Laboratory. “It made me think, which is always a good sign.”

Yusuf Hannun, Vice Dean for Cancer Medicine at Stony Brook University, thought the movie was “terrific” and had anticipated the film would be a “simpler” movie.

Jeff Keister, leader of the Detector and Research Equipment Pool at NSLS-II at Brookhaven National Laboratory, described the movie as “interesting” and “well acted.”

Joshua-Tor indicated she didn’t know anything about Robert Oppenheimer, the title character and leader of the Manhattan Project that built the atomic bomb. She “learned lots of new things” about him, she wrote. “I knew he was targeted by McCarthy-ism, but didn’t realize how that came about and the details.”

Keister also didn’t know much about Oppenheimer, who was played by actor Cillian Murphy in the film. “Oppenheimer seemed to quietly struggle with finding his role in the story of the development of the atomic bomb,” Keister said. “At times, he wore the uniform, then later seemed to express regret.”

Like other researchers, particularly those involved in large projects that bring together people with different skills and from various cultural backgrounds, Oppenheimer led a diverse team of scientists amid the heightened tension of World War II.

Oppenheimer was “shown to have been granted an extremely powerful position and was able to form a relatively diverse team, although he was not able to win over all the brightest minds,” Keister wrote.

Joshua-Tor suggested Oppenheimer “charmed” the other scientists, who were so driven by the science and the goal that they “accepted him. The leader of the team should be a great scientist, but doesn’t necessarily have to be the biggest genius. There is a genius in being able to herd the cats in the right way.”

Joel Hurowitz, Associate Professor in the Department of Geosciences at Stony Brook University, “loved” the movie. Hurowitz has worked with large projects with NASA teams as a part of his research effort.

Hurowitz suggested that the work that goes into coordinating these large projects is “huge” and it requires “a well laid out organizational structure, effective leadership, and a team that is happy working hard towards a common goal.”

‘Stunning’ first bomb test

Keister described the first nuclear bomb test as “stunning” in the movie. “I have to wonder how the environmental and health impacts of such a test came to be judged as inconsequential.”

Some local scientists would have appreciated and enjoyed the opportunity to see more of the science that led to the creation of the bomb.

Science is the “only place the movie fell short,” Hannun said. “They could have spent a bit more time to indicate the basic science behind the project and maybe a bit more about the scientific accomplishments of the various participants.”

Given the focus of the movie on Oppenheimer and his leadership and ultimate ambivalence about the creation of the atomic bomb, Keister suggested that scientists “could be better encouraged to understand the impacts of applied uses of new discoveries. Scientists can learn to broaden their view to include means of mitigating potential negative impacts.”

Research sponsors, including taxpayers and their representatives, have an “ethical responsibility to incorporate scientists’ views of the full impacts into their decisions regarding applications and deployment of new technology,” Keister said.

Joshua-Tor thinks there “always has to be an ongoing conversation between scientists and the citizenry” which has to be an “informed, somewhat dispassionate conversation.”

Recommended movies about scientists

Local researchers also shared some of their film recommendations about scientists.

Hurowitz wrote that his favorite these days is Arrival, a science fiction film starring Amy Adams. If Hurowitz is looking for more lighthearted fare, he writes that “you can’t go wrong with Ghostbusters,” although he’s not sure the main characters Egon, Ray and Peter could be called scientists.

Keister also enjoys science fiction, as it “often challenges us with ethical dilemmas which need to be addressed.” While he isn’t sure he has a favorite, he recommended the sci-fi thriller Ex Machina starring Alicia Vikander as a humanoid robot with artificial intelligence,.

Joshua-Tor recalls liking the film A Beautiful Mind starring Russell Crowe and Jennifer Connelly as John and Alicia Nash. She also loved the film Hidden Figures, starring Taraji P Henson, Octavia Spencer and Janelle Monáe.

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John Moses. Photo courtesy of CSHL

By Daniel Dunaief

It sounds like something straight out of a superhero origin story.

With resistance to widely used drugs becoming increasingly prevalent among bacteria, researchers and doctors are searching for alternatives to stem the tide.

That’s where shape shifting molecules may help. Cold Spring Harbor Laboratory Professor of Organic and Click Chemistry John Moses and his team have attached the drug vancomycin to a molecule called bullvalene, whose atoms readily change position and configuration through a process called a thermal sigmatropic rearrangement as atoms of carbon break and reform with other carbon atoms.

