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Leila Esmailzada, kneeling, with another BeLocal team member Caroline Rojosoa (in the black argyle sweater) distribute trial briquettes. Photo courtesy of BeLocal

By Daniel Dunaief

Leila Esmailzada set out to change the world but first had to perform a task that turns many people’s stomachs: clean someone else’s vomit off the floor.

The Stony Brook University graduate student, who is in the master’s Program in Public Health, traveled to Madagascar for a second consecutive summer with the nonprofit BeLocal Group to help several teams of student engineers put into place projects designed to improve the lives of the Malagasy people.

Before they could help anyone else, however, these students, many of them recent graduates from the College of Engineering, fought off a series of viruses, including a particularly painful stomach bug.

Esmailzada said she saw cleaning the vomit off the floor as part of the big picture.

“Compassion really plays into being abroad for your work and for your team, because you realize that everybody came here for a shared mission,” Esmailzada said. “What happens along the way is sometimes just a result of the path that brought them here.”

Briquettes lay out to dry in Madagascar. Photo courtesy of BeLocal

Indeed, beyond Esmailzada’s compassion, her ability to continue to accomplish tasks in the face of unexpected and potentially insurmountable obstacles encouraged BeLocal, a group started by Laurel Hollow residents Mickie and Jeff Nagel and Eric Bergerson, to ask her to become the group’s first executive director.

“I can’t say enough about [Esmailzada] being so resourceful over there,” said Mickie Nagel, who visited the island nation of Madagascar the last two years with Esmailzada. “She thinks about things in a different way. You can have the best product, but if you can’t connect it to the Malagasy and understand more deeply what they need, what their concerns or wants are” the project won’t be effective.

This past summer BeLocal tried to create two engineering design innovations that had originated from senior projects at SBU. In one of them, the engineers had designed a Da Vinci bridge, borrowing a model from the famous inventor, to help villagers cross a stream on their way to the market or to school. When the makeshift bridge constructed from a log or tree got washed away or cracked, the residents found it difficult to get perishable products to the market.

The first challenge the group faced was the lack of available bamboo, which they thought they had secured months before their visit.

“When the bamboo wasn’t delivered, I figured we were now going to do research on bamboo,” Nagel explained in an email, reflecting the group’s need to react, or, as she suggests, pivot, to another approach.

When they finally got bamboo, they learned that it was cut from the periphery of a patch of bamboo that borders on a national park. Government officials confiscated the bamboo before it reached BeLocal.

“We were happy to see that law enforcement recognized and acted on the ‘gray area rules’ of conserving the national park, which shows that the hard work Madagascar is putting into conservation is actually paying off,” Esmailzada said. She eventually found another provider who could deliver the necessary bamboo a few days later. This time, an important material was cut down from a local farm.

While they had the bamboo, they didn’t know how to cure it to prepare it for construction. Uncured, the bamboo could have become a soggy and structural mess. “We did try to cure [it] a few different ways, but we really didn’t have the time needed to properly treat all of it,” Nagel said. “We didn’t anticipate the bamboo not arriving cured since it was what we had been working on for months.”

Nagel credits the bridge team with adjusting to the new circumstances, constructing two girder bridges over creeks for more market research.

The BeLocal team also worked on a project to create briquettes that are healthier than the firewood the Malagasy now use for cooking. The wood produces considerable smoke, which has led to respiratory diseases and infections for people who breathe it in when they cook.

The group produced briquettes toward the end of their summer trip and presented their technique to an audience of about 120 locals, which reflected the interest the Malagasy had shown in the process during its development.

This fall, BeLocal is working on ways to move forward with sharing the briquette technique, which they hope to refine before the new year. BeLocal wants to develop clubs at Stony Brook and at the University of Fianarantsoa in Madagascar that can work together.

While BeLocal will continue to share senior design ideas on its website (www.belocalgrp.com) with interested engineers, the group is focusing its energy on perfecting the briquettes and getting them to people’s homes in Madagascar.

Nagel admired Esmailzada’s approach to the work and to the people in Madagascar.

Esmailzada said she studied how people in Madagascar interact and tried to learn from that, before approaching them with a product or process. She believes it’s important to consider the cultural boundaries when navigating the BeLocal projects, realizing that “you are not the first priority in a lot of these villagers’ lives in general. You have to understand they won’t meet and speak with you. It’s a reasonable expectation to ask maybe three times for something before you think you can get it done.”

Esmailzada also developed a routine that allowed her to shift from one potential project to another, depending on what was manageable at any given time.

The Stony Brook graduate student is delighted to be an ongoing part of the BeLocal effort.

“I love working with an organization that has the passion and vision as large as BeLocal,” she explained. “This work is fulfilling because you are working toward the chance of improving the well-being of another person or community.”

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Above, Mikala Egeblad works with graduate student Emilis Bružas in the Watson School of Biological Sciences. Photo from Pershing Square Soon Cancer Research Alliance

By Daniel Dunaief

For some people, cancer goes into remission and remains inactive. For others, the cancer that’s in remission returns. While doctors can look for risk factors or genetic mutations, they don’t know why a cancer may come back at the individual level.

