Tags Posts tagged with "Power of 3"

Power of 3

Markus Seeliger with a model of a protein kinase. Photo from SBU

By Daniel Dunaief

They are like couples looking for each other on a dating website. Each side could theoretically find a range of connections. The focus in this dating game, however, has heavily favored understanding the preferences of one side. 

Markus Seeliger, an associate professor in the Department of Pharmacological Sciences at the Stony Brook University Renaissance School of Medicine, has taken important steps to change that, albeit in a completely different area. Instead of working with two people who are searching for a date, Seeliger studies the interactions among protein kinases, which are like switches that turn on or off cellular signals, and inhibitors, which researchers and drug companies are creating to slow down or stop the progression of diseases.

Markus Seliger

Most scientists have looked at the pairing of these molecules and protein kinases from the perspective of the inhibitor, trying to figure out if it would bind to one of the 500 protein kinases in the human body.

Seeliger, however, is exploring the coupling from the other side, looking at the selectivity of the kinases. He published recent research in the journal Cell Chemical Biology.

“People have only ever looked at the specificity from the point of view of an inhibitor,” Seeliger said. “We’ve turned it around. We’re looking at it from the perspective of kinases,” adding that kinases have been important drug targets for decades.

In an email, Michael Frohman, a SUNY distinguished professor and the chair of the Department of Pharmacological Sciences, applauded Seeliger’s efforts and said his research “is representative of the innovative work going on in many of the labs here.” 

On a first level, Seeliger discovered eight kinases that bind to a range of potential inhibitors, while the others are more selective.

Within the smaller group that binds a range of inhibitors, there was no sequence relationship between the base pairs that formed the kinases. The kinases are also not closely related in the cellular functions they regulate. They all trigger similar signaling cascades. 

Seeliger wanted to know why these eight kinases were four to five times more likely to couple with an introduced inhibitor than their more selective kinase counterparts. The Stony Brook scientist performed a three-dimensional analysis of the structure of one of these kinases at Brookhaven National Laboratory.

“They have a very large binding pocket that can accommodate many different inhibitors,” Seeliger said. Indeed, he discovered this higher level of receptivity by separating out this group of eight, which also had more flexible binding sites. If the match between the configuration of the inhibitor and the kinase isn’t perfect, the kinase can still find a way to allow the molecule to connect.

For any potential inhibitor introduced into the human body, this more flexible and accommodating group of kinases could cause unintended side effects regardless of the level of specificity between the inhibitor or drug and other targets. This could have health implications down the road, as other researchers may use the properties of these kinases to switch off programs cancer or other diseases use to continue on their destructive paths.

“Studies point to the roles of protein kinases as driving (to at least allowing and permitting) cancer growth and development,” Yusuf Hannun, the director of the Stony Brook University Cancer Center, explained in an email. “Therefore, one needs to inhibit them.”

Hannun described Seeliger as “very rigorous” and suggested he was an “up and coming scientist” whose “novel approach” shed significant new light on protein kinases.

In his research, Seeliger’s next step is to look at the existing database to see what other groups of kinases he finds and then determine why or how these switches have similarities to others in other systems or regions of the body.

Seeliger likened kinases to a control panel on a space shuttle. “Nothing about the sequence tells you about the role of the switches,” which would make it difficult for astronauts to know which switch to turn and in what order to bring the shuttle home.

Another question he’d like to address involves a greater understanding of the complexity of a living system. So far, he’s looked at properties of these kinases under controlled conditions. When he moves into a more complex environment, the inhibitors will likely interact and yield unexpected binding or connections.

Frohman appreciated Seeliger’s overall approach to his work and his contribution to the field. He cited the popularity of a review article Seeliger wrote that documents how drug molecules find their target binding site. Frohman said this work, which was published in the Journal of the American Chemical Society, was cited over 400 times in other articles.

Seeliger has been “very dedicated to moving this field forward. We were very excited about the topic and have been very pleased with the work he’s done on it since arriving at SBU,” Frohman said.

