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Dave Tuveson. Photo by Gina Motisi/CSHL

By Daniel Dunaief

While one bad apple might spoil the bunch, the same might be true of one bad cancer gene.

Cold Spring Harbor Laboratory’s Cancer Director Dave Tuveson and Derek Cheng, who earned his PhD from Stony Brook University while conducting research in Tuveson’s lab, recently explored how some mutant forms of genes in pancreatic cancer can involve other proteins that also promote cancer.

A gene well-researched in Tuveson’s lab, mutated KRAS promotes cell division. Mutant versions of this gene continue to produce copies of themselves, contributing to cancer.

Derek Cheng

Turning off or blocking this gene, however, doesn’t solve the problem, at least not in the laboratory models that track a cancer cell’s response.

In laboratory models of pancreatic cancer, a disease for which the prognosis is often challenging, other proteins play a role, creating what researchers call an “adaptive resistance” to chemotherapy.

In a paper published in the journal Proceedings of the National Academy of Sciences, Cheng, who is the first author and is currently in his final year of medical school at the Stony Brook Renaissance School of Medicine, and Tuveson showed that a protein called RSK1 interacts at the membrane with mutated KRAS. When KRAS is inhibited, the RSK1 protein, which normally keeps RAS proteins dormant, becomes more active.

“If you antagonize KRAS, you would get a rebound” as the cancer cells develop a resistance to the original drug, Tuveson said. “We found a feedback loop.”

The research “focused on identifying protein complexes with oncogenic KRAS that would potentially be relevant in pancreatic cancer,” Cheng explained in an email. “My work suggests that an RSK1/NF1 complex exists in the vicinity of oncogenic KRAS.”

While Cheng was able to show that the role of membrane-localized RSK1 provided negative regulation of wild-type RAS, it “remains to be studied what the role of the RSK1 at the membrane [is] in the context of oncogenic KRAS.”

KRAS is a molecular switch that turns on and off with the help of other proteins. With certain mutations, the switch doesn’t turn off, continuing to signal for copying and dividing, which are hallmarks of cancer cells. With specific activating mutations, the switch can lose its ability to turn off and constitutively signal for proliferation, metabolic reprogramming, and other behaviors characteristic of cancer cells, Cheng explained.

A cell with an oncogenic KRAS has the tendency to be more fit than a normal cell without one. Such cells will likely grow at a faster rate under stressful conditions, which, over time, can enable them to outcompete normal cells, Cheng continued.

When KRAS is in an oncogenic state, another protein, called RSK1 is hanging around the membrane. RSK1 has several functions and can participate in numerous cellular signaling pathways.

KRAS cytoplasm

While RSK1 is involved in protein translation by phosphorylating S6 kinase, it also has other functions at the plasma membrane, where it shuts down wild type RAS proteins.

Other researchers have suggested a negative feedback for RSK1 and NF1.

“Our contribution demonstrated some relevance of this interaction in pancreatic cancer cells,” Cheng explained in an email.

Cheng said RSK is known to have various effects, depending on the context. In the paper, the scientists showed that RSK has a “negative feedback properties, such as that, upon the removal of mutant KRAS, it has this negative regulatory role.”

Graduate student Sun Kim and post doctoral researchers Hsiu-Chi Ting and Jonathan Kastan are currently exploring whether RSK has a pro-oncogenic function on the membrane in the tumor cell.

So far, these studies suggest that while a direct inhibitor against oncogenic KRAS would likely be the greatest target for an effective therapy, cancer cells may still be able to use signals from other RAS isoforms.

“A combination of targeting KRAS and modulating regulators of RAS such as RSK1/NF1 and SOS1 may enhance therapeutic efficacy,” Cheng suggested.

Cheng is grateful for the opportunity to learn from numerous Tuveson lab members on ways cancer cells differ from healthy cells.

The discovery of the potential roles of RSK1 in cancer provides some possible explanation for the potential resistance mechanisms of mutant KRAS inhibitors.

While he was encouraged that a prestigious journal published the research, Tuveson said he hopes this type of observation “will lead to something that will be useful for a pancreatic cancer patient and not just” provide compelling ideas.

Cheng attended medical school for two years before joining Tuveon’s lab for the next six years.

Cheng defended his thesis in 2020 during the pandemic on a zoom call.

“I was one of the first people to defend with this format for both CSHL and SBU,” Cheng explained. “I was able to invite many friends and family that probably would not have been able to make the trip.”

Cheng’s family has battled cancer, which contributed to his research interests.

When he was an undergraduate, he had an uncle develop glioblastoma, while another uncle and his grandfather developed colon cancer.

“I knew I wasn’t going to be able to do much about their medical condition, but I wanted to work on something that people cared about,” Cheng explained.

Outside of the lab, Cheng enjoys working on his car and his motorcycles. He feels a sense of autonomy working on his own projects.

He’s most proud of a motorcycle for which he rebuilt the front end with parts from another model to outfit a larger brake system.

A native of St. Louis, Cheng is a fan of the hockey team, the Blues. He owns a game-worn jersey from almost every member of the 2019 cinderella team that won the Stanley cup, with some of those jerseys coming from Stanley Cup final games.

Cheng plans to apply to residency in internal medicine this year because he wants to continue applying what he learned in his scientific and medical training.

The clinical work reminds him to treat patients and not just the tumors, while scientific research trained him to loo at evidence and literature carefully to find clinical gaps, he explained.

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Semir Beyaz (center) with research assistant Onur Eskiocak, left, and graduate student Ilgin Ergin. Photo by Gina Motisi/CSHL

By Daniel Dunaief

High fat diets present numerous health problems for humans and mice, which are often used as a model organism to understand disease.

In a recent multi-disciplinary study with mice, Cold Spring Harbor Laboratory Fellow Semir Beyaz and 32 colleagues from 15 other institutions explored how a high fat diet affects the development of intestinal tumors.

Semir Beyaz. Photo by Gina Motisi/CSHL

The diverse team of scientists brought together a range of expertise to discover the way a high fat diet disrupts the cross talk among the microbiome, stem cells and immune cells, triggering tumors through the reduction in the expression of an important gene, called major histocompatibility complex II, or MSC-II.

