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Jason Sheltzer. Photo by ©Gina Motisi, 2018/CSHL

By Daniel Dunaief

A diagnosis of cancer brings uncertainty and anxiety, as a patient and his or her family confront a new reality. But not all cancers are the same and not all patients are the same, making it difficult to know the severity of the disease.

As doctors increasingly focus on individual patient care, researchers are looking to use a wealth of information available through new technology to assist with everything from determining cancer risks, to making early diagnoses, to providing treatment and aftercare.

Jason Sheltzer, a fellow at Cold Spring Harbor Laboratory, and his partner Joan Smith, a senior software engineer at Google, have sought to use the genetic fingerprints of cancer to determine the likely course of the disease.

By looking at genes from 20,000 cancer patients, Sheltzer and Smith found that a phenomenon called copy number variation, in which genes add copies of specific long or short sequences, is often a good indicator of the aggressiveness of the cancer. Those cancers that have higher copy number variation are also likely to be the most aggressive. They recently published their research in the journal eLife.

While the investigation, which involved work over the course of four years, is in a preliminary stage, this kind of prognostic biomarker could offer doctors and patients more information from which to make decisions about treatment. It could also provide a better understanding of the course of a disease, as copy number variation changes as cancer progresses.

“The main finding is simply that copy number variation is a much more potent prognostic biomarker than people had realized,” Sheltzer said. “It appears to be more informative than mutations in most single genes.”

Additionally, despite having data from those thousands of patients, Sheltzer and Smith don’t yet know if there’s a tipping point, beyond which a cancer reaches a critical threshold.

Some copy number changes also were more problematic than others. “Our analysis suggested that copy number alterations affecting a few key oncogenes and tumor suppressors seemed to be particularly bad news for patient prognosis,” Sheltzer said, adding that they weren’t able to do a clinical follow-up to determine how genes changed as the cancer progressed. 

“Hopefully, we can follow up this study, where we can do a longitudinal analysis,” he said.

Joan Smith. Photo by Seo-young Silvia Kim

Smith, who has written computer code for Twitter, Oracle and now Google, wrote code that’s specific to this project. “The analysis we’ve done here is new and is on a much more significant scale than the analysis we did in the past,” she said.

Within the paper, Smith was able to reuse parts of code that were necessary for different related experiments. Some of the reusable code cleaned up the data and provided a useful format, while some of the code searched for genetic patterns.

“There is considerable refinement that went into writing this code, and into writing code in general,” she explained in an email.

Smith has a full-time job at Google, where she has to clear any work she does with Sheltzer with the search engine. Before publication, she sent the paper to Google for approval. She works with Sheltzer “on her personal time,” and her efforts have “nothing to do with Google or Google Tools.”

The search engine company “tends to be supportive of employees doing interesting and valuable external work, as long as it doesn’t make use of any Google confidential information or Google owned resources,” including equipment supplies or facilities, she explained in an email.

The phenomenon of copy number variation occurs frequently in people in somatic cells, including those who aren’t battling a deadly disease Sheltzer said. “People in general harbor a lot of normal copy number variation,” he added.

Indeed, other types of repetitive changes in the genome have played a role in various conditions.

Some copy number variations, coupled with deletions, can be especially problematic. A tumor suppressor gene called P53, which is widely studied in research labs around the world, can accumulate copy number variations.

“Patients who have deletions in P53 tend to accumulate more copy number alterations than patients who don’t,” Sheltzer said. “A surprising result from our paper is that copy number variation goes above and beyond P53 mutations. You can control for P53 status and still find copy number variations that act as significant prognostic biomarkers.”

The copy number variations Sheltzer and Smith were examining were affecting whole genes, of about 10,000 bases or longer.

“We think that is because cancers are Darwinian,” explained Sheltzer. “The cells are competing against one another to grow the fastest and be the most aggressive. If a cancer amplifies one potent oncogene, it’s good for the cancer. If the cancer amplifies 200 others, it conveys a fitness penalty in the context of cancer.”

Smith is incredibly pleased to have the opportunity to contribute her informatics expertise to Sheltzer’s research, bringing together skill sets that are becoming increasingly important to link as technology makes it possible to accumulate a wealth of data in a much shorter term and at considerably lower expense.

Smith has a physics degree from MIT and has been in the technology world ever since.

“It’s been super wonderful and inspiring to get to do both” technology work and cancer research, she said.

The dynamic scientific duo live in Mineola. They chose the location because it’s equidistant between their two commutes, which are about 35 minutes. When they are not working, the couple, who have been together for eight years and have been collaborating in their research for almost all of them, enjoy biking, usually between 30 to 60 miles at a time.

Sheltzer greatly appreciates Smith’s expertise in using computer programs to mine through enormous amounts of data.

They are working on the next steps in exploring patient data.

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Stony Brook’s iGem team pose with Randy Rettberg, president of the iGem Foundation, at the event. Photo from SBU

Stony Brook’s University’s 2018 team for the International Genetically Engineered Machine (iGEM) competition took home the university’s first gold medal during the four-day iGEM Giant Jamboree held at Hynes Convention Center in Boston in October. 

Since 2014, Stony Brook’s iGEM teams have competed at this annual event, previously receiving bronze and silver medals for their student-designed synthetic biology projects. This year’s competition involved 343 teams from around the world, including 60 from different colleges and universities in the U.S. Stony Brook was one of only seven collegiate teams from the U.S. to earn a gold medal.