A resident of Stony Brook, Seeliger lives with his wife Jessica Seeliger, an assistant professor in the Department of Pharmacological Sciences who works on developing drugs for tuberculosis. The couple has two young children.

“We are all very happy they are both here as independent scientists,” Frohman added.

Indeed, Hannun called Jessica Seeliger an “outstanding and highly talented scientist,” as well.

Seeliger grew up in Hanover, Germany. He became interested in science in high school when he watched “The Double Helix,” which showed the development of the structural model of DNA.

His lab currently has two postdoctoral researchers and two doctoral candidates. Ultimately, Seeliger hopes his research helps establish an understanding of the way various kinases are functionally similar in how they interact with drugs.

“We wish we would be able to design more specific inhibitors without having to test dozens and dozens of compounds by trial and error,” he explained. He hopes to continue to build on his work with kinases, including exploring what happens when mutations in these switches cause disease.

Malagasy women break up granite stones to be used as gravel in the construction of the IUCN research center. Photo from Ali Yapicioglu

By Daniel Dunaief

After considerable planning, fundraising and coordinating, Patricia Wright welcomed a star-studded group of scientists, government officials and conservationists recently for the roof raising of the new IUCN Saving Our Species Biodiversity Research Center in Madagascar.

The building, which cost about $1 million, is a part of Centre ValBio, which is a conservation and research center Wright, a Distinguished Service Professor and award-winning researcher  at Stony Brook University, founded in 2003. CVB is near Ranomafana National Park in the southeastern part of the African island nation.

Above, a sketch of the IUCN Saving Our Species Biodiversity Research Center/Image courtesy of InSite Architecture

When it is completed this summer, the new building, which includes a green roof balcony and a central staircase and breezeway, is expected to provide research facilities for about ten scientists. They will study insects and plants, frogs and lemurs, the primates Wright has observed, researched, and shared with the public for over 30 years. Visiting scientists can apply to work at the center starting in September.

Russell Mittermeier, the Chief Conservation Officer at Global Wildlife Conservation and a research professor in the Department of Anatomical Sciences at Stony Brook, suggested that these types of efforts pay dividends.

It’s “hard to predict what will be found but history has shown us that there are endless benefits to conserving biodiversity and maintaining healthy ecosystems,” Mittermeier, the Chair of the IUCN/ SSC Primate Specialist Group, explained in an email from Madagascar.

Conservationists credit Wright with adding the new Biodiversity Centre to the larger research and conservation presence in Madagascar.“Wright was instrumental” in developing the facility, said Christoph Schwitzer, the Director of Conservation at Bristol Zoological Society and the Deputy Chair and Red List Authority Coordinator of the IUCN SSC Primate Specialist Group. “Without her, it wouldn’t be there. She started this whole project.”

The IUCN expressed its appreciation for the work Wright put in to continue to build on her track record of conservation.

At IUCN, “we highly value our collaboration with [Wright] and we understand she has established a good relationship with the Park Manager of Ranomafana National Park,” Remco Van Merm, the Coordinator of IUCN’s Saving Our Species initiative, explained in an email.

Save Our Species funds projects that “enhance the conservation of threatened species,” Van Merm added. “In the case of the new SOS Biodiversity Research Centre at Centre ValBio in Madagascar, the research that will be carried out will contribute greatly to the conservation of lemurs and other threatened biodiversity” in the national park.

Wright insisted that the new biodiversity center use local materials and workers, as she did with the construction of Namanabe Hall, its much larger sister building on the CVB campus.

Wright “wants to have the local villagers be involved in the process,” said Ali Yapicioglu, a partner at InSite, an architectural firm in Perry, New York who worked on both buildings. The sand is from the river, while the gravel comes from granite pieces that local women break down into smaller pieces.

In addition to local labor and materials, Wright ensured that InSite provided education to Malagasy residents, which included classes at the construction site. Through the building process, InSite also trained electricians.

While CVB, which is the largest biodiversity research center in the country, is well-established, it took considerable work on the Stony Brook scientist’s part to create it.

