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Power of 3

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Photo courtesy of SBU

By Daniel Dunaief

Predicting extreme heat events is at least as important as tracking the strength and duration of approaching hurricanes.

Ping Liu

Extreme heat waves, which have become increasingly common and prevalent in the western continental United States and in Europe, can have devastating impacts through wildfires, crop failures and human casualties.

Indeed, in 2003, extreme heat in Europe caused over 70,000 deaths, which was the largest number of deaths from heat in recent years.

Recently, a trio of scientists at Stony Brook University’s School of Marine and Atmospheric Sciences (SoMAS) received $500,000 from the National Oceanographic and Atmospheric Administration to study heat events by using and analyzing NOAA’s Seamless System for Prediction and EArth System Research, or SPEAR, to understand heat waves and predict future such events.

The first objective is to evaluate simulations in the SPEAR model, by looking at how effectively this program predicts the frequency and duration of heat events from previous decades, said Ping Liu, who is the Principal Investigator on the project and is an Associate Professor at SoMAS.

Liu was particularly pleased to receive this funding because of the “urgent need” for this research, he explained in an email.

The team will explore the impact of three scenarios for increases in overall average temperature from pre-Industrial Revolution levels, including increases of 1.5 degrees Celsius, 2 degrees Celsius and four degrees Celsius, which are the increases the IPCC Assessment Reports has adopted.

Answering questions related to predicting future heat waves requires high-resolution modeling products, preferably in a large ensemble of simulations from multiple models, for robustness and the estimation of uncertainties, the researchers explained in their proposal.

“Our evaluations and research will provide recommendations for improving the SPEAR to simulate the Earth system, supporting NOAA’s mission of ‘Science, Service and Stewardship,’” they explained.

Kevin Reed, Professor, and Levi Silvers, research scientist, are joining Liu in this effort.

Liu and Reed recently published a paper in the Journal of Climate and have conducted unfunded research on two other projects. Liu brought Silvers into the group after Reed recommended Silvers for his background in climate modeling and dynamics.

Reed, who is Interim Director of Academic, Research and Commercialization Programs for The New York Climate Exchange, suggested that the research the heat wave team does will help understand the limitations of the SPEAR system “so that we can better interpret how the modeling system will project [how] blocking events and heat will be impacted by climate change.”

An expert in hurricanes, Reed added that blocking events, which can cause high pressure systems to stall and lead to prolonged heat waves, can also lead to unique hurricane tracks, such as Hurricane Sandy in 2012.

“A longer term goal of many of my colleagues at Stony Brook University is to better understand these connections,” said Reed, who is Associate Provost for Climate and Sustainability Programming and was also recently appointed to the National Academies’ Board on Atmospheric Sciences and Climate.

Liu will use some of the NOAA funds to recruit and train a graduate student, who will work in his lab and will collaborate with Reed and Silvers.In the bigger picture, the Stony Brook researchers secured the NOAA backing in the same year that the university won the bidding to develop a climate solutions center on Governors Island.

Reed suggested that the “results of the work can be shared with our partners and can help to inform future societally relevant climate research projects.”

Focus on two regions

The systems that have caused an increase in heat waves in the United States and Europe are part of a trend that will continue amid an uneven distribution of extreme weather, Liu added.

Heat waves are becoming more frequent and severe, though the magnitude and impact area vary by year, Liu explained.

The high pressure systems look like ridges on weather maps, which travel from west to east.

Any slowing of the system, which can also occur over Long Island, can cause sustained and uncomfortable conditions.

Over the past several years, Liu developed computer algorithms to detect high pressure systems when they become stationary. He published those algorithms in two journal papers, which he will use in this project.

Personal history

Born and raised in Sichuan, China, Liu moved to Stony Brook from Hawaii, where he was a scientific computer programmer, in November of 2009.

He and his wife Suqiong Li live in East Setauket with their 16-year old daughter Mia, who is a student at Ward Melville High School and  a pianist who has received classical training at the Manhattan School of Music. Mia has been trained by award-winning teacher Miyoko Lotto.

Outside of the lab, Liu, who is five-feet, seven-inches tall, enjoys playing basketball on Thursday nights with a senior basketball team.

Growing up in China, Liu was always interested in weather phenomenon. When he was earning his PhD in China at the Institute for Atmospheric Physics at the Chinese Academy of Sciences in Beijing, he had limited computer resources, working in groups with IBM and, at times, Dell computer. He built several servers out of PC parts.

With air trapped inside the basin surrounded by tall mountains, Sichuan is particularly hot in the summer, which motivated him to pursue the study of heat waves.

Liu appreciated how Stony Brook and Brookhaven National Laboratory had created BlueGene, which he used when he arrived.

As for the future of his work, Liu believes predicting extreme heat waves is increasingly important “to help planners from local to federal levels cope with a climate that is changing rapidly and fostering more frequent and more severe heat events,” he explained.