“This work nicely integrates efforts in stem cell biology, immunology, microbiology and metabolism in the context of understanding how diet is linked to cancer,” Beyaz explained in an email. With such interdisciplinary studies, “we hope to improve our understanding” of the mechanisms that link nutrition to diseases.

The paper, published in Cell Stem Cell, for which Beyaz is the first and corresponding author, shows how a high fat diet leads to immune evasion of tumor initiation stem cells due to the suppression of the immune recognition molecule MHC-II.

At the center of this study, the MHC-II gene encodes a protein that presents antigens, or foreign substances, to the immune system. When a cell is infected or cancerous, immune cells detect the unwelcome agents through their surveillance of MHC molecules, Beyaz said.

A high fat diet also results in the alteration of immune cells in the micro environment and the signals that they produce, called cytokines.

“The novel finding of our study is that the crosstalk between stem cells, microbes and immune cells is critical for eliminating tumor initiating cells and this cross talk is dampened in response to a high fat diet, demonstrating a mechanistic basis for how high fat diets may promote cancer,” said Beyaz.

A current hypothesis, which has some supporting evidence in Beyaz’s study, suggests that diet-related factors might facilitate early onset colorectal cancer.

To be sure, researchers need to conduct more work to understand the environmental factors that facilitate early onset colorectal cancer, Beyaz explained. “The knowledge of what causes early onset colorectal cancer in young adults is very limited,” he added.

Semir Beyaz with visiting clinical researcher Aaron Nizam (left) and research tech Katherine Papciak. Photo by Gina Motisi/CSHL

Beyaz believes diet is one of the most important environmental factors that contribute to cancer risk. Diet could affect sleep, stress and other factors.

“There are so many things we don’t know about how diet affects our body,” he said. “That’s why I’m very excited to work on understanding these mechanisms.”

Beyaz said the mice in his study consumed a lard-based pro-obesity diet that was high in carbohydrates.

A diet that is lower in carbohydrates and higher in fat is more similar to a ketogenic diet, which could have other outcomes. His ongoing studies are trying to tease apart some of these differences.

To counteract the effect of diet on the development of cancer, Beyaz plans to activate the altered pathways by using either microbes or small molecule drugs.

“We believe if we promote immune surveillance by activating these pathways, we can elicit preventative and therapeutic strategies against cancer,” he explained.

Additionally, in his ongoing research, Beyaz plans to address numerous other questions that link diet to disease.

An increasing number of studies are exploring how diet and microbes affect cancer, which he described as a “hot topic.”

Beyaz believes a high fat diet might turn on or off some genetic sequences, enabling the latent development of cancer.

His unique niche involves searching for a connection between diet and perturbations that affect cross talk among cells. While this field has numerous challenges, Beyaz suggested he was “drawn” to that difficulty.

Beyaz’s expertise is in stem cell biology and immunology. He appreciates and enjoys the opportunity to interact with researchers from other disciplines that could lead to actionable progress.

Hannah Meyer. Photo from CSHL

While science has to be reductionistic and focused on one molecule or cells at times, new conceptual and technical advances have made it possible for the lines between disciplines in biology to disappear slowly, he explained.

Beyaz and his colleagues are looking forward to taking some of the next steps in this effort.

For starters, he is excited to expand this study, to understand whether there is a threshold for a high fat diet that favors the growth of tumors. Diets that fall below a potential threshold might not promote the growth or development of tumors.

Such a threshold could become clinically relevant, providing health care workers with a pre-cancerous marker that could signal the need for lifestyle changes and medical vigilance that could stave off or avoid the formation of disease-bearing and life-threatening tumors.

“We have some ongoing work to delineate such thresholds and proxies,” Beyaz said. Additionally, they would like to see whether this effect is reversible, to determine whether an altered microbiome might promote the expression of MHC-II, which could derail the tumor forming process.

Pawan Kumar. Photo from SBU

Beyaz’s collaborators on this work include Hannah Meyer, who is a fellow at Cold Spring Harbor Laboratory Fellow, and Pawan Kumar, who is an Assistant Professor in the Department of Microbiology and Immunology at the Renaissance School of Medicine at Stony Brook University.

In his life outside the lab, Beyaz, who enjoys fishing, gardening, and hiking, avoids excessive sugar and fat consumption. He doesn’t eat fast food or consume sugary drinks.

Originally from the town of Samandag which is near the Mediterranean Sea in the southeastern part of Turkey, Beyaz enjoys cooking and is fond of making lamb, beef, chicken and eggplant kebabs.

When he was growing up, Beyaz said science was a passion for him.

“It is not a job or a career,” he explained. “It is the way I find meaning in life, by learning how to ask and (sometimes) answer questions at the edge of cumulative human knowledge.”

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Pixabay photo

By Elof Axel Carlson

Elof Axel Carlson

Scientists study nature. Nature is the world we can observe. It includes things like life, from viruses to plants and animals, and to all forms of  humanity.  It includes the earth and its continents, oceans, and atmosphere.  It includes the moon, the planets and stars and galaxies. It includes the composition of all the objects we can see, touch, taste, smell, or hear.

What does it not include? Scientists call that aspect of our experience the supernatural. What is the supernatural?  It includes a belief in gods, souls, ghosts, spirits, devils, angels, saints, witches, goblins, trolls, leprechauns, and mythical beasts like unicorns, or snakes that speak intelligible language we can understand, or a host of imagined possibilities such as a fountain of youth, turning other metals into gold, devising perpetual motion machines, pills that can convert water into gasoline, or using the ground powder of rhinoceros horns to cure impotence in middle aged men. 

It also includes pseudo-sciences such as astrology, alchemy, palmistry, mind-reading, telekinesis, and other forms of extrasensory perception. The list is long, and scientists would strike off some of the supernatural if carefully controlled experiments are done to demonstrate them. Unfortunately, that has not occurred. 

Magicians are often allied with scientists in exposing the tricks other magicians and charlatans use to fool inexperienced or gullible people. Science has more mysteries to solve and does not need supernatural unproven claims to compete for an interpretation of the universe. Science uses reason, gathering of information or data, proposals of theories, testing of theories, instruments to amplify or supplement our senses, and experimentation to test predictions of theories. 