In a mouse model of breast and prostate cancers, Mikala Egeblad, an associate professor at Cold Spring Harbor Laboratory, has found an important driver of cancer activation and metastasis: inflammation. When mice with cancer also have inflammation, their cancer is likely to become more active. Those who don’t have inflammation, or whose inflammation is treated quickly, can keep the dreaded disease in check. Cancer cells “may be dormant or hibernating and not doing any harm at all,” she said. “We speculated what might be driving them from harmless to overt metastasis.”

Egeblad cautioned that this research, which was recently published in the journal Science, is on mice and that humans may have different processes and mechanisms.

CSHL’s Mikala Egeblad. Photo from Pershing Square Soon Cancer Research Alliance

“It is critical to verify whether the process happens in humans,” Egeblad suggested in an email, which she will address in her ongoing research. Still, the results offer a window into the way cancer can become active and then spread from the lungs. She believes this is because the lungs are exposed to so many external stimuli. She is also looking into the relevance for bone, liver and brain metastases. The results of this research have made waves in the scientific community.

“This study is fantastic,” declared Zena Werb, a professor of anatomy and associate director for basic science at the Helen Diller Family Comprehensive Cancer Center at the University of California in San Francisco. “When [Egeblad] first presented it at a meeting six months ago, the audience was agog. It was clearly the best presentation of the meeting!”

Werb, who oversaw Egeblad’s research when Egeblad was a postdoctoral scientist, suggested in an email that this is the first significant mechanism that could explain how cancer cells awaken and will “change the way the field thinks.”

Egeblad credits a team of researchers in her lab for contributing to this effort, including first author Jean Albrengues, who is a postdoctoral fellow. This group showed that there’s a tipping point for mice — mice with inflammation that lasts six days develop metastasis.

Egeblad has been studying a part of the immune system called neutrophil extracellular traps, which trap and kill bacteria and yeast. Egeblad and other researchers have shown that some cancers trick these NETs to aid the cancer in metastasizing.

In the new study, inflammation causes cancer cells that are not aggressive to develop NETs, which leads to metastasis. The traps and enzymes on it “change the scaffold that signals that cancer should divide and proliferate instead of sitting there dormant,” Egeblad said.

To test out her theory about the role of enzymes and the NETs, Egeblad blocked the cascade in six different ways, including obstructing the altered tissue scaffold with antibodies. When mice have the antibody, their ability to activate cancer cells after inflammation is prevented or greatly reduced, she explained.

The numbers from her lab are striking: in 100 mice with inflammation, 94 developed metastatic cancer. When she treated these mice with any of the approaches to block the inflammation pathway, 60 percent of them survived, while the remaining 40 percent had a reduced metastatic cancer burden in the lungs.

If inflammation is a key part of determining the cancer prognosis, it would help cancer patients to know, and potentially treat, inflammation even when they don’t show any clinical signs of such a reaction.

In mice, these NETs spill into the blood. Egeblad is testing whether these altered NETs are also detectable in humans. She could envision this becoming a critical marker for inflammation to track in cancer survivors.

The epidemiological data for humans is not as clear cut as the mouse results in Egeblad’s lab. Some of these epidemiological studies, however, may not have identified the correct factor.

Egeblad thinks she needs to look specifically at NETs and not inflammation in general to find out if these altered structures play a role for humans. “We would like to measure levels of NETs and other inflammatory markers in the blood over time and determine if there is a correlation between high levels and risk of recurrence,” she explained, adding that she is starting a study with the University of Kansas.

Werb suggested that inflammation can be pro-tumor or anti-tumor, possibly in the same individual, which could make the net effect difficult to determine.

“By pulling the different mechanisms apart, highly significant effects may be there,” Werb wrote in an email. Other factors including mutation and chromosomal instability and other aspects of the microenvironment interact with inflammation in a “vicious cycle.”

In humans, inflammation may be a part of the cancer dynamic, which may involve other molecular signals or pathways, Egeblad said.

She has been discussing a collaboration with Cold Spring Harbor Laboratory’s Doug Fearon, whose lab is close to hers.

Fearon has been exploring how T-cells could keep metastasis under control. Combining their approaches, she said, cancer might need a go signal, which could come from inflammation, while it also might need the ability to alter the ability of T-cells from stopping metastasis.

In her ongoing efforts to understand the process of metastasis, Egeblad is also looking at creating an antibody that works in humans and plans to continue to build on these results. “We now have a model for how inflammation might cause cancer recurrence,” she said. 

“We are working very actively on multiple different avenues to understand the human implications, and how best to target NETs to prevent cancer metastasis.”

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placozoa

By Elof Axel Carlson

Elof Axel Carlson

Biologists classify living things using a system that Carl Linnaeus (1707–1778) introduced in the 18th century and that has grown in detail over the decades as new forms of life are found and studied. Humans are familiar with being vertebrates (a class of the phylum Chordata). Chordates are animals with a spinal cord, spine or an embryonic structure called a notochord. There are 55,000 chordate species. So far there are 109 phyla covering plants, animals, protozoa, fungi, bacteria and archaea, which are less precisely organized into kingdoms and domains.  