Stony Brook’s iGem team pose with Randy Rettberg, president of the iGem Foundation, at the event. Photo from SBU

Led by sophomores Priya Aggarwal and Matthew Mullin, the 14-member team’s project, The Sucrose Factory, focused on the use of cyanobacteria to economically sink carbon dioxide by simultaneously producing sucrose that can be used to produce biofuels and bioplastics. Their project proposal was the only one to win all three open competitions offered by the iGEM sponsors Genscript, Opentrons and Promega. 

The iGEM competition promotes the advancement of synthetic biology through education and a competition aimed at developing an open and collaborative community of young scientists. Synthetic biology projects developed by previous SBU iGEM teams have ranged from a search for innovative treatments for diabetes and pancreatic cancer to lowering the cost of vaccine preservation. At Stony Brook, new teams are recruited each year, and members are mentored by students from previous teams and advised by Peter Gergen, director of undergraduate biology and a professor in the Department of Biochemistry and Cell Biology. 

“The Jamboree was a great experience for the 14 students on the team, and I think there may actually be some long-term potential in the ideas behind their project,” said Gergen, who said he is very proud of this interdisciplinary and talented group of students. 

In addition to Aggarwal, a human evolutionary biology major, and Mullin, a mechanical engineering major, members of Stony Brook’s 2018 iGEM team are Stephanie Budhan ’21, chemistry; Woody Chiang ’19, biochemistry and psychology double major; Dominika Kwasniak ’20, biochemistry; Karthik Ledalla ’21, biomedical engineering; Matthew Lee ’21, biology; Natalie Lo ’21, biology; Lin Yu Pan ’20, health science; Jennifer Rakhimov ’21, biology; Robert Ruzic ’19, biomedical engineering; Manvi Shah ’21, psychology; Lukas Velikov ’21, computer science; and Sarah Vincent ’19, biology.

More details on the team’s project are available at http://2018.igem.org/Team:Stony_Brook/Team.

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Danny Bluestein and Wei-Che Chiu, a Stony Brook biomedical engineering doctoral student, with ventricular assist devices. Photo from SBU

By Daniel Dunaief

Some day, a doctor may save your life, repairing a calcified heart valve that jeopardizes your health. But then, the doctor may owe his or her latest lifesaving procedure to the work of people like Danny Bluestein, a professor in biomedical engineering and the director of the Biofluids Laboratory at Stony Brook University, and an international team of colleagues.

The group is working on restoring blood flow from the heart to the body using approaches for patients for whom open heart surgery is not an option.

Recently, the National Institutes of Health awarded the research crew a five-year $3.8 million grant to work on a broad project to understand ways to improve transcatheter aortic valve replacements, or TAVR, while reducing or minimizing complications from the procedure.

Danny Bluestein with his wife, Rita Goldstein. Photo from D. Bluestein

The grant is “not just about developing a new device, which we’ve been developing already for several years, but it’s also developing it in such a way that it answers challenges with disease and what clinical problems current technology offers solutions for,” Bluestein said.

TAVR provides a prosthetic valve for high-risk surgery patients. Like stents, TAVR is inserted through an artery, typically near the groin, and is delivered to the heart, where it improves the efficiency of an organ compromised by calcification on a valve and on the aorta itself.

Patients who have been candidates for TAVR are usually over 70 and often struggle to walk, as their hearts are enlarged and lose flexibility.

TAVR surgeries are performed in as many as 40 percent of such operations in some parts of Europe and the United States. The numbers have been increasing in the last couple of years as the technology has improved in different iterations of TAVR.

These valves are not only helping high-risk patients, but they are also assisting moderate and lower risk candidates.

Doctors have used TAVR for off-label uses, such as for people who have congenital difficulties with their valves, and for people who have already had open heart surgeries whose replacement valves are failing and who may be at risk for a second major heart operation.

Recovery from TAVR is far easier and less complicated than it is for cardiac surgery, typically requiring fewer days in the hospital.

Indeed, numerous researchers and cardiologists anticipate that this percentage could climb in the next several years, particularly if the risks continue to decline.

The team involved in this research effort is working with a polymer, hoping to reduce complications with TAVR and develop a way to tailor the valve for specific patients.

“If you’re a polymer person like me, you know we can make this work,” said Marvin Slepian, the director of the Arizona Center for Accelerated BioMedical Innovation at the University of Arizona. Slepian is pleased to continue a long collaboration with Bluestein, whose expertise in fluids creates a “unique approach to making something happen.”

The tandem is working with Rami Haj-Ali, the Nathan Cummings Chair in Mechanics in the Faculty of Engineering at Tel-Aviv University in Ramat Aviv, Israel. “To enable this technology, we need to better understand the current” conditions, said Haj-Ali, who uses computer methods to study the calcium deposited on the valve to understand the stages of the disease.

The valve Bluestein is proposing includes “new designs, new simulations, and new materials” that can create “less reactions with patients and overcome” problems TAVR patients sometimes face, Haj-Ali explained.

One of the significant challenges with TAVR is that it typically only lasts about five to six years.

“The idea of the NIH and this project is to extend the built-in efficiency of such a procedure,” Bluestein said. “TAVR is moving very fast to extend its functionality and durability.”

When the valve is inserted into the body, it is folded to allow it to fit through the circulatory system. This folding, however, can damage the valve, making it fail faster than in the surgical procedure.

As a part of this research, Bluestein and his team will explore ways to change the geometry of the TAVR according to the needs of the patient, which will enhance its functionality for longer. Bluestein and others will test these changing shapes through models constructed on high-performance computers, which can test the effect of blood flowing through shapes with specific physical passageways.