The supernatural depends on faith. It raises some difficulties. Whose gods are valid and whose have been demoted to myths? Is Zeus still alive? Is Osiris still alive? Is Gilgamesh still alive? Of our current deities, is Jesus an aspect of a Trinitarian deity or is he a human prophet who founded a new religion? If the Old Testament deity called Jehovah, Lord, or God is monotheistic, and if He is also the God of the Hebrew people of the Old Testament, is He the same God that Christians pray to and call Jesus?  

As these questions and concerns sink in, note that scientists exclude the numerous ways supernatural beings (represented in human or other forms of life) are accepted.  The supernatural events and things are accepted through faith. Science is universal and demands testable and repeatable evidence. It does not matter what country one lives in; water will consist of two atoms of hydrogen and one atom of oxygen. It will behave the same wherever it is studied and exists as a gas, liquid, or solid, depending on temperature and pressure. 

Science is very strict about the evidence needed for demonstrating something to science. Those who practice supernatural beliefs do so out of faith. There is no one universal supernatural system all people would agree to. But all people on earth will be convinced that striking a match to dry paper at room temperature, in breathable air, will ignite the paper and reduce it to ashes and release carbon dioxide into the air.

Elof Axel Carlson is a distinguished teaching professor emeritus in the Department of Biochemistry and Cell Biology at Stony Brook University.

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Chemist John Moses on the campus of Cold Spring Harbor Laboratory. Photo from CSHL

By Daniel Dunaief

If you build it, he will come.

That’s an iconic line from the movie “Field of Dreams,” starring Kevin Costner, in which a mythical voice calls to the Iowa farmer, encouraging him to plow through his corn to build a baseball field so the ghosts of past baseball players can entertain a modern audience.

It seems only fitting that this year, in which Major League Baseball hosted its first professional game in Iowa near the set of the popular movie, chemists have built something they hope brings together numerous other chemicals to produce products with various applications, from drug discovery to materials science.

About 120 years ago, researchers in France discovered a highly reactive gas called thionyl tetrafluoride, whose chemical symbol is SOF4.

The gas has numerous potential applications because researchers can control its reactions and derivatives. Scientists can swap each sulfur-fluorine bond with a bond between sulfur and something with desirable properties or applications.

While the gas serves as a potential building block, it is scarce and is not commercially available.

Thionyl tetrafluoride is “very reactive,” said chemist and Cold Spring Harbor Laboratory Professor John Moses. “It’s not something the Average Joe wants. It’s dangerous chemistry.” It was largely overlooked until the 1960’s, when chemists at DuPont reinvestigated it.

Once Suhua Li, the lead author of a recent paper in Nature Chemistry and a former post doctoral researcher in Nobel-prize winner K. Barry Sharpless’s lab at Scripps Research Institute in La Jolla, California, generated more of this gas, the team could work together to determine the types of connections that might be possible. 

While the research was a group effort in terms of planning and ideas, Li, who did the vast majority of the synthesis of the gas, is “the hero,” Moses said. “The gas itself, and reagents used to make the gas, are potentially very dangerous, and it takes courage and confidence to attempt such chemistry. ([Li] even had a bit of a mishap, to say the least, but still went ahead and tried again.”

Moses also appreciates how “ideas are just ideas until somebody takes the initiative to put them into practice.”

Moses, Sharpless, and Scripps Research Institute Associate Professor Peng Wu developed the polymer chemistry, while Hans Zuilhof of Wageningen University in the Netherlands helped elucidate the helical structure of the polymers.

The team used a technique Sharpless calls “click chemistry” to explore the substances they could create with this gas.

Thionyl tetrafluoride acts like a lego building block that can be connected with other building blocks in several dimensions.

Click reactions create defined products with absolute reliability, Moses explained. Scientists get what they expect, which is not always true in chemistry.

“In some reactions, you take A and B and you don’t always get C,” Moses said. “You get C as a major product, but you also get D, E and F.”

In click chemistry, however, the combination of A and B is guaranteed to produce C.

Some click reactions run better in water, or at least when water is present. Water is non-toxic, inflammable, inexpensive and a good heat sink.

Click philosophy is about using reliable reactions for the purpose of function discovery.

With thionyl tetrafluoride, Li and the other researchers made about 30 polymers, each of which had original structures using different fragments.

The group managed to attach antibiotics to a thionyl tetrafluoride-derived polymer and demonstrated that it retains antibacterial function.

As long as the module has a handle to exchange with the sulfur-fluorine bond, the gas has a broad range of potential applications.

With thionyl tetrafluoride as his inspiration, Moses coined the term multidimensional click chemistry, which identifies the gas a multi dimensional hub.

The chemists used a regular party balloon to transfer the gas, which is connected to a syringe and a needle. They inserted the needle through a rubber septum into a sealed flask. The reaction with reagents in the flask is straightforward to perform once the gas is available, Moses said.

Born and raised in Wrexham, North Wales, a town aglow after actors Ryan Reynolds and Rob McElhenney last year bought a 156-year-old local soccer team, Moses had no interest in science when he was young, although he was curious about life in general.

He left school to work in a factory that made life rafts and buoyancy jackets when he was 16.

The factory had a distinct odor of toluene and glue.

“It was dreadful,” he recalls. “I was lucky to escape that life.”

He eventually landed an apprenticeship at a company called App-Chem, that allowed him to study physics and chemistry in college one day per week. 

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Michelle and Paul Paternoster

By Daniel Dunaief

Part 2

Three families and their foundations jump-started a research mission on Long Island that offers a chance for change. Their stories reflect a desire to remember their family members and a need to offer hope and help to others.

Christina Renna

Christina Renna with sister Rae Marie Renna

Phil Renna waited while his 16-year old daughter Christina spoke with her doctor. He and his wife Rene had decided to allow their daughter, who was battling a form of connective tissue cancer called rhabdomyosarcoma (RMS), to be involved in decisions about her treatment.

When Christina came out of the room, Phil, director of operations in the communications department at Cold Spring Harbor Laboratory, asked if he should also speak with the doctor. Christina said it wasn’t necessary. On the way home, she told him it had to be a “really good Christmas.”

He knew what that meant, although she also asked him not to tell anyone how close she was to the end of her life.