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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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From left, Daisy Zavala, Stacey Scott and Krishna Veeramah Photo by John Griffin/Stony Brook University

By Daniel Dunaief

They can’t tell you whether the leading current presidential Republican and Democratic candidates demonstrate signs of cognitive decline or, for that matter whether any real or perceived cognitive decline is greater for one than the other.

Researchers at Stony Brook University, however, have conducted recent studies that may act as a platform to generate a measure of cognitive age that differs from chronological age.

Associate Professors Krishna Veeramah and Stacey Scott and graduate student Daisy Zavala recently published research in the Journal of Gerontology: Biological Sciences in which they studied a combination of cognitive testing done over different time periods and blood tests.

Indeed, the combination of looking at signs of epigenetic changes, or alterations in the environment that affect the way genes work, and studying the effectiveness and variability of tests of memory has the potential to offer some clues about how chronological age may differ from cognitive age. At this point, the scientists have been exploring that relationship, while future work may address not just what is happening, but also why.

Among the data from 142 subjects who took a host of learning tests from 2012 to 2016 during different time periods in the day, increasing epigenetic age was linked with poorer average processing speed and working memory, as well as with greater variability in test performance.

While the statistical analysis accounted for the fact that increasing chronological age had an effect, biological age had an even bigger impact, Veeramah, who is in the Department of Ecology and Evolution and a population geneticist at Stony Brook University, explained.

The study, which Veeramah described as an “early/pilot study,” and will require further follow up, offers another perspective on the different impacts the aging process can have on cognitive function.

The results matched the scientists’ prediction, which was that people who had greater epigenetic age acceleration processed information more slowly and had poorer memory performance on average across the study.

These individuals were not only performing more poorly on average, but were also more variable in their performance.

“This should give us pause about making judgments about people related to their age and what that means about their abilities,” said Scott, who is in the Psychology department.

This study suggests that “how old you are doesn’t tell you so much about how well you’re doing in your cognitive function,” said Scott. Theoretically, the extent to which a person’s body is older than a chronological age could be an indication of what might accelerate or decelerate cognitive function, although longitudinal studies will test this.

The researchers believe this study will contribute to a body of work that is trying to see if researchers can reliably identify biological age acceleration and, if so, how to slow it down.

Testing design

The researchers gathered data from participants who took tests on smartphones provided to them. These phones didn’t receive calls or messages and didn’t have access to the web.

Participants took tests during different times in the day. About 60 percent of study participants were African American and 20 percent were Hispanic/Latino. They also varied in household income, with most participants earning between $20,000 to $60,000.

In one test, people saw symbols at the top of the screen that they had to match with symbols at the bottom as quickly as possible. In another test, people viewed three red dots on a grid for a few seconds. They were distracted by searching for “E’s” and “F’s” on a screen and then had to place the dots back in their original place on the grid.

Participants completed dozens of tests over two weeks, offering a profile of their performance during different times of the day, situations and activities.

By testing people under various conditions, the researchers could get a more comprehensive, complete and realistic understanding of their cognitive state, which also reflects the way people experience a range of competing stimuli.

The scientists were profiling people “in terms of good and bad days” to get an understanding of their “typical performance,” explained Scott.

The SBU scientists suggested that inconsistency was increasingly proposed as a potential early indicator of dementia.

The “unique aspect” of what these scientists did is comparing epigenetic data to ambulatory cognitive measurements, rather than cognitive tests in a lab setting, Veeramah said.

To test the epigenome, Veeramah explored the degree of methylation of DNA from a single blood sample from each participant using a microarray to look at about a million positions in the human genome.

Adding a CH3 group, or methylating, genes tends to make the DNA coil more tightly, making it less likely to interact with other molecules that might turn it on.

Some parts of DNA show changes in methylation that correlate with age, while others are dependent on other things like the environment or specific cell type.

The underlying assumption is that cells pick up more damage and this includes the DNA sequence with time.

Zavala’s dissertation extends this work to look at more long term implications on cognitive health.

Zavala’s research “looks forward,” Scott explained in an email. “Does someone’s epigenetic age acceleration now at the beginning of the study predict their cognitive performance up to three years later?”

Dinner and a hypothesis

Veeramah and Scott, who got married in 2020, decided to combine their expertise for a research project.

“We were talking about our work over dinner and we thought about what I do and the kind of data we have from this existing sample of people” who participated in this cognitive study, said Scott.

The couple wrote a small grant to the research foundation at Stony Brook, which provided seed funding for this study.

Veeramah, whose research covers a broad scope of topics, suggested that the concept of studying these clocks is a fairly new area.

Researchers have been testing whether obesity, Alzheimer’s, and other factors could correlate with the internal environments that cause the kind of wear and tear often associated with aging.