“Eventually, the future would involve custom designed valves, which would be optimal for the specific patient and will extend the lifespan of such a device,” Bluestein said.

A current off-label use of the TAVR valve involves assisting people born with an aortic valve that has two leaflets. Most aortic valves have a third leaflet. People with bicuspid aortic valves develop symptoms similar to those with calcification.

Going forward, Bluestein and his team plan to design valves that are specific for these patients.

A small percentage of patients with TAVR also require pacemakers. The device can interact with the electrophysiology of the heart and impair its rhythm because it creates pressure on the tissue. It is likely pushing against special nodes that generate the heart rhythm.

These studies include exploring the mechanical stress threshold that requires implantation of a pacemaker. By moving the device to a slightly different location, it may not interfere with the heart rhythm.

A resident of Melville and Manhattan, Bluestein is married to Rita Goldstein, who is a professor of psychiatry and neuroscience at the Icahn School of Medicine at Mount Sinai. 

Bluestein was raised in Israel, where he did his doctoral work. He became intrigued by the study of the flow of blood around and through the heart because he was interested in blood as a living tissue.

As for the ongoing work, Haj-Ali is optimistic about the group’s prospects. The scientists that are a part of this effort “bring something to the table that, in combination, doesn’t exist” elsewhere, he said.

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Tim Sommerville. Photo by Brian Stallard, 2018/ CSHL

By Daniel Dunaief

Many research efforts search for clues about the signals or processes that turn healthy cells into something far worse. Scientists look at everything from different genes that are active to signs of inflammation to the presence of proteins that aren’t typically found in a system or organ.

Tim Somerville, a postdoctoral researcher in Chris Vakoc’s laboratory at Cold Spring Harbor Laboratory, recently took a close look at a specific protein whose presence in a high concentration in pancreatic cancer typically worsens the expectations for a disease with an already grim prognosis.

This protein, called P63, has a normal, healthy function in skin cells for embryos and in maintaining normal skin for adults, but it doesn’t perform any important tasks in the pancreas.

Tim Somerville at Cold Spring Harbor Laboratory. Photo by Brian Stallard, 2018/ CSHL

Somerville wanted to know whether the protein appeared as a side effect of the developing cancer, like the appearance of skinny jeans someone wears after a diet starts working, or whether it might be a contributing cause of the cancer’s growth and development.

“What was unclear was whether [the higher amount of P63] was a correlation, which emerges as the disease progresses, or something more causal,” he said, adding that he wanted to find out whether “P63 was driving the more aggressive features” of pancreatic cancer.

Somerville increased and decreased the concentration of P63 in tissue cells and organoids, which are copies of human tumors, hoping to see whether the change had any effect on the cancer cells.

The postdoctoral researcher knocked out the amount of P63 through the use of CRISPR, a gene-editing technique. He also overexpressed P63, which is also a transcription factor.

“From those complementary experiments, we were able to show that P63 is driving a lot of the aggressive features of cancer cells,” Somerville concluded. “Rather than being a correlation that’s observed, it is functionally driving the cancer itself.”

Somerville recently published his research in the journal Cell Reports.

As a transcription factor, P63 recognizes specific DNA sequences and binds to them. With P63, Somerville observed that it can bind to DNA and switch on many genes that are active in the worse form of pancreatic cancer. He and his collaborators describe P63 as a master regulator of the gene program.

Pancreatic cancer is often discovered after the irreversible conversion of normal, functional cells into a cancerous tumor that can spread to other organs. It also resists chemotherapy. Research teams in the labs of Vakoc and Dave Tuveson, the director of the Cancer Center at CSHL, and other principal investigators at CSHL and elsewhere are seeking to understand it better so they can develop more effective treatments.

Tim Somerville. Photo by Yali Xu

Vakoc was impressed with the work his postdoctoral researcher performed in his lab. Somerville is “one of the most scholarly young scientists I have ever met,” Vakoc explained in an email. “He is simply brilliant and thinks deeply about his project and is also driven to find cures for this deadly disease.”

At this point, Somerville is pursuing why P63 is activated in the pancreas. If he can figure out what triggers it in the first place, he might be able to interfere with that process in a targeted way. He also might be able to think about ways to slow it down or stop the disease.

The form of P63 that is active in the pancreas is not a mutated version of the protein that functions in the skin. If scientists tried to reduce P63, they would need to develop ways to suppress the cancer promoting functions of P63 without suppressing its normal function in the skin.

Many of the genes and proteins P63 activates are secreted factors and some of them contribute to inflammation. Indeed, researchers are exploring numerous ways inflammation might be exacerbating the progression of cancer.

P63 is also active in other types of cancer, including lung, head and neck cancers. Frequently, elevated levels of P63 in these other forms of cancer also lead to a worse prognosis.

Somerville explained that the changes P63 makes in a pancreatic cancer cell may expose new weaknesses. By studying cells in which he has overexpressed the protein, he hopes to see what other addictions the cells may have, which could include a reliance on other proteins that he could make compounds to target.

A resident of Huntington, Somerville has worked in Vakoc’s lab for three years. While he has spent considerable time studying P63, he is also looking at other transcription factors that are involved in pancreatic cancer.

Somerville wants to contribute to the discovery of why one form of pancreatic cancer is so much worse than the other. “If we can understand it, we can find new ways to stop it,” he said.

Originally from Manchester, England, Somerville is working in the United States on a five-year visa and plans to continue contributing to Vakoc’s lab for the next couple of years. At that point, he will consider his options, including a potential return to the United Kingdom.