Renna and parents throughout the country have had to cope with the agony of rhabdomyosarcoma, which mostly affects children. People battling this cancer have turned to medicine for help, only to find that the treatment options are limited.

That, Renna and others say, was as unacceptable to them when their children were battling cancer as it is now, when the next generation is struggling with this illness.

RMS doesn’t receive the same level of funding nationally as cancers that affect more people, such as breast, lung and prostate cancer, but the agony and suffering are just as significant.

Amid their battles with the disease, families have turned to their support groups, including friends, extended family, and community members to raise funds for basic research, hoping grass roots efforts allow future generations to have longer, healthier lives.

Supported by these funds and a willingness to fill a research gap, Cold Spring Harbor Laboratory CEO Bruce Stillman has backed efforts to gather information and to support research that may also help people with other forms of cancer.

Renna, who lives in Lindenhurst, struggled with his role as father and protector when Christina developed rhabdomyosarcoma.

“I’m supposed to protect my kids,” Renna said. “I should be able to tell them, ‘It’s going to be okay.’”

Renna went to Stillman to ask whether Christina, who was a patient at Memorial Sloan Kettering, might get better care somewhere else.

After conducting some research, Stillman told his colleague about the lack of basic research and other treatment options.

“That was a crushing moment for me,” Renna said.

During treatment, Christina had to be at Memorial Sloan Kettering at 7 a.m., which meant he and Christina’s mother Rene got in the car at 5 a.m. with their daughter.

Renna dropped them off, drove back to work, where he’d put in a full day, drive back to the hospital and return home at 10:30 p.m.

“That was every night, five days a week,” Renna recalled. While those were tough days, Renna said he and his wife did what they needed to do for their daughter.

Five years after his daughter died at the age of 16, Renna drove home from work one day to find his shirt was wet. It took him a while to realize the moisture came from the tears, as he cried his way back to his house. At one point, he thought he had post-traumatic stress disorder.

Renna continues to raise money to support research into this disease, while also helping people create and develop their own foundations, often after enduring similar pain.

“Every single foundation that has come and given money to the lab, I have personally met with,” he said. “I helped our advancement team onboard them.”

As someone who has lost a child and understands what a parent can be feeling, Renna is committed to helping others cope with their grief. 

“For me, it is about helping the lab, but also about helping families honor the memory of their child in a meaningful way and what better way than to help another family and perhaps find a cure,” he wrote in an email.

Renna believes investments in research will pay off, helping to answer basic questions that will lead to better treatments down the road.

So far, the foundation has given $387,300 to Cold Spring Harbor Laboratory for research. They also gave $50,000 to Make-a-Wish in Suffolk, and $25,000 to local scholarships. The foundation supported Memorial Sloan Kettering with an iPad program. Ultimately, Renna believes in the ongoing return from research investments.

“Everybody wants to find and fund the silver bullet,” he said. “Everybody wants to give money to fund a clinical trial. Basic research is where the discoveries are made.”

Renna urged people creating foundations to have a strong board that included business people and that might also have a scientific or medical advisory element. He also suggested funding foundations a year ahead of time. That helped his foundation in 2020, when finding donors became more challenging during the pandemic.

Being at Cold Spring Harbor Laboratory and helping others get through darker days that are all too familiar to him gives Renna comfort. “I know, in some way, every single day, I’m making an impact,” he said. “How measurable it is, I don’t know. There are days when I’m pretty proud.”

As far as he feels they have come, Renna said it’s not the time to look back, but to press ahead.

T.J. Arcati

A former summer intern in Bruce Stillman’s lab when he attended Notre Dame, T.J. Arcati was married and had two children when he succumbed to sarcoma.

“We know what we went through,” said his father, Tom Arcati, an oral and maxillofacial surgeon in Huntington. “He left a son and a daughter without a dad.”

Tom and his wife Nancy, who raised T.J. in Lloyd Harbor and live in Huntington, were with their son for his treatments and therapies.

Tom and Nancy Arcati are determined to extend people’s lives by more than a year or two and are actively engaged with other families who are coping in the midst of the cancer storm. “I’m talking to people now that unfortunately are going through what we did seven years ago,” Tom Arcati said.

While the Arcatis support other families, their empathy “brings you back to a place you never really leave,” Nancy Arcati said. These interactions “keeps T.J.’s life on people’s minds and in their hearts.”

Tom Arcati tries to be a source of solace to people who are trying to gather information.

In the aftermath of TJ’s death at the age of 34, Arcati reached out to Stillman to see if the lab could work towards better treatments.

One Saturday, Arcati and his son Matthew went to Stillman’s house, where they sat in his living room, with Stillman drinking tea and Arcati having coffee.“What do you think?” Arcati recalled asking. “Are you going to do sarcoma research?” Stillman looked back at his guest and mentioned that he was thinking about it. Stillman called Arcati a few days later.

“When he called me, he said, ‘We’re a cancer institute. We should be doing sarcomas.’ That’s how I remember this whole thing going down. It was pretty heart warming.”

The first step for CSHL was to host a Banbury conference. The site of international meetings on a range of scientific topics since 1978, the Banbury center brings together experts in various fields. The meetings provide a forum for scientific advances and result in various publications. By holding a Banbury Center meeting, CSHL helped advance research into sarcomas.

The Arcatis have remained active in the Friends of T.J. Foundation, which TJ and several college friends founded in 2009 after T.J. was diagnosed with sarcoma. They have stayed in close contact with CSHL Professor Chris Vakoc and his PhD student Martyna Sroka, who regularly keeps him informed of her progress. Sroka has spoken at some of the outings for the Friends of TJ Foundation. This year, Stillman will speak at the September 13th fundraiser at the Huntington Country Club.

“It’s really imperative that people who are supporting us know what their dollars are being spent on,” Arcati said.

The Friends of TJ Foundation has raised about $50,000 each year, bringing their total fundraising to about $400,000.

Arcati hopes something positive can come out of the losses the families who are funding Vakoc’s research suffered.

“If we can save one kid’s life somewhere by doing what we’re doing, then this whole process is worth it,” Arcati said.

Michelle Paternoster

Michelle Paternoster of Lindenhurst developed sarcoma in her sinuses. Her husband Paul Paternoster helped her through 38 surgeries, over 90 radiation treatments and several rounds of chemotherapy.