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From left, Joshua Rest and Jackie Collier. The blurred image in the background shows the genome structure of Aurantiochytrium limacinum, including the arrays of rDNAs at the chromosome ends, and the two mirusvirus elements that were discovered. Photo by Donna DiGiovanni

By Daniel Dunaief

They were trying for two years to solve a puzzle that didn’t make sense. Then, a combination of another discovery, some extensive analysis, and a deep dive into the past helped them put the pieces together.

Jackie Collier, Associate Professor at the School of Marine and Atmospheric Sciences at Stony Brook University and Joshua Rest, also an Associate Professor in the Department of Ecology and Evolution at Stony Brook, had been looking closely at the genetic sequence of a marine protist called Aurantiochytrium limacinum. A circular section and pieces at the end of the chromosome seemed inconsistent with the rest of the genes and with the specific type of single-celled organism.

But then, they saw a preprint of a paper in 2022 that the prestigious journal Nature published earlier this year that described a new type of virus, called a mirusvirus, which appeared to have genetic similarities and a signature that matched what they saw in their protist.

Mirus means “strange” or unknown in Latin, which was a way to describe the unusual evolutionary traits of these viruses.

Collier and Rest, working with a group of collaborators, found that a high copy circular structure and genetic elements that integrated at the end of one chromosome resembled this mirusvirus.

“From the perspective of the virus folks, ‘mirus’ was apt because the mirusviruses contain features of the two very distinct ‘realms’ of viral diversity,” Collier explained. “Our results confirm that strangeness, and add more strangeness in terms of two different ways to maintain themselves (circular episomes or integrated into a chromosome) in the same host genome.”

Researchers had discovered the mirusvirus by sequencing DNA they took from the ocean. “What our findings do is connect to a host and hopefully eventually prove that there is a protist that contains a mirusvirus genome,” said Collier.

The Aurantiiochytrium protist, which is part of the Thraustochytrids order, intrigues researchers in part because it produces essential omega-3 fatty acids and carotenoids, which enhances its biotechnology potential. This protist also intrigues Collier because it is involved in decomposing dead mangrove leaves in mangrove forests.

Dormant virus

The Stony Brook scientists have been working on analyzing the genome for a paper they recently published in the journal Current Biology since 2019.

“We had been struggling to figure out what that was,” said Collier. “We had a lot of hints that it had some relationship to some kind of viruses, but it wasn’t similar enough to any known virus. We were struggling to figure out what to call this thing,” which they had tentatively designated CE1, for circular element one.

Identifying viral elements provided the “hook” for the paper.

Rest suggested that the different confounding elements in the protist genome came from two different viruses.

At this point, Collier and Rest think the virus may be something like the herpesvirus, which hides out in human nerve cells. That virus enters a latent phase, remaining quiescent until a host becomes stressed.

John Archibald, Lucie Gallot-Lavallee and others from Dalhousie University in Canada, who are collaborators on this study, are creating the kind of conditions, such as lower food or colder temperatures, that might reactivate the viral DNA, causing it to release viral particles.

The research team has detected similar mirusvirus proteins in other Aurantiochytrium isolates and in four other Thraustochytrid genomes. 

Focusing on this protist

Collier started working on thraustochytrids in 2002, after the first outbreak of QPX disease in Raritan Bay hard clams.

Bassem Allam, who is now the Marinetics Endowed professor in Marine Sciences at SBU asked Collier if she would help understand what was going on with the clams which had QPX disease. That was caused by another Thraustochytrid.

The organism that caused QPX is a relative of the protist that interested Collier.  She chose Aurantiochytrium in part because it was the easiest to grow.

When the Gordon and Betty Moore Foundation started a program to develop molecular genetic methods for diverse marine protists about seven years ago, Collier approached Rest for a potential collaboration.

A key piece, half a century old

In her informatics work, Collier followed a path that Google or artificial intelligence might otherwise have missed.

Like traveling back hand over hand in time through older research, Collier pulled up the references from one study after another. Finally, she found an intriguing study from 1972 that had overlaps with their work.

Scientists had isolated a Thraustochytrid from an estuary in Virginia using the same kinds of methods Collier and Rest used to grow Aurantiochytrium. Using electron microscopy, these earlier researchers characterized its ultrastructure. Along the way, these 1970’s scientists noticed that starved cells released viral particles, which Collier and Rest believe might be the first record of a mirusvirus.

The researchers wrote a short paper that the prestigious journal Science published.

A cat connection

While Collier, who lives in Lake Grove, and Rest, who is a resident of Port Jefferson, are collaborators at Stony Brook, they have also have a feline connection.

In the beginning of the pandemic, a feral cat delivered kittens in Rest’s garage. Rest’s family initially tried to raise them, but allergies made such a pet arrangement untenable. 