Tim Somerville. Photo by Gina Motisi, 2018/CSHL

Somerville appreciates the opportunity to work on pancreatic cancer with Vakoc and with Tuveson, whose lab is next door. The researcher is enjoying his time on Long Island, where he takes walks, enjoys local restaurants and, until recently, had been playing on a Long Island soccer team, which played its matches in Glen Cove.

For Somerville, Cold Spring Harbor Laboratory has exceeded his high expectations. “The research that goes on here and the interactions you can have at meetings” have all contributed to a “great experience,” he said.

Somerville is excited to be a part of the pancreatic cancer team.

“With the work from [Tuveson’s] lab and ours, we’re finding new things we didn’t know,” he said. “It’s only when you understand those different things and the complexity that you can start thinking about how to tackle this in a more successful way. If the research carries on, we’ll make improvements in this disease.”

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By Elof Axel Carlson

Elof Axel Carlson

The first time I heard DNA enter popular culture was hearing a record played by my son Anders. I heard the refrain, “Hey hey, hey hey! It’s DNA that made me that way.” Anders told me it was from a song called “Sheer Heart Attack” by the rock band Queen (1977).  

Since then that idea has spread from teenage rock fans to the public sphere, and in its modified form, I hear “It’s in my DNA” when a person feels passionately about an idea. Metaphors are part of how we speak but they are not always scientifically accurate. Before the era of DNA (that began with the publishing of the double helix model of DNA in 1953 by James Watson and Francis Crick), a different set of metaphors were in use going back to antiquity. 

Intense belief or fixed behaviors have been attributed to the intestines (I feel it in my gut), to the heart (I offer my heart-felt thanks), to the skeletal system (I feel it to the marrow of my bones), to the blood (royalty are blue bloods and a psychopath’s behavior reflects bad blood) and to the nervous system (argumentative personalities are called “hot headed”). 

Sumerians studied the shape of animal guts and livers to predict the future (haruspicy). Until the Renaissance the brain was thought to be the place where blood is cooled (hence the hot-headed belief). Thoreau was described by one contemporary as sucking the marrow out of life; and blood was considered the vital fluid of life. In the Renaissance the first human blood transfusions were given to provide youthful vigor by old men who believed in rejuvenation.  

When people say, “It’s in my DNA” for a behavior, they are conveying a deeply held belief that it is part of their personality as far back as they can remember or that it is innate. But the evidence for innate human social behaviors is often lacking. There are single gene effects of the nervous system that are well documented such as Huntington’s disease, which leads to dementia and paralysis with an onset usually in middle age. 

There are also family histories of psychosis and learning difficulties. The fragile X syndrome is one such well-documented condition that leads to low intelligence. But human social traits have lots of inputs from parents, siblings, playmates, neighborhoods, regional culture, ethnicity and national identity.  

Children growing up in poverty have different expectations than children whose parents are well off and send them to elite schools. Each generation uses, as best as it can, what it knows. Our knowledge of many important aspects of life and behavior is incomplete. Hence, we keep modifying our interpretations of how life works.  

Much of what is called evolutionary psychology or genetic determinism will be modified or abandoned in years to come as we learn how our genes use memories and other acquired knowledge to shape our personalities. For many cellular processes we know the flow of information from DNA (genes) to cell organelles to cellular function to tissue formation and to organ formation.  

That detailed interpretation of human behavior is not possible now for social traits. I would love to say, “It’s in my DNA” to write these Life Line columns, but my conscience would remind me that it is based on Freudian “wish fulfillment” and not careful experimentation down to the molecular level.

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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Weisen Shen in front of a twin-otter airplane in the Antarctic during the 2017-18 season. Photo by Zhengyang Zhou

By Daniel Dunaief

Ever sit alone in a house and hear noises you can’t explain? Was that the wind, the house settling (whatever that means) or the cat swatting at the string hanging from the blinds?

Those sounds, which are sometimes inexplicable and are called ambient noise, are often hard to trace, even if we walk around the house and listen outside every room.

Weisen Shen
Photo by John Griffin

For Weisen Shen, an assistant professor in the Department of Geosciences at Stony Brook University, ambient noises deep below the Antarctic continent and elsewhere can be and often are clues that unlock mysteries hidden miles below the frozen surface.

A geoscientist who uses computer programs in his research, Shen would like to study the temperature well below the surface. He developed an in-house code to understand and interpret seismic data.

The speed at which Earth rumbling passes from one area to another can indicate the relative temperature of an area. Seismic activity moves more slowly through warmer rocks and moves more rapidly through colder crust, which has a higher rigidity. According to Shen, these temperature readings can help provide a clearer understanding of how much heat is traveling through the surface of the solid Earth into the ice sheet.

Shen traveled to the Ross Ice Shelf in the 2015-16 season and ventured to the South Pole in the 2017-18 season. He is currently seeking funding to go back to the Antartica. Earlier this year, he published an article in the journal Geology in which he found evidence that the lithosphere beneath the Transantarctic Mountains is thinner than expected.

Shen pointed out that seismic properties aren’t just related to temperature: They can help determine the density of the material, the composition and the existence of fluid such as water. He looks for surface geology and other types of geophysical data to detect what is the dominant reason for seismic structure anomalies. He also uses properties other than speed, such as seismic attenuation and amplitude ratios, in his analysis.

This kind of information can also provide an idea of the underlying support for mountain ranges, which get built up and collapse through a lithographic cycling.

As for ambient noises, Shen explained that they can come from ocean fluctuations caused by a hurricane, from human activities or, most commonly, from the bottom of the ocean, where the dynamic ocean wave constantly pushes against the bottom of the earth. By processing the noises in a certain way, he can extract information about the materials through which the noise traveled.