Michelle and Paul Paternoster

The couple tried immune therapy in the Bahamas in the fall of 2008 and went to New York in 2011 for treatment.

“We drove [to the city] for 90 days” excluding weekends, Paternoster recalled. The treatments seemed to have a positive effect during the trial, but shortly afterward, the cancer continued growing.

After Michelle died in 2013 at the age of 34, Paternoster was determined to help others, initially asking supporters to contribute to the fundraising effort from the Arcatis.

Donations to the Friends of T.J. Foundation reached $30,000, which helped underwrite the Banbury conference at Cold Spring Harbor Laboratory. Michelle and T.J. had seen each other in the radiation suite in the halls of Memorial Sloan Kettering.

Paternoster then started the Michelle Paternoster Foundation for Sarcoma Research. The President of Selectrode Industries Inc., which manufactures welding products and has two factories in Pittsburgh, Paternoster wanted to help people at a clinical level.

Through Michelle’s Clubhouse, he partnered with the Children’s Hospital of Pittsburgh, paying for hotels of pediatric cancer patients when the Ronald McDonald house is full. The clubhouse also provides gift cards to help pay for gas, tolls and copays on prescriptions.

“Knowing how difficult it is to go through this, I can’t imagine what it’s like to not have that capability” to pay for basic needs during treatment, Paternoster said. “That is why it is so important for our board to do something at the clinical level to support families in this battle.”

Paternoster said the relatively small but growing size of the group dedicated to helping each other makes each person’s contribution that much more important.

“Normally, when you’re doing any kind of charity work, you feel like you’re a tiny part of this project, especially when it comes to [diseases like] breast cancer and things that impact millions of people,” Paternoster said. When he attended the Banbury conference that launched the research effort at Cold Spring Harbor Laboratory, he said “you felt you could make a difference. You’re sitting in a room with 25, 30 people max. That was the entire effort to eradicate this disease.”

Paternoster, who lives in Cold Spring Harbor, called the collaboration that came out of the meeting “astounding.”

The Michelle Paternoster Foundation has raised $500,000, with about $350,000 of that supporting the work at Cold Spring Harbor Laboratory.

Ultimately, like the other families who raise funds, stay informed and offer help to strangers battling an all-too-familiar disease, Paternoster feels that the opportunity to make a meaningful contribution inspires him.

“That’s our dream,” he said, “to find a cure, so other people don’t have to feel what we felt.”

To read Part 1 of the article click here.

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Martyna Sroka. Photo by Sofya Polyanskaya

By Daniel Dunaief

Part 1:

A group of people may prove to be the guardian angels for the children of couples who haven’t even met yet.

After suffering unimaginable losses to a form of cancer that can claim the lives of children, several families, their foundations, and passionate scientists have teamed up to find weaknesses and vulnerabilities in cancers including rhabdomyosarcoma and Ewing sarcoma.

Rhabdomyosarcoma affects about 400 to 500 people each year in the United States, with more than half of those patients receiving the diagnosis before their 10th birthday. Patients who receive diagnoses for these cancers typically receive medicines designed to combat other diseases.

 

Christopher Vakoc. Photo from CSHL

A group of passionate people banded together using a different approach to funding and research to develop tools for a different outcome. Six years after the Christina Renna Foundation and others funded a Banbury meeting at Cold Spring Harbor Laboratory, the grass roots funders and dedicated scientists are finding reasons for optimism.

“I wish I could run up to the top of a hill and scream it out: ‘I’m more hopeful than I’ve ever been,’” said Phil Renna, director of operations, communications department at CSHL and the co-founder of the Christina Renna Foundation. “I’m really excited” about the progress the foundation and the aligned group supporting the Sarcoma Initiative at the lab has made.

Renna and his wife Rene started the foundation after their daughter Christina died at the age of 16 in 2007 from rhabdomyosarcoma. Renna’s optimism stems from work Cold Spring Harbor Laboratory’s Christopher Vakoc, a professor and Cancer Center co-director and his research team, including PhD candidate Martyna Sroka have performed.

The cause for optimism comes from the approach Vakoc has taken to cancers, including leukemia.

Vakoc has developed a way to screen the effects of genetic changes on the course of cancer.

“Usually, when you hear about a CRISPR screen, you think of taking out a function and the cell either dies or doesn’t care,” Sroka said, referring to the tool of genetic editing. Sroka is not asking whether the cell dies, but whether the genetic change nudges the cellular processes in a different direction.

“We are asking whether a loss of a gene changes the biology of a cell to undergo a fate change; in our case, whether cancer cells stop growing and differentiate down the muscle lineage,” she explained.

In the case of sarcoma, researchers believe immature muscle cells continue to grow and divide, turning into cancer, rather than differentiating to a final stage in which they function as normal cells.

Through genetic changes, however, Sroka and Vakoc’s lab are hoping to restore the cell to its non cancerous state.

Cold Spring Harbor Laboratory has had success with other diseases and other types of cancer, which is where the optimism comes from, explained Paul Paternoster, President of Selectrode Industries, Inc. and the founder of the Michelle Paternoster Foundation for Cancer Research.

As a part of her doctoral research which she’s been conducting for four years, Sroka is also working with Switzerland-based pharmaceutical company Novartis AG to test the effect of using approved and experimental drugs that can coax cells back into their muscular, non-cancerous condition.

The work Sroka and Vakoc have been doing and the approach they are taking could have applications in other cancers.

“The technology that we’ve developed to look at myodifferentiation in rhabdomyosarcoma can be used to study other cancers (in fact, we are currently applying it to ask similar questions in other cancer contexts),” said Sroka. “In addition, our findings in RMS might also shed light on normal muscle development, regeneration and the biology of other diseases that impact myodifferentiation, e.g. muscular dystrophy.”

Martyna Sroka’s journey

Described by Vakoc as a key part of the sarcoma research effort in his lab, Martyna Sroka, who was born and raised in Gdańsk, Poland, came to Long Island after a series of eye-opening medical experiences.

In Poland, when she was around 16, she shadowed a pediatric oncology doctor who was visiting patients. After she heard the patient’s history, she and the doctor left the room and convened in the hallway.