A cat lover, Collier was searching for kittens. She adopted two of the kittens, bottle feeding them starting at three days old. When Collier and Rest speak by zoom, Rest’s children Julia, nine, and Jonah, five, visit with the cats virtually.

As for their work, Collier and Rest are intrigued by the possibility of gathering additional pieces to answer questions about this virus.

“For me, the most intriguing question is how common our observations will turn out to be — do many Thraustochytrids have latent mirusviruses?” she explained.

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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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The free event will be held on Oct. 30 at 4 p.m. at Stony Brook University’s Staller Center for the Arts, Theater Two, 100 Nicolls Road, Stony Brook.

By Daniel Dunaief

Want to hear characters from Mary Shelley’s Frankenstein discussing artificial intelligence? Or, perhaps, get an inside look at an interaction between a scientist studying penguins and a potential donor? Maybe you’d like something more abstract, like a thought piece on aspects of memory?

You can get all three at an upcoming Science on Stage performance of three one-act plays written by award-winning playwrights that feature the themes of cutting edge research from Stony Brook University.

Ken Weitzman Photo courtesy of SBU

On October 30th at 4 p.m. at Staller Center for the Arts’ Theater Two, which holds up to 130 people, professional actors will read three 10-minute scripts. Directed by Jackson Gay, topics will include research about artificial intelligence, climate change in Antarctica and collective memory. Audience members can then listen to a discussion hosted by Program Founder and Associate Professor of Theater Ken Weitzman that includes the scientists and the playwrights. The event is free and open to the public.

Funded by a grant from the Office of the Provost at Stony Brook University and supported by the College of Arts and Sciences and the Alan Alda Center for Communicating Science, the performances are an “amuse-bouche,” or an appetizer, about some of the diverse and compelling science that occurs at Stony Brook University, said Weitzman. 

“The hope is that [the plays] generate interest and get people to want to ask the next question or that [the plays] stick with audience members emotionally or intellectually and makes them want to discover more.”

The upcoming performance features the writing of two-time Tony Award winning playwright Greg Kotis, who wrote Urinetown; Michele Lowe, whose first play made it to Broadway and around the world; and Rogelio Martinez, whose plays have been produced around the U.S. and internationally.

The short plays will feature the scientific work of Nilanjan Chakraborty, Associate Professor of Mechanical Engineering; Heather Lynch, Professor of Ecology and Evolution, and Suparna Rajaram, Distinguished Professor of Cognitive Science in the Psychology Department.

“It’s a good example of what we are doing and the opportunities for us as we continue to put funding in the arts and the humanities and also in the intersection of that from an interdisciplinary perspective,” said Carl Lejuez, Stony Brook Provost, in an interview. This kind of collaborative effort works best “when it’s truly bi-directional. Both sides benefit.”

Lejuez credits President Maurie McInnis with setting the tone about the importance of learning the humanities and the sciences. Lejuez said McInnis talks during her convocation speech about how she had intended to become a physician when she attended college, but took an art history course that was part of a general education curriculum that changed her life. The sixth president of Stony Brook, McInnis earned her PhD in the History of Art from Yale University.

Lejuez highlighted a number of interdisciplinary efforts at Stony Brook University. Stephanie Dinkins, Professor in the Department of Art, bridges visual art and Artificial Intelligence. She has focused her work on addressing the shortcomings of AI in understanding and depicting black women.

The Simons Center for Geometry and Physics has an arts and culture program, while the Collaborative for the Earth has faculty from numerous disciplines. They are starting a new Tiger Teams to develop key areas of study and will offer seed funding for interdisciplinary work to tackle climate change.

Lejuez plans to attend Science on Stage on October 30th.

“I feel an almost desperation to learn as much as I can about all the aspects of the university,” he said. Not only is he there to “show respect for the work and give it gravitas, but it’s the only way [he and others] can do [their job] of representing and supporting faculty and staff” in science and the humanities.

An enjoyable experience

The participants in Science on Stage appreciate the opportunity to collaborate outside their typical working world.

Heather Lynch, who conducts research on penguins in Antarctica and worked with Lowe, described the experience as “immensely enjoyable” and suggested that the “arts can help scientists step out of their own comfort zone to think about where their own work fits into society at large.”

Lynch explained that while the specific conversation in the play is fictionalized, the story reflects “my aggregate angst about our Antarctic field work and, in that sense, is probably more literally true than any conversation or interaction with any real life traveling guest.”

Lynch believes the play on her work is thought provoking. “Science is a tool, what matters is what you do” with that science, she said.

Lynch was thrilled to work with someone new and believes Lowe probably learned about Antarctica and the challenges it faces.

Bringing talent together

The first iteration of Science on Stage occurred in 2020 and was available remotely in the midst of the pandemic. Weitzman had reached out to scientists at Stony Brook to see who might be willing to partner up with playwrights.