Shen published an article in the Journal of Geophysical Research in which he discussed a noise source in Kyushu Island in the Japanese archipelago. “The noise is so subtle that people’s ears will never catch it,” he said. “By deploying these very accurate seismic sensors, we will be able to monitor and study all the sources of those noises, not just the earthquakes.”

Studying these lower volume, less violent noises is especially helpful in places like Antarctica, which is, Shen said, a “quiet continent,” without a lot of strong seismic activity. He also uses the images of earthquakes that occur elsewhere, which travel less violently and dramatically through Antarctica.

Shen decided to study Antarctica after he earned his doctorate at the University of Colorado at Boulder. “I have this ambition to get to all the continents,” he said. In graduate school he told himself, “If you ever want to get that work done, you have to crack this continent.”

During his postdoctoral work, Shen moved to St. Louis, where he worked at Washington University in the laboratory of Doug Wiens, professor of Earth and planetary sciences.

In addition to conducting research in Antarctica, Shen collaborated with Chen Cai, a graduate student in Wiens’ lab. Together with other members of the Washington University team, they used seismic data in the Mariana Trench to show that about three to four times more water than previously estimated traveled beneath the tectonic plates into the Earth’s interior.

That much water rushing further into the Earth, however, is somehow offset by water returning to the oceans, as ocean levels haven’t changed dramatically through this part of the water cycle process.

“People’s estimates for the water coming out is probably out of balance,” Wiens said. “We can’t through millions of years bring lots of water through the interior. The oceans would get lower. There’s no evidence” to support that, which means that “an upward revision of the amount of water coming out of the Earth” is necessary. That water could be coming out through volcanoes or perhaps through the crust or gas funnels beneath the seafloor, he suggested.

Wiens praised all the researchers involved in the study, including Shen, whom he said was “very important” and “wrote a lot of the software we used to produce the final images.”

A resident of Queens, Shen lives with his wife Jiayi Xie, who works as a data scientist at Xaxis, a subcompany of the global media firm GroupM. The couple has an infant son, Luke.

Shen grew up in the southwestern part of China. When he was younger, he was generally interested in science, although his particular passion for geoscience started when he was in college at the University of Science and Technology of China, USTC, in Hefei, Anhui, China.

The assistant professor, who teaches a geophysics class at Stony Brook University, currently has two graduate students in his lab. He said he appreciates the support Stony Brook provides for young faculty.

As for his work, Shen is excited to contribute to the field, where he enjoys the opportunity and camaraderie that comes from exploring parts of Earth that are relatively inaccessible. He feels his detailed studies can help change people’s understanding of the planet.

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Photo by Ela Elyada

By Daniel Dunaief

What if, instead of defeating or removing enemy soldiers from the battlefield, a leader could convince them to join the fight, sending them back out to defeat the side they previously supported? That’s the question Giulia Biffi, a postdoctoral researcher at Cold Spring Harbor Laboratory, is asking about a particular type of cells, called fibroblasts, that are involved in pancreatic cancer.

Fibroblasts activated by cancer cells secrete a matrix that surrounds cancer cells and makes up about 90 percent of pancreatic tumors.

Giulia Biffi. Photo by ©Gina Motisi, 2018/CSHL

Responding to a molecule called IL-1, an inflammatory potential tumor-promoting fibroblast may enhance the opportunity for cancer to grow and spread. Another type of fibroblast responds to TGF-beta, which potentially enables them to restrain tumors.

Researchers had suggested that the inflammatory fibroblasts are tumor promoting, while the myofibroblasts are tumor defeating, although at this point, that still hasn’t been confirmed experimentally.

Researchers knew TGF-beta was important in biology, but they didn’t know that it was involved in preventing the activation of an inflammatory tumor-promoting version.

Biffi, however, recently found that IL-1 promotes the formation of inflammatory fibroblasts. She believes these fibroblast promote tumor growth and create an immunosuppressive environment.

In an article published in the journal Cancer Discovery, Biffi showed that it’s “not only possible to delete the population, but it’s also possible to convert [the fibroblasts] into the other type, which could be more beneficial than just getting rid of the tumor-promoting cells,” she said.

Biffi works in Director Dave Tuveson’s CSHL Cancer Center laboratory, which is approaching pancreatic cancer from numerous perspectives.

Her doctoral adviser, Sir Shankar Balasubramanian, the Herchel Smith Professor of Medicinal Chemistry at the University of Cambridge, suggested that the work she did in Tuveson’s lab is an extension of her successful research in England.

“It is evident that [Biffi] is continuing to make penetrating and important advances with a deep and sophisticated approach to research,” Balasubramanian explained in an email. “She is without a doubt a scientist to watch out for in the future.”

To be sure, at this stage, Biffi has performed her studies on a mouse model of the disease and she and others studying fibroblasts and the tumor microenvironment that dictates specific molecular pathways have considerable work to do to extend this research to human treatment.

She doesn’t have similar information from human patients, but the mouse models show that targeting some subsets of fibroblasts impairs cancer growth.

“One of the goals we have is trying to be able to better classify the stroma from pancreatic cancer in humans,” Biffi said. The stroma is mixed in with the cancer cells, all around and in between clusters of cells.

The results with mice, however, suggest that approaching cancer by understanding the molecular signals from fibroblasts could offer a promising additional resource to a future treatment. In a 10-day study of mice using a specific inhibitor involved in the pathway of inflammatory fibroblasts, Biffi saw a reduction in tumor growth.