One phylum, first discovered in 1883, consisted of just one species until recently. These are the Placozoa (placo = flat and zoa = animal). They are small (about an eighth of an inch or 1 mm) and are roughly disc shaped with three layers. The top layer has cells with a hairlike thread called a cilium. The bottom layer is also ciliated but has additional cells that take in food from the ocean muck on which the placozoa live. The middle layer has amebalike cells and fiber-bearing cells that contract, making the placozoa lumpy in appearance.  

They reproduce by forming a bud that enlarges and eventually pinches off to produce identical twins. In laboratories, some of the placozoa produce sex cells (sperm and eggs), but these rarely survive the embryonic stage with about 150 cells at the time they die. No such embryos are found in samples of ocean sediments where placozoa dwell. Their DNA has been analyzed and it shows they have a past history of doubling their gene number and rearranging the sequences of their genes as they have moved about the oceans for more than 500 million years.  

Today three species are recognized from samplings around the world. They have about 12,000 genes and portions of these they share with sponges (the phylum Porifera) and comb jellies (the phylum Ctenophora).

Note that the placozoa do not have organized tissues (we have epithelial, muscular, connective and nervous tissues), a basic symmetry (we have a bilateral or left and right sides that are roughly mirror images) or body organs (we have kidneys, lungs, internal bones and eyes, ears, a nose and mouth). They have no nerve cells, muscle cells, bony structure, intestines or sense organs.  

What makes the placozoa interesting to biologists in this molecular era is the opportunity to compare the genomes of related phyla and see what genes they have to work out a molecular tree similar to the trees of life that have been worked out by comparative anatomists since Darwin’s theory of evolution provided a model of how to organize life. They represent the launching state of life before the familiar phyla of sponges, worms and more complex phyla appear in the fossil records.  

Most of the familiar phyla appear in the Cambrian era about 500 million years ago, and the placozoa are first seen in rocks designated as Ediacaran, which existed 100 million years earlier. Rocks can be dated by isotopes present in atoms that have decayed over the millennia. 

Of future interest will be identifying genes in later phyla and genes in placozoa and how they function in these different organizations of life. Also, it will be interesting to follow the genes in placozoa and in their ancestors back to protozoa in the animal kingdom. As interesting as placozoa are, they are too small to be adopted as pets in saltwater aquariums and hard to differentiate without a lens from the muck that accumulates in a fish tank.     

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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Aaron Sasson. Photo courtesy of Stony Brook Medicine

By Daniel Dunaief

Thanks to the efforts of Stony Brook University School of Medicine’s Chief of Surgical Oncology Aaron Sasson and numerous doctors and researchers at Stony Brook, Long Island has its first National Pancreas Foundation Center.

A nonprofit organization, the National Pancreas Foundation goes through an extensive screening process to designate such centers around the country, recognizing those that focus on multidisciplinary treatment of pancreatic cancer. The NPF offers this distinction to those institutions that treat the whole patient and that offer some of the best outcomes and improved quality of life for people suffering with a disease who have an 8 percent survival rate five years after diagnosis.

Sasson appreciates the team effort at the medical school. “As opposed to one person leading this, there are many people here who are required to have an interest in pancreatic cancer,” he said. “We are not only looking to build a great infrastructure for the treatment of pancreatic cancer, but we’re also looking to build a team for research on pancreatic cancer.”

Sasson highlighted the research efforts led by Yusuf Hannun, the director of the Cancer Center at SBU, who has helped attract a “tremendous number of scientists” to engage in research into this disease.

The recognition by the NPF helps the university recruit physicians who are clinically interested in developing ways to improve the outcome for patients.

Pancreatic cancer presents particular challenges complicated by its biological aggressiveness, its difficulty to detect and by the many subtypes of this disease. “It’s similar to lung and breast cancer,” Sasson said. “There are many facets of those cancers. You can’t lump them all together.”

Researchers and clinicians are still trying to understand pancreatic cancer in greater detail. Once they have done that, they can advance to treating the possible subtypes.

Numerous researchers at SBU have developed collaborations with scientists at Cold Spring Harbor Laboratory. David Tuveson, the director of the National Cancer Institute-designated Cancer Center, has engaged in collaborations with SBU scientists in his work on organoids, which are model human organs grown in a lab. Scientists use organoids to test drugs and molecular pathways involved in pancreatic cancer.

Members of the Long Island community can take comfort in the continuing dedication of the numerous staff members committed to finding a cure. “Residents of Suffolk County and Long Island should be proud of what Stony Brook has been able to accomplish,” Sasson said.

Stony Brook University has been involved in several clinical efforts. The university developed a drug called CPI-613, for which Rafael Pharmaceuticals is in the early stage of clinical trials in combination with other drugs.

In early stages, the treatment increases the vulnerability of cancer cells to numerous other drugs. Newark, New Jersey-based Rafael Pharmaceuticals is testing this treatment in pancreatic cancer and in acute myeloid leukemia.

At SBU facilities, Sasson explained that researchers and clinicians are taking a multidisciplinary approach in their work. One study, he said, is exploring the effects of a kind of radiation therapy for a subpopulation of pancreatic cancer that combines expertise in radiology, gastroenterology, pathology and medical and surgical oncology.