He  is eager to share the diverse combination of topics in a live setting from this year’s trio of scientists. “I did some nudging to make sure there were a variety” of grand challenge topics, he said.

Weitzman explained that bringing the humanities and arts together in such an effort generated considerable enthusiasm. “There’s such incredible research being done here,” he said. “I want to engage for this community.”

He hopes such a performance can intrigue people at Stony Brook or in the broader community about science, theater writing or science communication.

While the plays are each 10 minutes long and include actors reading scripts, Weitzman said the experience would feel like it’s being performed and not read, particularly because professional actors are participating. 

He also hopes one or more of the playwrights sees this interaction as an opportunity to create a longer piece.

“I would love it if [this experience] encourages a playwright to think it justifies a full length” script, Weitzman said.

Lynch wrote a pilot screenplay herself called “Forecast Horizon” that she describes as an intellectual exercise. If Netflix calls, however, she’s “definitely interested in having it live on,” she said. Writing the screenplay gave her a “better appreciation for how much more similar science is to the arts than I would have thought. Both involve solving puzzles.”

As for future funding, Lejuez suggested that the University was still figuring out how to allocate available funds for next year and in future years.

He would like to see how this first time in person goes. Depending on the interest and enthusiasm, he could envision a regular source of funds to support such future similar collaborations.

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Some of the ways SBU combines arts and humanities with science

By Daniel Dunaief

The southern flagship State University of New York facility, Stony Brook University seeks ways to bring the best from the arts and humanities together with science, technology, engineering and mathematics.

Provost Carl Lejuez. Photo from SBU

Indeed, the school provides a home for the Alan Alda Center for Communicating Science, where researchers tap into famed actor Alda’s improvisational acting skills, among other techniques, to connect with their audiences and share their cutting-edge work and discoveries.

In addition to the October 30th Science on Stage production at Staller Theater 2, Provost Carl Lejuez recently highlighted numerous additional interdisciplinary efforts.

This past spring, the Simons Center for Geometry and Physics presented artwork by Professor of Mathematics Moira Chas. Chas created artwork that combines yarn and wire, clot and zippers to illustrate mathematical objects, questions or theorems.

The Office of the Provost has also provided several grants to support interdisciplinary work. This includes two $25,000 grants that promote the development of new research teams to explore interdisciplinary areas of scholarly work and address challenges such as Digital Futures/ Ethical Artificial Intelligence, Sustainability, Critical health Studies/ Health Disparities, Global Migration, and other areas.

Additionally, the Collaborative for the Earth brings together faculty from the arts, humanities and social sciences with behavioral science and STEM faculty. The university is starting a new Tiger Teams that will develop key areas of study and offer seed funding to tackle climate change. The funding will explore ways to create solutions that policy makers and the public can adopt, as well as ways to address disparities in the impact of climate change and ways to support people who are disproportionately affected by this threat.

SBU added interdisciplinary faculty. Susannah Glickman, Assistant Professor in the Department of History, has interests such as computing, political economy, 20th century US and world history and the history of science.

Matthew Salzano, IDEA Fellow in Ethical AI, Information Systems and Data Science and Literacy, meanwhile, has a joint appointment with the College of Arts and Sciences and the School of Communication. He studies rhetoric and digital culture, emphasizing how digital technology, including artificial intelligence, impacts and interacts with social justice.

Through course work, members of the university community can also address interdisciplinary questions. Associate Professor in the Department of Art Karen Lloyd teaches an Art and Medicine course, while  Adjunct Lecturer Patricia Maudies, also in the Art Department, teaches Art + The Brain. Both of these courses bring in guest lecturers from STEM and medicine.

Stony Brook also hosts centers aimed at interdisciplinary research, such as the Institute for Advanced Computational Science (IACS).

One of the current goals and objectives of the IACS strategic plan is to advance the intellectual foundations of computation and data, with high-impact applications in engineering, in the physical, environmental, life, health and social sciences, and in the arts and humanities.

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Jon Heusel Photo by Henry David

By Daniel Dunaief

Growing up in Hooper, a small town in the central part of Nebraska, Jon Heusel considered following in his parents’ footsteps.

His father William took him on house calls where he provided for a wide range of medical needs.

Jon Heusel with his father William.

Along the way, however, Heusel, whose mother Mona was also an intensive care unit nurse towards the end of her career, discovered genetics and immunology as he earned his bachelor’s degree at the University of Nebraska and then his MD, PhD at the University of Washington in St. Louis.

Enamored with these sciences and inspired to pursue a path of patient care from a different perspective, Heusel blazed his own trail, albeit one in which health care remained a professional focus.

Indeed, the second-generation doctor, who became Vice Chair for Clinical Pathology at the Renaissance School of Medicine at Stony Brook University on October 2nd, has devoted his career to the translation of new technologies into healthcare solutions.