Schwitzer said Wright “fought against various forces trying to set this center up and she succeeded. She’s an excellent fundraiser.”

Madagascar has presented numerous challenges for conservation, in large part because of the changes in governments.Mittermeier recently had a “good discussion” with Andry Rajoelina about biodiversity just before Rajoelina was inaugurated as president of Madagascar last week. “Let’s see what he does” on biodiversity, Mittermeier explained. The Stony Brook professor plans to recommend that Rajoelina visit Ranomafana. 

For visitors, the CVB site offers ecotourists a firsthand opportunity to observe the charismatic lemur species, which are a part of the “Madagascar” animated films and were also the subject of an Imax movie about Wright’s work called “Island of Lemurs: Madagascar.”

“People who go there can see quite a few interesting lemur species in the wild,” Schwitzer said, adding that the station also gives Schwitzer “hope for lemur conservation,” he said.

The SOS lemur program originated with a 2013 published report, which included permanently managed field stations as a critical element. Research and field stations deter logging and lemur hunting, while also contributing scientific information that the government can use to set policies and make informed decisions, he added.

The lemur action plan includes the construction of this building. Schwitzer indicated that these types of initiatives, spread throughout the country, are critical to protecting species under various pressures, including habitat destruction.

“If we don’t keep up the effort, we could very well lose one,” Schwitzer said. He hastened to add that no lemurs have gone extinct in modern times, but “we can’t become complacent.” Indeed, the rarest of lemurs, the Northern Sportive Lemur, is down to 60 individuals in the world.

In the future, Schwtizer hopes Malagasy leaders and institutions will apply for international funding for themselves, as they drive the conservation goal forward.

This September, Wright will also finish an Education Center on the lower campus. On the upper campus, which is just across the road, she is building a wildlife center that will include a vet clinic, a frog breeding center, a mouse lemur facility, and a climate and drone center. The facility will also include bungalows for long-term researchers.

In addition to providing a field station for researchers, the site will also provide information accessible to the public.

“We are producing online identification systems like iNaturalist and also putting vocalizations and videos of the wildlife online,” Wright explained in an email.

Schwitzer said he has attended meetings where Wright has shared her vision for CVB with scientists and conservationists.

“Everybody looks at this and says, ‘This is cool. I want to do something like that,’” Schwitzer said.

From left, graduate students Prakhar Avasthi, Alisa Yurovsky, Charuta Pethe and Haochen Chen with director Steven Skiena, center. Photo by Gary Ghayrat/Stony Brook University

By Daniel Dunaief

Steven Skiena practices what he teaches. Named the director of the Institute for AI-Driven Discovery and Innovation in the College of Engineering and Applied Sciences at Stony Brook University, Skiena is using artificial intelligence to search for three staff members he hopes to hire in this new initiative.

He is looking for two tenured professors who will work in the Department of Computer Science and one who will be a part of the Department of Biomedical Informatics.

“We hope to use an artificial intelligence screen,” which Skiena calls a Poach-o-matic to “identify candidates we might not have thought of before. Ideally, the program will kick up a name and afterward, we’d bump our hand on our head and say, ‘Of course, this person might be great.’”

Steven Skiena. Photo from SBU

Artificial intelligence and machine learning have become popular areas in research institutions like Stony Brook, as well as in corporations with a wide range of potential applications, including in search engine companies like Google.

Skiena, who is a distinguished teaching professor, said he has “several candidates and we’re now actively interviewing,” adding that many departments on campus have faculty who are interested in applying machine learning in their work.

“There’s been an explosion of people from all disciplines who are interested in this,” Skiena said. He recently met with a materials scientist who uses machine learning techniques to improve experimental data. He’s also talked with people from the business school and from neuroscience.

SBU students have also shown considerable interest in these areas. Last semester, Skiena taught 250 graduate students in his introduction to data science class.

“This is a staggering demand from students that are very excited about this,” he said. Machine learning has become a “part of the standard tool kit for doing mathematical modeling and forecasting in many disciplines and that’s only going to increase.”