Sasson himself is interested in screening and biomarkers. At least half of his work is related to pancreatic cancer. When he thinks about people who have battled pancreatic cancer, several patients come to mind. He had a patient who was about 80 at the time of his diagnosis. His primary doctor told him to get his affairs in order.

“We operated on him and he lived another six or seven years,” Sasson recalls. “He was grateful to see his grandchildren graduate and to see his great-grandbabies being born.”

While every patient is unlikely to have the same outcome, Sasson said surrendering to the disease and preparing for the inevitable may not be the only option, as there may be other courses of action.

Another patient had advanced pancreatic cancer for 18 months before Sasson met her. She had received no treatment and yet the cancer didn’t progress, which is “almost unheard of and unbelievable.” In fact, the case defied medical expectations so dramatically that the doctors conducted two more biopsies to confirm that she had pancreatic cancer. “She did well for many years despite having advanced pancreatic cancer.”

In another case, a patient was receiving surveillance for lung cancer every three months. In between those visits, he had developed metastatic pancreatic cancer. This patient example and the previous one show the range of cancer progression.

The value of having an integrated clinical and research program is that scientists can look for subtle clues and signals amid the reality of cancer with a wide range of outcomes. Indeed, scientists attend the weekly tumor board meeting, so they can learn about the clinical aspects of the disease. Doctors also attend research collaborations so they can hear about developments in the lab.

Rather than dictating how researchers and clinicians should collaborate, Sasson hopes to facilitate an environment that sparks these partnerships.

Sasson joined Stony Brook Medical School almost three years ago. He said he is “impressed with the caliber of physicians.” It took time to get the critical mass and organization for pancreatic cancer to match the number of basic science investigators.

“I’m hopeful for the progress we’ll be able to make to treat this terrible disease,” he said.

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J. Anibal Boscoboinik. Photo courtesy of BNL

By Daniel Dunaief

It was discovered in Sweden in 1756 and its name means “boiling stone,” which suggests something that might be a part of a magic show.

All these years later, zeolites, as this class of crystalline porous aluminosilicates are known, have become a key part of many products, such as in water and air purifiers, in detergents and in petroleum refining and hydrocarbon synthesis. They are even a part of deodorizers for people’s homes.

While these rocks, which are produced naturally and synthetically, act as sieves because their contained pores are the size of small molecules, the surface science plays a role in their interactions involves some mysteries.

For researchers like associate materials scientist J. Anibal Boscoboinik, who works at Brookhaven National Laboratory in the Center for Functional Nanomaterials, the unknowns stem from the way the reactions occur inside three-dimensional pores, which is inaccessible to the typical tools of surface science.

Scientists Anibal Boscoboinik (right) with Bill Kaden from the University of Central Florida and Fernando Stavale from the Brazilian Center for Research in Physics at a Humboldt Foundation dinner in Berlin. Photo from Anibal Boscoboinik

Boscoboinik, who is also an adjunct professor of materials science and engineering at Stony Brook University, has addressed this problem by creating synthetic two-dimensional models of this versatile substance. The models, which he designed when he was at the Fritz Haber Institute of the Max Planck Society in Berlin, have the same active sites and behave chemically like zeolites.

Using the high-tech tools at BNL, including the National Synchrotron Light Source, which is the predecessor to the current NSLS II, Boscoboinik derived an unexpected result. “We found, by accident, that when we exposed [zeolites] to noble gases, they got trapped in the little cages the structure has” at room temperature, he said.

Noble gases — including argon, krypton, xenon and radon — can become enmeshed in zeolite. The only noble gases that pass directly through or enter and exit easily are helium and neon, which are too small to bind to the surface.

When a noble gas with a positive charge enters zeolite, it gains an electron immediately upon entering, so it becomes neutral. The noble gases can also get trapped even when silicates don’t have a negative charge. These gases’ ions are produced when researchers use X-rays. The ions are smaller than the neutral atom, which allows them to enter the cage.

“The energy required to get them out of the cage is high,” Boscoboinik explained. “Once they are in, it’s hard to get them out.”

This finding, which Boscoboinik and his colleagues made last year, was named one of the top 10 discoveries and scientific achievements at BNL. These zeolite cages have the potential to trap radioactive gases generated by nuclear power plants or filter carbon monoxide or other smaller molecules.

The science behind understanding zeolites is akin to the understanding of the inner workings of a battery. Zeolites and batteries are both commonly used in industry and commercial applications, even though researchers don’t have a precise understanding of the reactions that enable them to function as they do.

Indeed, scientists at BNL and elsewhere hope to gain a better understanding of the way these processes work, which offers the hope of creating more efficient, less expensive products that could be technologically superior to the current designs.

Boscoboinik, who has been at BNL for almost five years, is especially     appreciative of the opportunities to collaborate with scientists at the Department of Energy-sponsored facility and worked closely with Deyu Lu on the noble gas experiments.

He would not have learned as much only from experiments, Boscoboinik said. The theory helped explain the trapping of radon, which he didn’t work on for safety reasons because of its radioactivity.

Trapping radon gas could have significant health benefits, as the gas is often found in the ground or in basements. Radon is the second leading cause of lung cancer.