For the past decade, this involved next generation sequencing, but also other new technologies and computerized systems for analyzing the data.

Heusel is inspired by a drive to improve the healthcare at academic medical centers like Stony Brook and Washington University, where new discoveries can affect positive change.

“The more I learned about Stony Brook, which is an up-and-coming university, the more I thought it was a magnificent opportunity for me,” said Heusel, who admired the recent jump Stony Brook University has made in the U.S. News and World Report rankings.

Mandate

Pathology Chair Kenneth Shroyer described Heusel as a “wonderful recruitment” and believes his background makes him especially well suited to his role.

“We want to develop in-house capacity to do advanced molecular testing to find actionable mutations that could inform therapeutic decision making,” said Shroyer. “He’s extremely experienced in that area.”

John Heusel’s medical school graduation with his parents William and Mona Heusel.

Shroyer suggested Stony Brook wants to develop opportunities for advanced sequencing technology within the molecular pathology lab, with a focus on molecular oncology.

Heusel described the development of a comprehensive diagnostic service in cancer as a high priority.

The cost of building new services with new technologies will require significant investment. The Pathology Department will work in partnership with the Cancer Center to build services.

“Ideally, the clinical services we build will also be attractive in supporting research and contract testing from companies in the pharmaceutical and biotech spaces,” Heusel explained.

By using informatics and digital pathology, Stony Brook can become a place where medical students and professionals in related areas including computational biology, genetic counseling and oncology increasingly want to come.

Heusel particularly appreciates the opportunity to translate technology and science into healthcare solutions.

“If you do this correctly, the tests, systems, programs and people you have recruited to run them will extend far into the future,” he said. “When this happens, you leave behind a legacy of excellence.”

Heusel will replace Eric Spitzer, who will retain his role of medical director of labs until Heusel takes over that role in January.

Shroyer described Spitzer’s contributions to the department and hospital as “tremendous,” adding that he has “been outstanding in his position as leader of the hospital laboratory. While we know [Heusel] is going to be extremely successful in part due to [Spitzer’s] help in the transition phase, we’re still going to miss” Spitzer.

Spitzer has been a valuable counselor to Shroyer and a mentor to many and is an “outstanding educator” who has been a “very impactful educator for our residents and medical students,” Shroyer said.

Educational opportunities

Heusel not only has ambitions for the university, but also for himself in his new job.

The new pathology vice chair is looking for opportunities to put his knowledge and instincts to work to make Stony Brook better — even if only in the slightest of ways, he said.

“The tumblers of fate must align themselves to become opportunities for transformational leadership; those are relatively rare,” he explained. “It’s my hope that I am well prepared and can recognize them when they cross my path.”

As for the public, Heusel recognizes that primary school teachers have a tough job in educating the public in general and in sharing the intricacies of science such as genetics. He admires them for their work.

He suggested that primary education could be reimagined amid the exponential growth in knowledge.

“I am hopeful that biology and genetics will be taught in a way that empowers people to understand their bodies and their health or disease better, but I think it is more important to teach our children to think critically,” he explained.

Part of Heusel’s job is to make the results of complex testing accessible to patients and, in many cases, their doctors.

“The growing importance of genetics in our understanding of health and disease means people will, over time, gain new insights simply because they are reading and hearing about these concepts much more often,” he explained. “It also highlights the critical role that well trained genetic counselors have in the healthcare of today and the foreseeable future.”

Jon Heusel with his wife Jean at a Gallery North art show.

Heusel and his wife Jean enjoy living in the Stony Brook area, where they have found the people welcoming. In the past, they have gone scuba diving and sky diving and have also done canoeing, hiking, kayaking and skiing.

As they have gotten older, they have tended towards quieter experiences. They have found the West Meadow Beach sunsets “amazing” and have enjoyed their introduction to shows at the Staller Center for the Arts.

Heusel also appreciates a life outside work that includes working with wood, painting, doing pottery, cooking and making up poems, songs on the ukulele and bad puns.

His parents generated a sense of compassion in Heusel and his sisters, with a “wonder of the human body, and with the ability to find humor in almost anything.”

As for his work, Heusel is thrilled that Shroyer recruited him to join the university. He admits, though, that he has had to adjust to local driving styles.

“I am surprised by the aggressive manner in which people drive inside their cars which is so very opposite from the friendliness they exude outside of them,” he said.

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Educational Programs Administrator Michele Darienzo Photo from BNL

By Daniel Dunaief

Brookhaven National Laboratory hopes to inspire the scientists of the future.

The Department of Energy sponsored national laboratory, which attracts scientists from all over the world to its state-of-the-art facility, opens its doors regularly to local students and teachers, with researchers and educators translating what they do to area residents at all levels of scientific development and understanding.

Amid so many other efforts and with a welcome return to on-site education after pandemic restrictions over the last few years, BNL received DOE funding to help eight area teachers learn how to create computer coding.