If Biffi can figure out a way to affect the signals produced by fibroblasts, she might be able to make the stroma and the cancer cells more accessible to drugs. One potential reason other drugs failed in mouse models is that there’s increased collagen, which is a barrier to drug delivery. Drugs that might have failed in earlier clinical efforts could be reevaluated in combination with other treatments, Biffi suggested, adding if scientists can manage to target the inflammatory path, they might mitigate some of this effect.

A native of Bergamo, Italy, which is near Milan, Biffi earned her doctorate at the Cancer Research UK Cambridge Institute. Biffi lives on a Cold Spring Harbor property which is five minutes from the lab.

When she was young, Biffi wanted to be a vet. In high school, she was fascinated by the study of animal behavior and considered Dian Fossey from “Gorillas in the Mist” an inspiration. When she’s not working in the lab, she enjoys the opportunity to see Broadway shows and to hike around a trail on the Cold Spring Harbor campus.

Biffi started working on fibroblasts three years ago in Tuveson’s lab. “I really wanted to understand how fibroblasts become one population or the other when they were starting from the same cell type,” she said. “If they have different functions, I wanted to target them selectively to understand their role in pancreatic cancer to see if one might have a tumor restraining role.”

A postdoctoral researcher for over four years, Biffi is starting to look for the next step in her career and hopes to have her own lab by the end of 2019 or the beginning of 2020.

When she was transitioning from her doctoral to a postdoctoral job, she was looking for someone who shared her idealistic view about curing cancer. Several other researchers in Cambridge suggested that she’d find a welcome research setting in Tuveson’s lab. Tuveson was “popular” among principal investigators in her institute, Biffi said. “I wanted to work on a hard cancer to treat and I wanted to work with [Tuveson].”

Biffi hopes that targeting the inflammatory pro-tumorigenic fibroblasts and reprogramming them to the potentially tumor-restraining population may become a part of a pancreatic cancer treatment.

She remains optimistic that she and others will make a difference. “This can be a frustrating job,” she said. “If you didn’t have hope you can change things, you wouldn’t do it. “I’m optimistic.”

Biffi points to the hard work that led to treatments for the flu and for AIDS. “Years back, both diseases were lethal and now therapeutic advances made them manageable,” she explained in an email. “That is where I want to go with pancreatic cancer.”

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Andrew Schwartz. Photo courtesy of Stony Brook University

By Daniel Dunaief

In the era of social media, people reveal a great deal about themselves, from the food they eat, to the people they see on a subway, to the places they’ve visited. Through their own postings, however, people can also share elements of their mental health.

In a recent study published in the journal Proceedings of the National Academy of Sciences, Andrew Schwartz, an assistant professor in the Department of Computer Science at Stony Brook University, teamed up with scientists at the University of Pennsylvania to describe how the words volunteers wrote in Facebook postings helped provide a preclinical indication of depression prior to a documentation of the diagnosis in the medical record.

Using his background in computational linguistics and computational psychology, Schwartz helped analyze the frequency of particular words and the specific word choices to link any potential indicators from these posts with later diagnoses of depression.

Combining an analysis of the small cues could provide some leading indicators for future diagnoses.

“When we put [the cues] all together, we get predictions slightly better than standard screening questionnaires,” Schwartz explained in an email. “We suggest language on Facebook is not only predictive, but predictive at a level that bears clinical consideration as a potential screening tool.”

Specifically, the researchers found that posts that used words like “feelings” and “tears” or the use of more first-person pronounces like “I” and “me,” along with descriptions of hostility and loneliness, served as potential indicators of depression.

By studying posts from consenting adults who shared their Facebook statuses and electronic medical record information, the scientists used machine learning in a secure data environment to identify those with a future diagnosis of depression.

The population involved in this study was restricted to the Philadelphia urban population, which is the location of the World Well-Being Project. When he was at the University of Pennsylvania prior to joining Stony Brook, Schwartz joined a group of other scientists to form the WWBP.

While people of a wide range of mental health status use the words “I” and “me” when posting anecdotes about their lives or sharing personal responses to events, the use of these words has potential clinical value when people use them more than average.

That alone, however, is predictive, but not enough to be meaningful. It suggests the person has a small percentage increase in being depressed but not enough to worry about on its own. Combining all the cues, the likelihood increases for having depression.

Schwartz acknowledged that some of the terms that contribute to these diagnoses are logical. Words like “crying,” for example, are also predictive of being depressed, he said.

The process of tracking the frequency and use of specific words to link to depression through Facebook posts bears some overlap with the guide psychiatrists and psychologists use when they’re assessing their patients.

The “Diagnostic and Statistical Manual of Mental Disorders” typically lays out a list of symptoms associated with conditions such as schizophrenia, bipolar disorder or depression, just to name a few.

“The analogy to the DSM and how it works that way is kind of similar to how these algorithms will work,” Schwartz said. “We look at signals across a wide spectrum of features. The output of the algorithm is a probability that someone is depressed.”

The linguistic analysis is based on quantified evidence rather than subjective judgments. That doesn’t make it better than an evaluation by mental health professional. The algorithm would need more development to reach the accuracy of a trained psychologist to assess symptoms through a structured interview, Schwartz explained.

At this point, using such an algorithm to diagnose mental health better than trained professionals is a “long shot” and not possible with today’s techniques, Schwartz added.

Schwartz considers himself part computer scientist, part computational psychologist. He is focused on the intersection of algorithms that analyze language and apply psychology to that approach.