Lu, who is a physicist and theorist at the Center for Functional Nanomaterials, said in a recent email he was “impressed by the novelty of [Boscoboinik’s] research on two-dimensional zeolite.” 

The two researchers received funding starting in 2014 on a four-year collaboration. Lu said that he wanted his computational modeling to “confirm the hypothesis from the experiment that noble gas atoms prefer to enter the nano-sized pore [rather] than the interfacial area of the zeolite bi-layer.”

The two-dimensional zeolite model system “gives us a wonderful playground to learn physical insights from both theory and experiments,” he continued. Boscoboinik is “one of the few experts who can synthesize the two-dimensional zeolite film, and he is leading the field to apply synchrotron X-ray techniques to study this remarkable new material,” Lu explained.

More broadly, Boscoboinik is interested in developing a deeper awareness of the process through which zeolite breaks down hydrocarbons. He would also like to get a specific model for the way zeolite can convert methane — a gas that is increasing in the atmosphere and has been implicated in the greenhouse gas effect — into methanol, a liquid that can be converted into gasoline.

A resident of Stony Brook, Boscoboinik, who was raised in Argentina, is married and has two young children. His family enjoys going to the beach and recently visited Orient Point State Park. When he was growing up in South America and had more discretionary time, he enjoyed reading. His favorite authors are Jorge Luis Borges and Julio Cortazar.

Boscoboinik appreciates the curiosity-driven questions he gets from his children. In his work, he “tries to think like a kid. At work, I try to ask the same question my five-year old asks,” although he thinks like an adult in matters of safety.

As for his work, Boscoboinik said he knows he has a long way to go before he answers the questions he asks. “When working in this environment, you never know what you’re going to find,” he said. 

“You have to keep your eyes open for the unexpected so you don’t miss things that are really interesting, even if they are not what you were aiming at.”

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'Sky Quest'

Avalon Park & Preserve in Stony Brook will present a free screening of the documentary “Sky Quest” at its barn off Shep Jones Lane on Friday, Aug. 24 at 8 p.m. A family favorite, it tells the story of one woman’s quest for astronomy exploration and her childhood dreams of the stars.

Led by David Cohn and David Barnett, the film will be followed by Sky Lab and Sky Dome viewing of Venus, Jupiter, Saturn, Mars, a waxing gibbous Moon and various deep sky objects around 9 p.m. (weather permitting). Free. For more information or directions, call 631-689-0619 or visit www.avalonparkandpreserve.org.

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Michael Schatz. Photo courtesy of Cold Spring Harbor Laboratory

By Daniel Dunaief

What if an enormous collection of Scrabble letters were spread out across the floor? What if several letters came together to form the word “victory”? Would that mean something? On its own, the word might be encouraging, depending on the context.

Genetic researchers are constantly looking at letters for the nucleotides adenine, guanine, cytosine and tyrosine, searching for combinations that might lead to health problems or, eventually, diseases like cancer.

For many of these diseases, seeing the equivalent of words like “cancer,” “victory” and “predisposition” are helpful, but they are missing a key element: context.

W. Richard McCombie

Michael Schatz, an adjunct associate professor at Cold Spring Harbor Laboratory who is also the Bloomberg distinguished associate professor at Johns Hopkins, and W. Richard McCombie, a professor at Cold Spring Harbor Laboratory, use long-read sequencing technology developed by Pacific Biosciences to find genetic variants that short-read sequencing missed.

The two scientists recently teamed up to publish their work on the cover of the August issue of the journal Genome Research. They provided a highly detailed map of the structural variations in the genes of a breast cancer cell.

“This is one of many covers [of scientific journals] that we are pleased and proud of,” said Jonas Korlach, the chief scientific officer at Menlo Park, California-based Pacific Biosciences. 

“This is another example of how long-read sequencing can give you a more complete picture of the genome and allow researchers to get a more complete understanding of the underlying biology and here, specifically, that underlies the transition from a health to a cancer disease state,” he said.

Schatz and McCombie were able to see fine detail and the context for those specific sequences. They were able to see about 20,000 structural variations in the cancer genome. “It’s like using Google maps,” explained Schatz in a recent interview. “You can see the overall picture of the country and then you can see roads and zoom out.”

In the context of their genetics work, this means they could see large and small changes in the genome. Only about a quarter of the variants they found could be detected without long-read technology.

In breast cancer, scientists currently know about a family of genes that could be involved in the disease. At this point, however, they may be unaware of other variants that are in those genes. Schatz is hoping to develop more sensitive diagnostics to identify more women at risk.

People like actress and advocate Angelina Jolie have used their genetic screens to make informed decisions about their health care even before signs of any problems arise. Jolie had a double mastectomy after she learned she had the mutation in the BRCA1 gene that put her at an 87 percent risk of developing breast cancer.

By studying the sequence of genes involved in breast cancer, researchers may be able to identify other people that are “at high risk based on their genetics,” Schatz said.

Knowing what’s in your genome can help people decide on potentially prophylactic treatments. 

When people discover that they have breast cancer, they typically choose a specific type of treatment, depending on the subtype of cancer.

“There’s a lot of interest to divide [the genetic subtypes] down into even finer detail,” said Schatz, adding, “There’s also interest in transferring those categories into other types of cancer, to give [patients] better treatments if and when the disease occurs.”