In their classrooms, these educators have shared what they studied this past summer with their students.

Amanda Horn

Coding, which uses programs like Python and Arduino, can help scientists create a set of instructions that allow computers to process and sort through data more rapidly than any person could by hand.

At the same time, a knowledge of coding can and does provide students with tools that scientists seek when they are choosing graduate students, technicians or staff in their laboratories.

Coding helps to set students “up for a job,” said Michele Darienzo, Educational Programs Administrator and one of the two teachers for the four-week summer program. “It puts you at the top of the pile.”

Darienzo added that efforts such as these prepare the science, technology, engineering and math workforce for the future.

Using modern technology, researchers collect data in a wide range of fields at a rate that requires technological help to sort through it and derive meaning from it.

“We’re at the point where lots of projects are collecting so much data and information,” said Darienzo. “We have one experiment [that is producing] many iPhones per second worth of data. That’s not something a person can do in their lifetime.”

Darienzo taught the programming language Python to the class of teachers, while Amanda Horn, who is also an Educational Programs Administrator, instructed these educators with Arduino.

“It went really well,” said Horn. “The teachers seemed really engaged in everything we were doing.”

A day in the life of a river

Bernadette Uzzi

Beyond the on site experience at BNL, Horn accompanied a class this fall or a Day in the Life of the Carmans River at Smith Point County Marina.

The students used sensors to measure numerous variables, such as temperature, pressure and humidity. With another sensor, they were able to measure carbon dioxide levels.

“If you cup your hand around the sensor, you can graph [the level of the gas] in real time using the code,” said Horn. Variabilities occurred because of the movement of air, among other factors, she added.

The students on the trip “seemed excited [to use the sensors] and to get a sense of how they worked,” Horn said.

In the context of global warming in which greenhouse gases such as carbon dioxide drive an increase in temperature, Horn addressed why it’s important to measure the levels of the gas.

Ongoing efforts

Training teachers to code represents one of numerous educational efforts BNL offers.

The Office of Educational Programs has hosted over 30,000 participants in various programs in its K-12 and university science education programs.

Kenneth White

Bringing students back on site this year after suspending in person visits amid the pandemic created a “big difference” for students, in terms of their excitement and enthusiasm, said Kenneth White, Manager of the Office of Educational Programs.

Jeffrey Tejada, a junior at Brown University, conducted summer research in the Computational Sciences Initiative.

Tejada, who grew up in Patchogue and moved to Medford, appreciated the opportunities he’s had since he started coming to BNL at the age of 14.

“It’s crazy how incredible BNL Is as a resource,” said Tejada, whose parents are immigrants from the Dominican Republic.

Indeed, the first year Tejada attended, Aleida Perez, Manager, University Relations and DOE Programs at BNL, needed to convince his mother Rosa Tejada that the effort, which didn’t involve any pay, would benefit her son.

“My mom asked [Perez,], ‘how worth it is this?’” Tejada recalled. Perez told Rosa Tejada, “You have to do this.”

His mom didn’t understand, but she listened and “that’s all that mattered,” as Tejada not only conducted research over the years, but is also planning to earn his PhD after he graduates.

White suggested that the recent coding effort was a recognition that students coming for internships at BNL or for scientific training opportunities elsewhere ended up spending considerable time trying to “figure out the basics” of coding.

Aleida Perez

In the first year of the teaching program, BNL reached out to teachers in 20 school districts that met particular criteria, including serving a high percentage of students that are traditionally under-represented in STEM fields. This included Longwood, Hampton Bays, Williams Floyd, South Huntington, Roosevelt, Central Islip, Middle Country and Brentwood.

The first week of the program was “frightening” for some of the teachers, who hadn’t had coding experience, said Perez. The teachers were “glad they came back for week two.”

As a part of the program, teachers presented their coding lessons to high school students on site at BNL, said Bernadette Uzzi, Manager, K-12 Programs in the Office of Educational Programs.

The final assessment test was a “pretty fun day,” Uzzi said, as the students pushed teachers to go further with their outdoor explorations.

Uzzi was thrilled when she had read that the Department of Energy had invited BNL to write a proposal for this pilot program. “Coding skills are important to be a scientist, no matter what field you’re in” she said. “There’s definitely a gap in what students are learning in school versus what is needed in the STEM workforce.”

Summer of ’24

At this point, it’s unclear if the DOE will build on this pilot program and offer additional teachers the opportunity to learn coding and bring this skill back to their classroom.

Uzzi said she would like to increase the number of teacher participants to 12 next year and to add physics applications to the current course work, which included a focus on environmental climate science.

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Wei Yang at a poster session for a conference. Photo by Dr. Bo Zhou

By Daniel Dunaief

When cancer spreads, it becomes especially dangerous. Indeed, metastatic cancer accounts for 90 percent of deaths from this disease.