The combination of the bullvalene and vancomycin proved more effective than vancomycin alone in wax moth larva infected with vancomycin resistant Enteroccoccus bacteria.

“Can I make a molecule that changes shape and will it affect bacteria? That was the question,” Moses said. The promising early answer was, yes!

Moses believes that when the bullvalene core is connected to other groups like vancomycin, the relative positions of the drug units change, which likely change properties related to binding.

The urgency for novel approaches such as this is high, as drug resistant bacteria and fungi infect about 2.8 million people in the United States per year, killing about 35,000 of them. 

In his own life, Moses said his father almost died from a bacterial infection five years ago. Vancomycin saved his father’s life, although the infection became resistant to the treatment. Other drugs, however, conquered the resistant strain.

“We need to work hard and develop new antibiotics, because, without them, there will be a lot more misery and suffering,” Moses explained.

To be sure, an approach like this that shows promise at this early stage with an insect may not make the long journey from a great idea to a new treatment, as problems such as dosage, off target effects, toxicity, and numerous other challenges might prevent such a treatment from becoming an effective remedy.

Still, Moses believes this approach, which involves the use of click chemistry to build molecules the way a child puts together LEGO blocks, can offer promising alternatives that researchers can develop and test out on a short time scale.

“We shouldn’t be restricted with one set of ideas,” Moses said. “We should keep testing hypotheses, whether they are crazy or whatever. We’ve got to find alternative pathways. We’re complementary” to the standard approach pharmaceutical companies and researchers take in drug discovery.

Looking to history, Moses explained that the founders of the Royal Society in 1660 followed the motto “nullius in verba,” or take nobody’s word for it. He believes that’s still good advice in the 21st century.

The shape shifting star

Moses has described this bullvalene as a Rubik’s Cube, with the parts moving around and confounding the bacteria and making the drug more effective.

The CSHL scientist and his team don’t know exactly why shape shifting makes the drug work in this moth model.

He speculated that the combination of two vancomycin units on either side of a bullvalene center is punching holes in the cell wall of the bacteria.

Moses is eager to try to build on these encouraging early developments. “If you can make it, then you can test it,” he said. “The sooner the better, in my opinion.”

Moses acknowledged that researchers down the road could evaluate how toxic this treatment might be for humans. It didn’t appear toxic for the wax moth larvae.

Welcoming back a familiar face

Adam Moorhouse
Photo by Rebecca Koelln

In other developments in his lab, Moses recently welcomed Adam Moorhouse back to his team. Moorhouse, who serves as Chemistry Data Analyst, conducted his PhD research in Moses’s lab at the University of Oxford.

Moorhouse graduated in 2008 and went on to work in numerous fields, including as an editor for the pharmaceuticals business and for his own sales consultancy. In 2020, he had a motorcycle accident (which he said was his fault) in which he broke 16 bones and was hospitalized for a while. During his recovery, he couldn’t walk.

At the time, he was working in the intense world of sales. After the accident, Moorhouse decided to build off his volunteer work with disabled children and become a high school teacher. After about 18 months of teaching, Moorhouse reconnected with Moses.

“It’s nice getting here and thinking about chemistry and thinking about ideas and communicating those ideas,” Moorhouse said.

He has hit the ground running, contributing to grants and helping to translate intellectual property into commercial ventures.

The chance to work on projects that get molecules into humans in the clinic was “really exciting,” Moorhouse said. “I’m back to try and support that.”

Moorhouse will be working to procure funding and to build out the business side of Moses’s research efforts.

“Where I’d like to lend a hand is in driving ongoing business discussions,” Moorhouse said. He wants to “get these small molecules into the clinic so we can see if they can actually treat disease in humans.” The vehicle for that effort eventually could involve creating a commercial enterprise.

Like Moses, Moorhouse is inspired and encouraged by the opportunity for small operations like the lab to complement big pharmaceutical companies in the search for treatments.

Moses believes the work his lab has conducted has reached the stage where it’s fundable. “We’ve done something that says, ‘we checked the box,’” he said. “Let’s find out more.”

Currently living on campus at CSHL, Moorhouse appreciates the opportunity to do some bird watching on Long Island, where some of his favorites include woodpeckers, herons, egrets, robins and mockingbirds.

He is tempted to get back on a motorcycle and to return to mountain biking.

As for his work, Moorhouse is excited to be a part of Moses’s lab.

“Back in my PhD days, [Moses] was always an idea machine,” Moorhouse said. “The aim is to move ideas to the clinic.”

 

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