The reduced cost of sequencing has made these kinds of studies more feasible. In 2012, this study of the breast cancer genome would have cost about $100,000. To do this kind of research today costs closer to $10,000 and there’s even newer sequencing technology that promises to be even less expensive, he said.

Pacific Biosciences continues to see a reduction in the cost of its technology. The company plans to introduce a new chip next year that has an eightfold higher capacity, Korlach said.

Schatz said the long-term goal is to apply this technique to thousands of patients, which could help detect and understand genetic patterns. He and McCombie are following up on this research by looking at patients at Northwell Health.

In this work, Schatz’s group wrote software that helped decipher the code and the context for the genetic sequence.

“The instrument doesn’t know anything about genes or cancer,” he said. “It produces raw data. We write software that can take those sequences and compare them to the genome and look for patterns to evaluate what this raw data tells us.”

Schatz described McCombie, with whom he speaks every day or so, as his “perfect complement.” He suggested that McCombie was one of the world’s leaders on the experimental side, adding, “There’s a lot of artwork that goes into running the instruments. My lab doesn’t have that, but his lab does.”

Working with his team at CSHL and Johns Hopkins has presented Schatz with numerous opportunities for growth and advancement.

“Cold Spring Harbor is an internationally recognized institute for basic science, while Johns Hopkins is also an internationally recognized research hospital and university,” he explained. He’s living in the “best of both worlds,” which allows him to “tap into amazing people and resources and capacities.”

Korlach has known Schatz for at least a decade. He said he’s been “really impressed with his approach,” and that Schatz is “highly regarded by his peers and in the community.”

Schatz is also a “terrific mentor” who has helped guide the development of the careers of several of his former students, Korlach said.

Down the road, Schatz also hopes to explore the genetic signature that might lead to specific changes in a cancer, transforming it from an organ-specific disease into a metastatic condition.

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From left, Peter Tonge with Eleanor Allen and Fereidoon Daryaee. Photo from SBU

By Daniel Dunaief

The journey begins at one point and ends at another. What’s unclear, however, is the process that led from beginning to end. That’s where Peter Tonge, a professor in the Department of Chemistry and Radiology at Stony Brook University’s College of Arts & Sciences, recently discovered important details.

Working with a protein called dronpa, Tonge wanted to know how the protein changed configurations as it reacted to light. There was more than one theory on how this process worked, Tonge said. “Our studies validated one of the previous hypotheses,” he said. Structural changes occur on different time scales. With a team of collaborators, Tonge was able to follow the photoreaction from absorption to the final activated form of the photoreceptor.

The technique Tonge used is called infrared spectroscopy. Through this approach, he looks at the vibration in molecules. People generally “have this picture of a molecule that isn’t moving,” he said. “In fact, atoms in the molecule are vibrating, like balls on a spring going backwards and forwards.”

Tonge uses the technique to look at vibrations before and after the absorption of light and subtracts the two. “People knew what the structure of dronpa was at the beginning and they knew the final structure,” but they had only developed educated theories about the transition from one state to another, he explained. The application of this work isn’t immediate.

“The knowledge we gained will be a foundation that will be combined with other knowledge,” Tonge said. Theoretically, scientists or drug companies can redesign the protein, fine-tuning its light-sensitive properties.

Tonge’s lab, which includes 11 graduate students, two postdoctoral researchers, two undergraduates and six high school students, explores several different scientific questions. They are studying how proteins use the energy in a photon of light to perform different biological functions.

In optogenetics, scientists have developed ways to use light to turn processes on or off. Eventually, researchers would like to figure out ways to control gene transcription using this technique. According to Tonge, scientists are “interested in using these processes that have naturally evolved to tailor them to our own purposes.”

Tonge’s other research focus involves understanding how drugs work. Most drugs fail when they reach clinical trials. “Our ability to predict how drugs will work in humans needs to be improved,” he said, adding that he focuses on something called the kinetics of drug target interactions to improve the process of drug discovery.

In kinetics, he explores how fast a drug binds to its target and how long it remains bound. Companies look to design drugs that remain bound to their desired target for longer, while separating from other areas more rapidly. This kind of kinetic selectivity ensures the effectiveness of the drug while limiting side effects.

By thinking about how long a drug binds to its target, researchers can “improve the prediction of drug activity in humans,” explained Tonge. “We need to consider both thermodynamics and kinetics in the prediction of drug activity.”

A study of kinetics can allow researchers to consider how drugs work. Understanding what causes them to break off from their intended target can help scientists make them more efficient, reducing their failure rate.

Borrowing from sports, Tonge suggested that kinetics measures how quickly an outfielder catches a ball and throws it back to the infield, while thermodynamics indicates whether the outfielder will be able to make a catch. He believes the most interesting work in terms of kinetics should occur in a partnership between academia and industry.

Tonge is the newly appointed director of the Center for Advanced Study of Drug Action at Stony Brook, where he plans to develop a fundamental understanding of how drugs work and the role kinetics play in drug action.