Martyna Sroka. Photo by Sofya Polyanskaya

“He turned to me and said, ‘Yeah, this child has about a month or two tops.’ We moved on to the next case. I couldn’t wrap my head around it. That’s as far as we could go. There’s nothing we could do to help the child and the family,” said Sroka.

Even after she started medical school, she struggled with the limited ammunition modern medicine provided in the fight against childhood cancer.

She quit in her first year, disappointed that “for a lot of patients diagnosed with certain rare types of tumors, the diagnosis is as far as the work goes. I found that so frustrating. I decided maybe my efforts will be better placed doing the science that goes into the development of novel therapies.”

Sroka applied to several PhD programs in the United Kingdom and only one in the United States, at Cold Spring Harbor Laboratory, where she hoped to team up with Vakoc.

Sroka appreciated Vakoc’s approach to the research and his interest in hearing about her interests.

“I knew that we could carve out an exciting scientific research project that tries to tackle important questions in the field of pediatric oncology, [the] results of which could potentially benefit patients in the future,” she explained in an email.

The two of them looked at where they could make a difference and focused on rhabdomyosarcoma.

Sroka has “set up a platform by which advances” in rhabdomyosarcoma medicines will be possible, Vakoc said. “From the moment she joined the sarcoma project, she rose to the challenge” of conducting and helping to lead this research.

While Sroka is “happy” with what she has achieved so far, she finds it difficult at times to think about how the standard of care for patients hasn’t changed much in the last few decades.

“Working closely with foundations and having met a number of rhabdomyosarcoma patients, I do feel an intense sense of urgency,” she wrote.

Read Part 2 here.

 

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Maurizio Del Poeta in his laboratory at Stony Brook University. Photo by Antonella Rella

By Daniel Dunaief

Researchers at Stony Brook University, the University of Arizona and Wake Forest University School of Medicine in North Carolina may have found an enzyme that drives the worst COVID-19 symptoms. Secreted phospholipase A2 group IIA, or sPLA2-IIA may lead to severe symptoms and death, making this enzyme a potential therapeutic target.

P116, Maurizio DelPoeta, Microbiology

In an examination of plasma samples from 127 patients hospitalized at Stony Brook University Medical Center between January and July 2020 and a mix of 154 patient samples from Stony Brook and Banner University Medical Center in Tucson between January and November 2020, scientists including Distinguished Professor Maurizio Del Poeta of the Renaissance School of Medicine at Stony Brook University found that 63 percent of people with concentrations of the enzyme that were over 10 nanograms/ milliliter generally died. Most healthy people have circulating levels of the enzyme around 0.5 nanograms/ milliliter.

“It is possible that sPLA2 levels represent a tipping point and when it reaches a certain level, it is a point of no return,” said Del Poeta.

The collaborators involved in the study, which was published this week in the Journal of Clinical Investigation, were encouraged by the finding.

“This is exciting as it is leading to really novel connections for COVID-19,” Yusuf Hannun, Director of the Cancer Center at Stony Brook and a contributor to the research who participated in the discussion and data analysis, explained in an email. “It may lead to both diagnostics (for risk prediction) and therapeutics.”

Looking closely at the levels of sPLA2-IIA together with blood urea nitrogen, or BUN, which is a measure of the performance of the kidney, the researchers in this study found that the combination of the two measures predicted mortality with 78 percent accuracy.

“That is an opportunity to stratify patients to those where an inhibitor” to sPLA2-IIA could help patients, said Floyd Chilton, director of the University of Arizona Precision Nutrition and Wellness Initiative and senior author on the paper, said.

While they found a difference in the amount of the enzyme between healthier and sicker patients, the scientists recognize that this could reflect a correlation rather than a causation. The progression of the disease and the threat to people’s lives may come from other contributing factors that also intensify the severity of the illness.

“These studies do not establish causality at the moment, but the strength of the correlation and the known functions of this enzyme raise the possibility of participating in the pathology of the disease,” Del Poeta explained.

Floyd Chilton. Photo from University of Arizona

Indeed, Chilton has studied sPLA2-IIA for over three decades and has described some patterns in other diseases, including sepsis.

The enzyme performs an important role in fighting off bacterial infection by destroying microbial cell membranes. When the concentration of sPLA2-IIA rises high enough, however, it can threaten the health of the patient, as it can attack and destroy cells in organs including the kidney.

The enzyme “plays a critical role in host defense,” said Chilton. “These same systems can really turn on the host.”

In order to determine a causative link between sPLA2-IIA and the progression of the disease, Chilton, Del Poeta and others will need to increase their sample size.

“We’ve been very fortunate at getting individuals at some of the top global organizations… who have connected me with medical centers” that have a larger patient population, Chilton said. These executives may be able to expedite the process of expanding this study.

In the 1990’s, scientists studied an inhibitor that had the ability to act on the enzyme. 

That effort had mixed results in phase 2 clinical trials.

“In 2005, the first phase of the phase 2 clinical trials were highly encouraging,” Chilton said. “It really inhibited mortality at 18 hours” by reducing severe sepsis. The second part of those tests, which used a slightly different protocol, failed.

While he’s not a clinical trials expert, Chilton is hopeful that researchers might find success with this same drug to treat COVID-19.

Only clinical trials would reveal whether inhibitors would work with COVID-19, scientists said.

As with many drugs, inhibitors of sPLA2-IIA have side effects.

By blocking the activity of these enzymes, “we do also decrease the production of arachidonic acid, which is a precursor of prostaglandins,” said Del Poeta. “In condition of hyperinflammation, this is a good thing, but prostaglandins are also important in a variety of cellular functions” including blood clots and starting labor.

Chilton pointed out that sPLA2-IIA is similar to the active enzyme in rattlesnake venom. It can bind to receptors at neuromuscular junctions and disable the function of these muscles, he explained.

In nature, some animals have co-evolved with snakes and are no longer susceptible to these toxins. Researchers don’t yet understand those processes.

While copying such evolutionary solutions is intriguing, Chilton said he and his collaborators are “much more interested in the inhibitors” that were taken through clinical trials in 2005 because that might present a quicker solution.