Stony Brook University Associate Professor Wei Yang, who joined the Pathology Department on August 1st, hopes to reduce metastatic mortality.

Yang is looking both upstream for the kind of molecular biological signals that might make cancer more likely to spread and downstream, for processes that overcome the body’s natural defenses and that lead to increased morbidity and mortality.

As he described, the goal is to prevent micrometastases, which are metastatic tumors that are too small for a radiographic scan, from growing into clinically relevant macrometastases that can be detected through imaging such as X-ray scans.

Micrometasases can form at an early stage, sometimes even before the detection of primary tumors. They are typically asymptomatic and are rarely lethal, as many cancer survivors die with, but not of, these micrometastases.

In work he conducted in California at the Cedars-Sinai Medical Center, Yang focused on the protein kinase RIPK2, which is over expressed in prostate cancer.

By inhibiting RIPK2 kinase in cell culture and animal models, Yang reduced prostate cancer metastasis by over 90 percent after four weeks of treatment. Inhibiting this protein made cancer progression over 10 times slower.

Innate immune cells and epithelial cells express RIPK2 at various levels. RIPK2 is over expressed in about 18 cancer types and the high expression is generally associated with worse patient outcomes.

RIPK2 is localized in the cytoplasm, which is inside the cell, rather than on the cell surface, which makes it difficult to train the immune system to destroy it. Small molecule compounds, however, can penetrate into the cytoplasm of tumor cells.

Developing oral drugs to shut off RIPK2 is a promising approach to disrupting this protein.

Repurposing an existing drug

The Food and Drug Administration has already approved a multi-kinase inhibitor called Ponatinib, which can inhibit the pro-metastatic RIPK2 signaling pathway in prostate cancer.

Yang believes it is “very promising” to repurpose this drug to treat prostate cancer patients who don’t respond to hormone therapies.

His animal experiments showed that RIPK2-higher tumor cells can grow into macromestases in multiple organs, such as bones, liver and adrenal glands. RIPK2 was also detected in cancers such as kidney and breast. Its expression levels are typically higher than in normal tissues.

Yang is the first to demonstrate that targeting RIPK2 reduces cancer metastasis.

He has been working on prostate cancer since he conducted his postdoctoral research at Harvard University/ Boston Children’s Hospital in 2006.

He started by analyzing three comprehensive and publicly available clinical databases. Using stringent criteria, he identified seven promising drug targets in prostate cancer metastasis. Among the seven, RIPK2 was the most significantly overexpressed and its expression increased along with prostate cancer progression from benign to lethal cancer.

Most patients diagnosed with metastatic prostate cancer die within two to three years. About 31 percent live five years or longer. 

For Yang, who earned his PhD from Peking University, the goal is to understand and prevent the lethal process of metastatic progression. He aims to develop clinically actionable drug targets and biomarkers.

Upstream and downstream

Yang is searching for genes and proteins that regulate the expression of this protein kinase, to find out what increases the expression of RIPK2 in tumor cells.

He has identified three transcription factors that are important for the expression of RIPK2 mRNA in prostate cancer cells. Previous studies showed that these factors are key drivers of prostate cancer aggressiveness.

He explained that it’s promising that patients with the overexpression of these transcription factors may benefit from targeting RIPK2 to reduce cancer aggressiveness. He is also identifying a gene signature associated with RIPK2 signaling activity. This will allow him to identify additional patients who may benefit from inhibiting this protein.

Seeking collaborators

Yang said he came to Stony Brook University for a host of reasons, including to have more lab space where he can employ two post doctoral researchers, two or three graduate students, one research support specialist and two undergraduates.

He is in the second year of a five year National Cancer Institute grant and is also in the second year of a three-year Department of Defense grant.

Yang would like to find collaborators at Stony Brook who can bring specific levels of expertise in areas such as lipid signaling.

In addition to RIPK2, Yang also focuses on palmitoylation signaling in cancer metastasis. Palmitoylation is a type of lipid modification on proteins and is a reversible post-translational modification whose deregulation contributes to diseases including cancer.

Stony Brook has a “world class lipid signaling research center,” he explained in an email, and he would like to find collaborators in this arena.

Hobbies

Married with a 14-year old son, Yang enjoys traveling with his family to cities and national parks and reading history and science fiction books. One of his favorite authors is Yuval Noah Harari.

As a child, Yang was particularly interested in science. Cancer affected his family, as his grandfather had liver cancer that was diagnosed early enough to receive treatment and his aunt is living with lung cancer.

While he has a sense of urgency to study metastatic cancer, Yang said the field does not receive as much funding and attention as other areas of cancer research. He estimates that about 10 percent of the cancer budget supports investigations into metastatic cancer.

His approach, he said, will remain focused on actionable plans and on efforts that have “high translational potential,” he explained.

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