Joanna Fowler, a senior chemist emeritus at Brookhaven National Laboratory, worked with Tonge for several years starting in 2005. She said Tonge developed ways to label tuberculosis and other molecularly targeted molecules he had developed in his lab. They did this to image and follow it in the body using the imaging tools BNL had at the time.

In an email, she described Tonge as a “scholar” and a “deep thinker,” who investigates mechanisms that govern the interactions between chemical compounds including drugs and living systems, adding, “He uses his knowledge to address problems that affect human beings.”

Finally, Tonge is also pursuing research on positron emission tomography. He would like to synthesize new radio tracers and use PET to see where they go and learn more about how drugs work. He would also like to enhance ways to locate bacteria in humans.

The professor is trying to detect infections in places where it is difficult to diagnose because of the challenge in getting clinical samples. Samples from throat cultures or mucus are relatively easy to obtain — the short-term agony from a swab in the back of the throat notwithstanding.

“It is more difficult to get samples from locations such as prosthetic joints,” which makes it more challenging to detect and diagnose, he said.

If an infection isn’t treated properly, doctors might have to remove the prosthesis. Similarly, bone infections are difficult to detect and, if left unchecked, can lead to amputations.

A resident of Setauket, Tonge lives with his wife, Nicole Sampson, who is a professor in the chemistry department at SBU and is the interim dean for the College of Arts and Sciences, and their two children, Sebastian, 18, and Oliver, 14.

Tonge, who was raised in the United Kingdom, said he enjoys running on Long Island.

Tonge and Sampson are co-directors of a graduate student training program in which they train students to improve their ability to communicate their science. One of the activities they undertook was to visit a high school and have grad students present their research to high school students.

As for his work, Tonge said he is “genuinely curious about the chemistry that occurs in biological systems.”

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Kenneth Shroyer and Luisa Escobar-Hoyos are the recent recipients of a two-year research grant from PanCAN. Photo by Cindy Leiton

By Daniel Dunaief

Stony Brook University has collected its first PanCAN award. Pathology Chair Kenneth Shroyer and Assistant Professor and Co-Director of the Pathology Translational Research Lab Luisa Escobar-Hoyos have earned a two-year $500,000 research grant from the Pancreatic Cancer Action Network.

The tandem has worked together for seven years on the protein keratin 17, or k17, which started out as an unlikely participant in pancreatic cancer and as a molecule cancer uses to evade chemotherapy.

Shroyer and Escobar-Hoyos were “thrilled to get the award,” said Shroyer in a recent email. “While we thought our proposal was very strong, we knew that this was a highly competitive process.”

Indeed, the funding level for the PanCAN grants program was between 10 and 15 percent, according to PanCAN.

The grants review committee sought to identify projects that “would constitute novel targets for treating pancreatic cancer,” said Maya Bader, the associate director of scientific grants at PanCAN. 

“Given that k17 represents a potential new target, the committee felt the project was a good fit with exciting potential to meet this goal. We are thrilled to welcome Dr. Shroyer to the PanCAN grantee research community and look forward to following both his and Dr. Escobar-Hoyos’ contributions to the field,” she said.

Escobar-Hoyos explained that she and Shroyer hope “this work will shed scientific insight into potential novel ways to treat the most aggressive form of pancreatic ductal adenocarcinoma,” which is the most common type of pancreatic cancer.

Although they are not sure if their approaches will be successful, she believes they will provide information that researchers can use to “further understand this aggressive disease.”

Thus far, Shroyer and Escobar-Hoyos have focused on the role of k17 in pulling the tumor suppressor protein p27 out of the nucleus into the cytoplasm, where it is degraded. More recently, however, they have explored how the k17 the tumor produces reprograms the cancer metabolome.

They have data that suggests that k17 impacts several dozen proteins, Escobar-Hoyos suggested. If the tumors of patients express k17, around half the protein content will go to the nucleus of the cell. 

In addition to understanding what k17 does when it enters the nucleus, Escobar-Hoyos and Shroyer are testing how they might stop k17 from entering the nucleus at all. Such an approach may prevent pancreatic cancer from growing.

Shroyer and Escobar-Hoyos are working with a graduate student in the lab, Chun-Hao Pan, who is testing molecular pathways that might make pancreatic cancer more resistant to chemotherapy.

Dr. Yusuf Hannun, the director of the Stony Brook Cancer Center, was pleased that his fellow Stony Brook scientists earned the PanCAN distinction.

“It is an important award and speaks to our growing significant efforts in research in pancreatic cancer,” he said, suggesting that the research could have important benefits for patients battling with pancreatic cancer.

“This defines at the very least a novel and important biomarker for pancreatic cancer that can also extend into novel therapeutic approaches,” Hannun said. This type of research could enhance the diagnostic process, allowing doctors to subtype pancreatic cancers and, if the pathways become clearer, enhance the effect of chemotherapy.

The funds from the PanCAN award will support experiments in cell culture and in animal models of pancreatic cancer, Shroyer explained.

Shroyer has teamed up with numerous researchers at Stony Brook and Cold Spring Harbor Laboratory on this work.

As proof of principle for one aspect of the proposal, he accessed chemosensitivity data from pancreatic cancer organoids. Hervé Tiriac, a research investigator who works in David Tuveson’s lab at CSHL, generated these organoids from SBU pancreatic cancer specimens.