In an recent email, Andrew Schwartz, a core faculty at the institute and an assistant professor in the Department of Computer Science at Stony Brook, said he believes bringing in new faculty “should attract additional graduate students that may become future leaders in the field.”

Increasing coverage of AI beyond the current expertise in vision, visualization, natural language processing and biomedical engineering can “go a long way. There are a large amount of breakthroughs in AI that seemingly come from taking an idea from one subfield and applying it to another.” Schwartz appreciates the impact Skiena, who is his faculty mentor, has had on the field.

Skiena has “managed to contribute to a wide range of topics,” Schwartz explained. His book, “The Algorithm Design Manual,” is used by people worldwide preparing for technical interviews. Knowing this book thoroughly is often a “suggested step” for people preparing to interview at Google or other tech companies, Schwartz added.

The students in Schwartz and Skiena’s labs share space and have regular weekly coffee hours. Schwartz appreciates how Skiena often “presents a puzzling question or an out-of-the-box take on a question.”

The core technical expertise at the institute is in machine learning, data science, computer vision and natural language processing.

The creation of the institute shows that Stony Brook is “serious about being one of the top universities and research centers for expertise in AI,” explained Schwartz.

A few years ago, researchers realized that the artificial intelligence models developed biases based on the kind of training data used to create them. “If you’re trying to build a system to judge resumes to decide who will be a good person to hire for a certain type of job” the system has a danger of searching for male candidates if most or all of the people hired had been male in the past, Skiena explained.

Unintentional biases can creep in if the data sets are skewed toward one group, even if the programmer who created the artificial intelligence system was using available information and patterns.

In his own research, Skiena, who has been at Stony Brook since 1988, works on natural language processing. Specifically, he has explored the meaning of words and what a text is trying to communicate.

He has worked on sentiment analysis, trying to understand questions such as whether a particular political figure who receives considerable media coverage is having a good or bad week.

Another project explores the quality of news sources. “Can you algorithmically analyze large corpuses of news articles and determine which are reliable and which are less so?” he asked. 

One measure of the reliability of a news source is to determine how much other articles cite from it. “It is important to teach skepticism of a source” of news or of data, Skiena said. 

“When I teach data science, a lot of what I teach includes questions of why you believe a model will do a good thing and why is a data source relevant,” he added.

A resident of Setauket, Skiena lives with his wife Renee. Their daughter Bonnie is a first-year student at the University of Delaware, where she is studying computer science. Their tenth-grade daughter Abby attends Ward Melville High School and joins her father for bike rides on Long Island.

Skiena, who grew up in East Brunswick, New Jersey, said he appreciates the university community. By working in the AI field, Skiena, who has seven doctoral students in his lab, said he often observes glitches in online models like article classification on Google News or advertisements selected for him on a website to try to figure out why the model erred. He has also developed a sense of how probability and random events work, which he said helps him not overinterpret unusual events in day-to-day life.

As for his work at the institute, Skiena hopes Stony Brook will be recognized as a major player in the field of machine learning and areas of artificial intelligence. “We have good faculty in this area already and we’re hiring more. The hope is that you reach critical mass.”

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.

Left, Lauren Hale; above, teenagers need 8 to 10 hours of sleep every night.

By Daniel Dunaief

Around this time of year, people shop for gifts for others, decorate for the holidays, and generally raise their stress level as they search for the perfect holiday plan. Somewhere in between the to-do lists and the to-buy lists, some ambitious holiday revelers also consider making a for-me list, or the equivalent of a collection of pre-New Year’s resolutions.

Often appearing in that collection is a desire to live better, to stick to a diet, to embark on a healthy lifestyle and to enjoy the moments, big and small, on the horizon in 2019.

Often overlooked in the end-of-the-year cycle is if people hope for the chance to get more sleep. That, however, may make many of those other goals — weight loss, better work performance or a calm reaction to events — more manageable.