The research collaboration started with Chilton, who partnered with Arizona Assistant Research Professor Justin Snider. The first author on the paper, Snider earned his PhD at Stony Brook, where he knew Del Poeta well.

Snider “knew what a great researcher [Del Poeta] was. I also knew [Hannun] in a former life. We were both working on similar biochemistry 20 to 25 years ago,” Chilton said.

Chilton called the efforts of his Stony Brook collaborators, including Research Assistant Karen You, Research Associate Professor Chiara Luberto and Associate Professor Richard Kew,  “heroic” and explained that he and his colleagues recognize the urgency of this work.

“I’ve been continuously funded by the [National Institute of Health] for 35 years, and I’m very grateful for that,” Chilton said. “There is nothing in my life that has felt this important,” which is why he often works 18 hour days, including on weekends.

After studying the effects of variants on the population, Chilton recognized that building a firewall against COVID-19 through vaccinations may not be enough, especially with the combination of lack of access to the vaccine for some and an unwillingness to take the vaccine from others.

“We may have to go to the other side of the equation,” HE said. “We’ve got to move to specific therapeutics that are agnostic to the variant.”

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BNL LECTURE: ZHANGBU XU

By Daniel Dunaief

Gregory Breit and John Wheeler were right in the 1930s and Werner Heisenberg and Hans Heinrich Euler in 1936 and John Toll in the 1950s were also right.

Breit, who was born in Russia and came to the United States in 1915, and Wheeler, who was the first American involved in the theoretical development of the atomic bomb, wrote a paper that offered theoretical ideas about how to produce mass from energy.

Breit and Wheeler suggested that colliding light particles could create pairs of electrons and their antimatter opposites, known as positrons. This idea was an extension of one of Albert Einstein’s most famous equations, E=mc2, converting pure energy into matter in its simplest form.

Zhangbu Xu in front of the time-of-flight detector, which is important for identifying the electrons and positrons the STAR Collaboration measured. Photo from BNL

Working at the Relativistic Heavy Ion Collider (RHIC) at Brookhaven National Laboratory, a team of scientists in the STAR Collaboration has provided experimental proof that the ideas of some of these earlier physicists were correct.

“To create the conditions which the theory predicted, even that process is quite exhausting, but actually quite exciting,” said Zhangbu Xu, a senior scientist at BNL in the physics department.

The researchers published their results recently in Physics Review Letters, which provides a connection to Breit and Wheeler, who published their original work in a predecessor periodical called Physics Review.

While Breit and Wheeler wrote that the probability of two gamma rays colliding was “hopeless,” they suggested that accelerated heavy ions could be an alternative, which is exactly what the researchers at RHIC did.

The STAR team, for Solenoidal Tracker at RHIC, also proved another theory proposed decades ago by physicists Heisenberg, who also described the Heisenberg Uncertainty Principle, and Hans Heinrich Euler in 1936 and John Toll, who would later become the second president at Stony Brook University, in the 1950s.

These physicists predicted that a powerful magnetic field could polarize a vacuum of empty space. This polarized vacuum should deflect the paths of photons depending on photon polarization.

Researchers had never seen this polarization-dependent deflection, called birefringence, in a vacuum on Earth until this set of experiments.

Creating mass from energy

Xu and others started with a gold ion. Without its electrons, the 79 protons in the gold ion have a positive charge, which, when projected at high speeds, triggers a magnetic field that spirals around the particle as it travels.

Once the ion reaches a high enough speed, the strength of the magnetic field equals the strength of the perpendicular electric field. This creates a photon that hovers around the ion.

The speeds necessary for this experiment is even closer to the speed of light, at 99.995%, than ivory soap is to being pure, at 99.44%.

When the ions move past each other without colliding, the photon fields interact. The researchers studied the angular distribution patterns of each electron and its partner positron.

“We also measured all the energy, mass distribution, and quantum numbers of the system,” Daniel Brandenburg, a Goldhaber Fellow at BNL who analyzed the STAR data, said in a statement.

Even in 1934, Xu said, the researchers realized the cross section for the photons to interact was so small that it was almost impossible to create conditions necessary for such an experiment.

“Only in the last 10 years, with the new angular distribution of e-plus [positrons] and e-minus [electrons] can we say, ‘Hey, this is from the photon/ photon creation,’” Xu said.

Bending light in a vacuum

Heisenberg and Euler in 1936 and Toll in the 1950’s theorized that a powerful magnetic field could polarize a vacuum, which should deflect the paths of photons. Toll calculated in theory how the light scatters off strong magnetic fields and how that connects to the creation of the electron and positron pair, Xu explained. “That is exactly what we did almost 70 years later,” he said.

This is the first experiment on Earth that demonstrates experimentally that polarization affects the interactions of light with the magnetic field in a vacuum.

Xu explained that one of the reasons this principle hasn’t been observed often is that the effect is small without a “huge magnetic field. That’s why it was predicted many decades ago, but we didn’t observe it.”

Scientists who were a part of this work appreciated the connection to theories their famous and successful predecessors had proposed decades earlier.

“Both of these findings build on predictions made by some of the great physicists in the early 20th century,” Frank Geurts, a professor at Rice University, said in a statement. 

The work on bending light through a vacuum is a relatively new part of the research effort.

Three years ago, the scientists realized they could study this, which was a surprising moment, Xu said.

“Many of our collaborators (myself included) did not know what vacuum birefringence was a few years ago,” he said. “This is why scientific discovery is exciting. You don’t know what nature has prepared for you. Sometimes you stumble on something exciting. Sometimes, there is a null set (empty hand) in your endeavor.

Xu lives in East Setauket. His son Kevin is earning his bachelor’s degree at the University of Pennsylvania, where he is studying science and engineering. His daughter Isabel is a junior at Ward Melville High School.

As for the recent work, Xu, who earned his PhD and completed two years of postdoctoral research at Yale before coming to BNL, said he is pleased with the results.

“I’ve been working on this project for 20 years,” he said. “I have witnessed and participated in quite a few exciting discoveries RHIC has produced. These are very high on my list.”

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From left, postdoctoral researcher Yunjun Zhao and Brookhaven Lab biochemist Chang-Jun Liu in a greenhouse with poplar trees. Photo from BNL

By Daniel Dunaief

Plants not only make our food, produce the oxygen we breathe, and provide key ingredients in medicines, but they could also contribute chemicals that might otherwise require fossil fuels to produce.