In addition to their work with organoids at CSHL, Shroyer and Escober-Hoyos benefited from their collaboration with SBU’s Ellen Li, a professor of medicine, who ensured patient consent and specimen collection.

Going forward at Stony Brook University, the key collaborator for this project will be Richard Moffitt, an assistant professor in the departments of Biomedical Informatics and Pathology.

Shroyer described Moffitt as an “internationally recognized leader in the field of pancreatic cancer subtyping” who is working to understand better how k17 could serve as a prognostic biomarker.

At the same time, Wei Hou from the Department of Family, Population and Preventive Medicine will provide biostatistical support throughout the course of the project.

PanCAN, which has donated $48 million to support pancreatic cancer research, awarded nine grants this year in the United States, Canada and France, for a total contribution of $4.2 million. 

The other scientists include Andrew Aguirre from the Dana-Farber Cancer Institute, Scott Lowe, who had previously worked at Cold Spring Harbor Laboratory and is now at Memorial Sloan-Kettering Cancer Center and George Miller at New York University School of Medicine.

Previous recipients of PanCAN awards have been able to leverage the funds to attract research dollars to their work.

Grantees who had received $28.2 million from 2003 to 2015 went on to receive $311 million in subsequent funding to support their pancreatic cancer research, according to PanCAN. That means that every dollar awarded by PanCAN converts to $11.01 to fund future research aimed at understanding, diagnosing and treating pancreatic cancer, according to Bader. Most of the subsequent funding comes from government sources.

PanCAN award recipients have published research that other scientists have cited more than 11,000 times in other papers published in biomedical journals. This means “other researchers are reading, learning from and building upon our grantees’ work,” Bader added.

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We are now in a molecular age in which individual genes can be sequenced and their functions studied.

By Elof Axel Carlson

Elof Axel Carlson

You are a multicellular organism. In fact you have about 37 trillion cells. That’s 37,000,000,000,000 if you like numbers. Cells were first described in 1665 by Robert Hooke who looked at cork bark under a crude microscope he had invented. The cells he saw were empty boxes. He believed this was the cause of cork’s buoyancy. 

It wasn’t until the mid-1800s that lenses and stain technology developed to reveal detail inside cells. It also permitted several biologists to promote a theory that all cells arise from pre-existing cells and that organisms are composed of cells. 

In that stage of our knowledge of life, scientists worked out mitosis (how cells divide) and meiosis (how cells form reproductive cells). They learned that chromosomes carried the genes, or hereditary units, that produce all the components and cellular types in an organism. In the last half of the 20th century they learned how to take apart and put together components of the living cell. 

We see multicellular life among plants and animals around us, but we cannot see single-celled organisms without a microscope. Microscopic single cells exist for bacteria, certain algae, certain fungi and most protozoa. The presence of multicellular organisms goes back to about 2.5 billion years ago with filaments of cells in ancient rocks.  

About 20 years ago I was delighted to read about experiments by Nicole King (UC Berkeley) showing that one-celled organisms, similar to those found in sponges, could be selected to join in clumps. That has been greatly extended to algal cells (Chlamydomonas, Volvox) and fungi (yeast). 

William Ratcliff at Georgia Tech recently published results of selection for larger and heavier yeast cells that settled down on the bottom of test tubes. He isolated some that developed adhesions. From continued selection (hundreds of generations of yeast) he obtained some that formed flakelike arms or branches and that reproduced by breaking off branches. 

King, who continues her work, has isolated more than 300 genes associated with multicellularity, many of them found in single-celled organisms. By combining different groups of genes, she can increase the likelihood of producing multicellular units.  

Multicellular organisms can be simple like balls or they can be complex with specialized tissues and organs. They can dig deeper into the earth or extend their range from a few feet to miles or across continents. There have been millions of species that constantly change the way the surface of the earth appears. We are now in a molecular age in which individual genes can be sequenced and their functions studied. 

If I see a picture of myself, I see my surface of skin and hair clothed or unclothed. With X-rays I can see my bones, but not as well as a human skeleton mounted in an anatomy laboratory. I have seen what my tissues look like from a box with a hundred or more slides that I studied at NYU as an undergraduate. 

I have lived through the discoveries of identifying my genes as made of DNA, and we are now capable of sequencing them and understanding what they do. Each finding adds to both our medical knowledge for pathologists and to basic science in understanding how a living organism works.  

I would not be surprised to see experiments that will produce synthetic multicellular organisms using genes from different organisms to produce differentiated cells for each task desired. It will be a biological engineering that goes beyond applications to the pharmaceutical industry. Think of them as microscopic or miniature tools. Imagine tools snipping away tumors less than a millimeter in diameter. Imagine such tools extracting and expelling miniature pellets of gold and rare metals from ocean water. 

For those who worry about unintended consequences of applied science, two things are important to consider. Such experiments should be well regulated by ethical and safety review boards by universities, hospitals and corporations. The odds of such synthetic organisms are remote. Similar safety concerns in the 1980s accompanied the development of genetically modified bacteria and yeast cells, which today continue to produce human insulin for diabetics, human growth hormone for children with pituitary hormone deficiencies and hundreds of other modifications.  

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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