Times Beacon Record News Media recently spoke with Stony Brook University sleep expert Lauren Hale, who is a professor of family, population and preventive medicine and teaches in the Program in Public Health at Stony Brook. Hale is also the editor-in-chief of Sleep Health.

TBR: You recently published a journal article in Sleep Health in which you linked late night social media use by National Basketball Association players with their performance. Can you talk about that?

LH: This is a coarse estimate at showing that being up late is associated with worse outcomes. It’s not necessarily saying it’s only because they’re staying up late.

TBR: How much data did you examine?

LH: We looked at seven seasons of data. We were interested in how players did on games following late night tweets compared to games following no tweeting activity. … If your shooting percentage drops by 1.7 percentage points, that could be the difference between a win and a loss.

TBR: Have you extended this work to any teams?

LH: I’m talking with the Stony Brook Athletics Department to incorporate sleep hygiene into the players’ routines. We’re hoping to start with men’s basketball in the spring of 2019.

TBR: What are some sleep strategies?

LH: There is a list of sleep hygiene strategies. Many will seem like common sense. They include having a regular bedtime, which you calculate based on when you need to wake up and how many hours of sleep you need to get, limiting caffeine, tobacco and alcohol… [They also include] not eating too many heavy foods right before bed, exercising, preferably earlier in the day and reducing screen time at night.

TBR: Does the optimum number of hours of sleep change with age?

LH: Yes. Little kids sleep a lot and need a nap. As they get older, they lose the nap, but still need to sleep 9 to 11 hours. Teenagers need 8 to 10. Adults typically need 7 to 9 hours.

TBR: How do you manage sleep in your house?

LH: We have young children, so we know how challenging it can be. The younger one goes to day care and naps two hours. It’s hard to get him to go to sleep. I’m not good about putting my phone down in the hour before bed. We do have a charging location downstairs in our house, so the devices are limited in the bedroom. The children don’t watch screens in the half hour or hour before bed.

TBR: What’s the link between sleep and weight loss?

LH: Sleep duration is inversely associated with weight gain. Individuals not getting enough sleep are more likely to gain weight. The choices of food you make when you’re sleep deprived are worse. Your hormones make you hungrier and less full. The choices you make also show less self-discipline. When you’re sleep deprived, you’re unlikely to make yourself a salad.

TBR: Did you see the recent study that links sleep and anger?

LH: It is consistent with some work I’m doing on teenagers. We know sleep is important for emotional regulation. I’m not surprised that it’s linked.

TBR: Should people who want to lose weight focus on sleep?

LH: There are obesity experts who have taken on sleep as one of the three pillars of optimal health: sleep, exercise and diet. Among those three, sleep is usually the one that’s the most overlooked.

TBR: How else does sleeping affect weight?

LH: If you want to stick to your diet, stay on a regular sleep schedule that’s going to give you the sleep you need. Eating during normal activity phases — daytime for humans — prevents obesity. 

TBR: Is there evidence that too much sleep can be bad for health as well?

LH: There’s not good evidence of a casual link between long sleep and poor health. There is strong evidence that there’s an association, due to reverse causality, that shows that sicker people need more sleep. If you’re sleeping more than 11 hours, that might be a sign that you have an underlying condition that is contributing to you needing 11 hours.

TBR: What is your next sleep-related study?

LH: My primary current research is about studying teenagers and the causes and consequences of their insufficient sleep. Some of the factors that affect adolescent sleep are screen-based media use and early school start times.

TBR: Could sleep patterns be an important indicator of health?

LH: We would love to see sleep treated as a vital sign, in which every patient gets asked. It’s not asked about and it’s not, in and of itself, sufficient [for a specific diagnosis]. It’s a good marker of well-being.

TBR: Did people believe a certain amount of sleep was optimal 50 years ago and has that number risen or fallen since then?

LH: The number of recommended hours has been relatively consistent over time. There’s just more science to support the recommendations now.

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.

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.”

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.

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.”

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.”

Social

9,211FansLike
0FollowersFollow
1,137FollowersFollow
33SubscribersSubscribe