A person who is in therapy might offer an update through his or her writing on a monthly basis that could then offer a probability score about a depression diagnosis.

Linguistic tools might help determine the best course of treatment for people who have depression as well. In consultation with their clinician, people with depression have choices, including types of medications they can take.

While they don’t have the data for it yet, Schwartz said he hopes an algorithmic assessment of linguistic cues ahead of time may guide decisions about the most effective treatment.

Schwartz, who has been at SBU for over three years, cautions people against making their own mental health judgments based on an impromptu algorithm. “I’ve had some questions about trying to diagnose friends by their posts on social media,” he said. “I wouldn’t advocate that. Even someone like me, who has studied how words relate to mental health, has a hard time” coming up with a valid analysis, he said.

A resident of Sound Beach, Schwartz lives with his wife Becky, who is a music instructor at Laurel Hill Middle School in Setauket, and their pre-school-aged son. A trombone player and past  member of a drum and bugle corps, he met his wife through college band.

Schwartz grew up in Orlando, where he met numerous Long Islanders who had moved to the area after they retired. When he was younger, he used to read magazines that had 50 lines of computer code at the back of them that created computer games.

He started out by tweaking the code on his own, which drove him toward programming and computers.

As for his recent work, Schwartz suggested that the analysis is “often misunderstood when people first hear about these techniques. It’s not just people announcing to the world that they have a condition. It’s a combination of other signals, none of which, by themselves, are predictive.”

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Sam Aronson. Photo courtesy of BNL

By Daniel Dunaief

Sam Aronson, the retired head of Brookhaven National Laboratory, has set his sights on a new project far from Long Island.

Teaming up with Acacia Leakey, the project management and engineering consultant of a company called SOSAED and a member of the famed family that has made seminal discoveries about human evolution in Kenya, Aronson would like to stimulate the growth of businesses through the use of solar power that provides products and services.

“This [part of Africa] is an area where there’s really little infrastructure,” Aronson said. “We’re looking to help people get up on the economic pyramid.”

The people Aronson and Leakey would like to help are representative of the one billion people without access to electric power. Two-thirds of them live in sub-Saharan Africa.

Through SOSAED — which stands for Sustainable Off-grid Solutions for African Economic Development — Aronson and Leakey are working with the Turkana Basin Institute of northern Kenya, Stony Brook University, Strathmore University in Nairobi and other Kenyan educational institutions and businesses to integrate business creation in off-grid areas into the larger Kenyan economic ecosystem.

The group would like to create a business model, using local workers and managers, for a range of companies, Leakey explained.

SOSAED plans to start with a small-scale solar-powered clothing production business, which would create affordable clothing for the heat, including skirts, shirts and shorts. SOSAED expects to build this plant adjacent to the TBI research facility.

Ideally, the manufacturer will make the clothing from local material. The clothing business is a pilot project to see whether the model can work for other types of projects in other areas. The Turkana Basin Institute will provide some of the infrastructure, while SOSAED will acquire the equipment and the raw materials and training to do the work.

SOSAED hopes the project will become “self-sustaining when it’s up and running,” Aronson said. “To be sustainable, it has to be the work of local people.” He hopes what will differentiate this effort from other groups’ attempts to build economic development is the commitment to maintenance by people living and working in the area.

“To an extent, the suitability of technology is rarely rigorously considered when humanitarian or generic development projects are implemented,” Leakey explained in an email. “Not only are the skills required for maintenance an important consideration, the availability of spare parts and the motivation and ability to pay for these are also important.”

Developing a system that includes upkeep by people living and working in the area could “make a project move ahead on its own steam,” Aronson said. The area has limited infrastructure, although some of that is changing as new roads and government-funded water projects begin.

Leakey suggested that a long-term project would need extensive participation of the users in every step of the development and implementation. “The project will likely look very different once complete to how we envisage it now, and part of our success (if it comes) will lie in working in a way which allows a great degree of flexibility as it is unlikely we’ll design the ‘right’ system the first time around,” she explained in an email.

In areas with mature systems, Leakey suggested that some organizations had difficulty changing direction, retrofitting existing systems or adapting new technology. New York, she explained, is struggling to adopt sustainable technologies to the extent that it could. “Legislative and physical infrastructure imposes unfortunate roadblocks in the way of clean technologies,” she wrote in an email. “We’re fortunate that with electricity provision we have a fairly blank slate” in Kenya and that the “Kenya government also recognizes the value of off-grid initiatives.”

Leakey appreciates the support TBI played in helping to create SOSAED and is grateful for the ongoing assistance. Through Stony Brook University, SOSAED is beginning to engage business students on economic questions. In the future, the group may also work with engineering students on technological challenges.

“Research may include developing new productive uses of solar power, optimizing the existing system and using the site to rigorously test technologies developed at Stony Brook,” she explained.

Aronson’s initial interest in this project came from his technological connection to Brookhaven National Laboratory, where he retired as the director in 2015. He has been eager to bring new technology to a population he is confident they can help in a “way that makes sense to them and addresses their needs.”

With the support of the Turkana Basin Institute and Stony Brook, Aronson hopes to have a functioning solar hub and factory near TBI that serves a few surrounding villages within the next 18 months. “That’s a very ambitious goal,” he acknowledged. “We’re working in an environment that, because of the history and development, people you’re trying to serve are somewhat skeptical that you’re serious and that you have the staying power to make something that looks like what you’re talking about work.” 

While Aronson and Leakey are continuing to make connections in Kenya with government officials and residents interested in starting businesses, they are searching for ways to make this effort financially viable.