Scientists have known since 1955 that poplar trees produce small amounts of a product called p-hydroxybenzoic acid that they attach to the lignin in their cell walls. What they didn’t know, however, was how they were attached.

After years of cloning genes and, more recently, using the gene editing tool CRISPR, Chang-Jun Liu, a plant biochemist at Brookhaven National Laboratory, and collaborators in Japan discovered the gene that codes for an enzyme that catalyzes the attachment of pBA to the lignin.

Up to now, companies have produced pBA by using fossil fuels as raw materials and for the energy required to generate enough heat and pressure for the catalytic reactions.

This discovery, which Liu published in the journal Nature Plants, could provide a more eco-friendly way to produce a chemical involved in the manufacture of toothpaste, shampoos, commercial moisturizers, shaving gels, and spray tanning solutions, among other products.

The global market value of p-hydroxybenzoic acid was $59 million in 2020 and is expected to climb to $80 million in the next five years.

“We wanted to identify the enzyme that is responsible for attaching pBA into lignin and reconstitute this pathway and promote its storage in the cell wall,” Liu said. Ideally, he’d like to combine the pathways that produce the donor molecule containing pBA with their enzyme to promote pBA storage in cell walls.

Once Liu found the gene responsible for that enzyme, he did what scientists typically do to check on the importance of a genetic sequence: first, he knocked it out and second, he overexpressed it.

By knocking out the genetic sequence, he found that poplar trees stopped producing pBA. Overexpressing the gene, on the other hand, not only increased the amount of this chemical by about 48 percent, but also raised the strength of the lignin and, consequently, the durability of the cell wall.

Aside from the benefit of increasing the natural production of the chemical, changing the amount of pBA could have implications for the environment and industry. Less durable lignin, which has a lower amount of pBA, could be useful in producing pulp, paper and biofuel, making it easier to access the biomass of the wood.

More durable lignin could be useful in the timber industry, while also enabling the plant to remove more carbon, mostly in the form of carbon dioxide, from the air.

“If we can engineer the plant to produce more of this carbon-dense compound, … particularly in the root, we can fix more carbon into the underground fraction, which will absorb more carbon from the air to promote carbon sequestration,” Liu said.

A long process

The work that led to identifying the gene that codes for the enzyme that attaches pBA to lignin took about 15 years.

Liu knew this enzyme worked to attach pBA, among other chemicals, in a test tube, but the journey to prove its importance in the poplar trees took considerable work.

Liu cloned 20 genes that are expressed in woody tissues and encoded enzymes called acyltransferases. While expressing these enzymes, he mixed them with an isotope-labeled carbon, which allowed him to check to see whether the enzyme contributed to the process of attaching pBA to lignin.

He tried using RNA interference to knock down the targeted gene, but that didn’t work.

The breakthrough that established the importance of this gene came when Liu used CRISPR. 

Next steps

Scientists aren’t sure of the specific steps or even why plants produce pBA in the first place.

Plants produce pBA through the shikimate pathway, but the exact routes leading to pBA formation are still undiscovered. 

As for why plants produce pBA, one hypothesis is that the plant uses a higher amount as a defense mechanism, making its lignin harder to remove for an insect. It could also provide resistance to mechanical stress caused by wind or snow.

“We do not have solid evidence to prove that,” he said, but “we need to explore that further.”

Liu also hopes to take a synthetic biology approach to build a more effective pathway by using the enzyme to make the plant a partner in producing pBA and in capturing and storing organic carbon.

The biochemist hopes to find a commercial partner who might be interested in exploring the development of a process that occurs naturally in poplar trees.

The environmental impact of increasing pBA in plants on the ecology of the areas in which these poplar trees might grow is unclear.

“We do not know at this moment whether this will benefit or be harmful to the soil microbial community,” he said. “In some cases, it can help the plant absorb more nutrients. It potentially can also kill other microbial life.”

For the plant, it’s unclear what the effect of higher pBA might be. The enzyme Liu identified moves pBA from inside the cell to the cell where, which would likely mitigate any toxicity because that is dead material. 

“We expect the increase of cell wall-bound pBA should promote the trees’ ability in withstanding environmental changes,” he explained.

Altering the cell’s metabolic processes by rebuilding a new pathway that produces high amounts of pBA could negatively affect a tree’s normal growth. Liu would need to conduct more experiments to explore this possible effect.

A resident of Rocky Point, Liu lives with his wife Yang Chen, who is a special education teacher assistant at Rocky Point Middle School. Their son Allen is in his third year at Purdue University, while Bryant is in his second year at the University of Southern California. The family enjoys skiing and hiking trips.

The work to confirm the link between the gene and the production of pBA involved numerous post doctoral researchers.

Liu appreciates the effort of his research team over the years. “I’m very happy that we were finally able to resolve this issue,” he said.

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Charles and Helen Reichert Planetarium

The Reichert Planetarium at the Suffolk County Vanderbilt Museum, 180 Little Neck Road, Centerport presents an exciting new program for young astronomers from Monday, Aug. 23 to Thursday, Autg. 26. Enroll your kids in the Junior Astronomer Workshops for four days filled with stellar activities, crafts, games, and Planetarium shows – presented by the Vanderbilt’s talented astronomy educators.

Erin Bennett, lead Planetarium educator, said, “Junior astronomers will learn about astronomy topics that include the Solar System, how to use a telescope, and how to identify constellations they can see from their own backyard. This program focuses on hands-on learning activities and crafts supplemented by interactive presentations in the Planetarium theater.”

Each session is from 9 a.m. to 1 p.m. Each day includes a show in the Planetarium, an educational activity or game, a craft, and a break for lunch. Lunch will not be provided. Junior Astronomers are expected to bring a bag lunch, which will be refrigerated. Registration is open for students between 8 and 12 years old. Cost: $145 for non-members; $125 for members. Space is limited, early registration is encouraged.

Anyone who is not vaccinated must wear a face mask. There will be time set aside for campers to eat lunch and take a mask break.

For any questions, please email erin.bennett@vanderbiltmuseum.org.

 

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