SOSAED is raising money through philanthropic grants and foundations to get the project going. Eventually, they hope to approach venture capital firms who are patient and prepared to invest for the longer term in a number of projects.

After they have an initial example, they will approach other financial backers with more than just a good idea, but with a model they hope will work in other locations.

Aronson lauded the effort and knowledge of Leakey. “We wouldn’t be making much progress right now for a variety of reasons in Kenya if [Leakey] hadn’t come on board,” Aronson said. “I value in the extreme her ability to get the work done.”

SOSAID would like to submit proposals to funding sources that can drive this concept forward.

If this effort takes root, Aronson believes there is a “tremendous market out there.” That would mean this would “become a much bigger organization.”

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Gábor Balázsi. Photo by Dmitry Nevozhay

By Daniel Dunaief

An especially hot July day can send hordes of people to Long Island beaches. A cooler July temperature, however, might encourage people to shop at a mall, catch a movie or stay at home and clean out clutter.

Similarly, genes in yeast respond to changes in temperature.

Gábor Balázsi, the Henry Laufer associate professor of physical and quantitative biology at Stony Brook University, recently published research in the Proceedings of the National Academy of Sciences on the effect of temperature changes on yeast genes.

“We are looking at single cells and at genetic systems and we can dissect and understand gene by gene with a high level of detail,” said Balázsi, who used synthetic genetic systems to allow him to dissect and understand how temperature affects these genes.

Understanding the basic science of how genes in individual cells respond to temperature differences could have broad applications. In agriculture, farmers might need to know how genes or gene circuits that provide resistance to a pathogen or drought tolerance react when the temperature rises or falls.

Similarly, researchers using genetically designed biological solutions to environmental problems, like cleanups at toxic spills, would need to understand how a change in temperature can affect their systems.

Lingchong You, an associate professor of biomedical engineering at Duke University, believes the research is promising.

“Understanding how temperature will influence the dynamics of gene circuits is intrinsically interesting and could serve as a foundation for the future,” You said. Researchers “could potentially design gene circuits to program the cell such that the cell will somehow remember its experience with the fluctuating temperatures,” which could provide clues about the experience of the cell.

Balázsi suggested the goal of his work is to understand the robustness of human control over cells in nonstandard conditions.

While other researchers have explored the effects of gene expression for hundreds of genes at different temperatures, Balázsi looked more precisely at single genes and human-made synthetic gene circuits in individual cells. He discovered various effects by inserting a two-gene circuit into yeast.

At the whole-cell level when temperatures rise from 30°C to 38°C, some cells continued growing, albeit at a slower rate, while others stopped growing and started to consume their proteins.

For the second type of cells, changing temperatures can lead to cell death. If the temperature comes down to normal levels soon enough, however, researchers can rescue those cells.

“How this decision happens is a question that should be addressed in the future,” Balázsi said.

While the dilution of all proteins slows down, the chemical reactions in which they participate speed up at a higher temperature, much like children who become more active after receiving sugar at a birthday party.

At another level, certain individual molecules change their movement between conformations at a higher temperature. Proteins wiggle more between different folding conformations even if they don’t change composition. This affects their ability to bind DNA.

Balázsi said he is fortunate that he works through the Laufer Center for Physical and Quantitative Biology, which partly supported the work, where he was able to find a collaborator to do molecular dynamic simulations. Based on the pioneering experiments of postdoctoral fellow Daniel Charlebois, with help from undergraduate researcher Sylvia Marshall, the team collected data for abnormal behaviors of well-characterized synthetic gene circuits. They worked with Kevin Hauser, a former Stony Brook graduate research assistant, who explained how the altered conformational movements affected how the protein and cells behaved.

The way proteins fold and move between conformations determines what they do.

Gábor Balázsi with his daughter Julianna at West Meadow Beach
Photo from Gábor Balázsi

Taking his observations and experiments further, Balázsi found that proteins that were unbound to a small molecule didn’t experience a change in their conformation. When they were linked up, however, they demonstrated a new behavior when heated. This suggests that understanding the effects of temperature on these genetic systems requires an awareness of the proteins involved, as well as the state of their interaction with other molecules.

While Balázsi explored several ways temperature changes affect the yeast proteins, he acknowledged that other levels or forces might emerge that dictate the way these proteins change.

Additionally, temperature changes represent just one of many environmental factors that could control the way the genetic machinery of a cell changes. The pH, or acidity, of a system might also change a gene or group of genes.

A main overarching question remains as to how much basic chemical and physical changes combine with biological effects to give predictable, observable changes in the behaviors of genes and living cells.

Balázsi may test other cell types. So far, he’s only looked at yeast cells. He would also like to know the order in which the various levels of reactions — from the whole cell to the molecular level — occur.

He is interested in cancer research and possibly defense applications and would like to take a closer look at the way temperature or other environmental factors impact human disease processes and progression or think about their relevance for homeland security or biological solutions to renewable energy.

Balázsi recognizes that he and others in this field have numerous hurdles to overcome to find acceptable appreciation for the application of synthetic gene circuits.

“It’s not so simple to engineer these cells reliably,” he said. “Some roadblocks need to be eliminated to convince people it’s feasible and useful.”

Balázsi suggested that the field of virology might benefit from pursuing some of these research questions. Viruses move from the environment or even from other hosts into humans. Avian influenza, for example, can begin inside a bird and wind up affecting people. These viruses “might have different expression patterns in birds versus humans,” he said.

Ultimately, he added, this kind of scientific pursuit is “multipronged and the applications are numerous.”

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