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Power of 3

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By Daniel Dunaief

We have to walk before we can learn to run. It’s a common metaphor that suggests learning new skills, like playing the bassoon, requires a comfort level with notes and scales before taking on complex compositions.

As it turns out, the expression also applies literally and evolutionarily to the part of our anatomy that is so instrumental in enabling us to walk and, eventually, run — the foot.

Carrie Mongle. Photo courtesy of SBU

Carrie Mongle, a doctoral candidate in the Interdepartmental Doctoral Program in Anthropological Sciences at Stony Brook University, recently joined a host of other researchers, including former SBU scientist Peter Fernandez and current clinical assistant professor in biomedical sciences at Marquette University, in a study on the evolution of bones in the foot that made the transition to a bipedal lifestyle possible.

Published in the journal Proceedings of the National Academy of Sciences (PNAS), the work by Fernandez, Mongle and other collaborators explored the forefoot joints of ancient hominins, looking at primitive primates from as far back as 4.4 million years ago.

By comparing the toe joint shapes of fossil hominins, apes, monkeys and humans, they were able to find specific bony shapes in the forefoot that are important in the development of bipedal locomotion — or walking on two feet.

“This study demonstrates that early hominins must have been able to walk upright for millions of years, since the 4.4-million-year-old fossil Ardipithecus ramidus, but that they did not fully transition to a modern walk until much later, perhaps in closer relatives within our own group, Homo,” Mongle explained in an email.

While modern humans are most pronounced in doming, a few primates that walk on the ground have similar foot biomechanics to bipedalism and have similar morphologies in their toes. Those, however, aren’t expressed exactly the same way because their toe bones look different from hominins generally, she explained.

Like the drawings so often associated with a knuckle-walking ancestor that transition to a familiar outline of a person walking, the foot also went through various stages of development, balancing between the need to grasp onto objects like tree limbs and an efficient ability to walk, and then run.

“The foot is a complex assemblage of bones, so it makes sense that not all of them would have changed at exactly the same time,” Mongle suggested. “Our study supports the hypothesis that the transition to bipedalism was a gradual, mosaic process.”

Mongle got involved in this study after discussions with Fernandez, who was at SBU two years ago when the work began. Fernandez suggested to her that, “If we team up together, we can combine our interests and answer some questions about this feature,” she recalled.

Fernandez and Mongle found this dome shape developed in the foot bone even as this early fossil still maintained the ability to grasp tree limbs or other objects.

Fernandez and several other researchers involved in the study collected the data from the fossils, while Mongle, who focuses on cranial morphology and teeth in her own research, performed the evolutionary modeling. “My role in this research was in analyzing and explaining the evolutionary models, which allowed us to reveal the timing and sequence of events that produced the modern human forefoot,” she explained.

As for her doctoral research, Mongle is broadly interested in updating the hominin family tree. She uses mathematical models to look at variations in the fossil record. She is currently studying a cave in South Africa, where researchers have been recovering fossils since the 1930s.The cave has a considerable number of teeth that are all blended together from a period of between 2.5 million and 3 million years ago.

The teeth could tell a more complete story about how human ancestors divided up the food and local resources available to them. If different species were in the same space, they might have divided up into different groups to relieve competitive stress.

Frederick Grine, the chairman in the Department of Anthropology at SBU, offered a strong endorsement of Mongle’s research.“I have no doubt whatever that her work on the cranium and the dentition will provide invaluable insights into human phylogeny,” he wrote in an email, calling her an “exceptionally gifted research scientist” and described her as having an “extremely keen intellect.”

One of Mongle’s overarching research questions is, “How did we become human?” Reconstructing the phylogenetic tree is an important part of that exploration.

While it isn’t central to her thesis work, Mongle appreciated the opportunity to explore the transition to bipedalism, which is one of the “major turning points” in the development of humans.

Mongle explained that several possibilities exist on why human ancestors might have stood upright and walked on two feet.

“One of the prevailing theories is that upright walking may have evolved because climate change led to a loss of forests,” she wrote in an email. “As a consequence of walking upright, we now have free hands to carry tools.

Bipedalism evolved from a type of locomotion that was already efficient, so the question of its evolution remains open and is “hotly debated,” Mongle explained.

The next steps, literally and figuratively, are to study other bones in the feet. “We only looked at one particular part of the foot,” she said. “We would like to expand these approaches to using other bones in the forefoot,” seeking patterns and changes that would also contribute to a bipedal lifestyle.

Mongle, who started her doctoral research in 2012, hopes to graduate from the program next May, at which point she will be looking for postdoctoral research opportunities.

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Ute Moll. Photo courtesy of Stony Brook University

By Daniel Dunaief

In the battle against cancer, human bodies have built-in defenses. Cancers, however, can hijack those systems, turning them against us, not only allowing them to avoid these protective systems, but converting them into participants in a process that can often become fatal.

Such is the case for the p53 gene. One of the most closely studied genes among researchers and clinicians, this gene eliminates cells with damaged DNA, which could turn into cancer. Mutations in this genetic watchdog, however, can turn this genetic hero into a villainous cancer collaborator. Indeed, changes in the genetic code for p53 can allow it to produce a protein that protects cancer from degradation.

Ute Moll. Photo courtesy of SBU

Ute Moll, professor and the vice chair for research in the Department of Pathology at the Stony Brook University School of Medicine, has made important strides in studying the effect of mutations in this gene over the last five years, demonstrating how the altered gene and the protein it creates are an important ally for cancer.

Moll published her most recent finding in this arena in the journal Cancer Cell. The Stony Brook scientist, working with an international team of researchers that included collaborators from her satellite lab at the University of Göttingen, advanced the work on previous results.

This research, which is done on mice that develop tumors through a process that more closely resembles human cancer growth, is a “very good mimic in the molecular and clinical features of human colon cancer,” Moll said.

The main research was done on a faithful mouse model of human colorectal cancer that produces mutant p53, Moll explained. She then confirmed key findings in human colon cancer cells and in survival analysis of patients.

This model allowed Moll to “study tumors in their natural environment in the intact organism with its tumor surrounding connective tissue and immune system,” Ken Shroyer, the chairman of the Department of Pathology at SBU School of Medicine, explained in an email.

The tumors that develop in these mice are driven by mutant p53 and are dependent on it for their continued growth. “These tumors overexpress mutant p53 at high levels,” which makes them a “formidable drug target for their removal,” Moll said.

By deleting the mutant p53 gene, she was able to slow and even stop the progression of the cancer. “We can show that when we remove mutant p53 either genetically or pharmacologically, we are cutting down invasiveness.” Mice with deleted mutants had fewer and smaller tumors and showed over a 50 percent reduction in invasive tumor numbers, she explained.

Finding ways to mitigate the effect of mutant p53 is important for a wide range of cancers. The mutated version Moll studied is the single most common p53 mutation in human cancer, which has a mutation that switches an amino acid for an incorrect one. This amino acid change destroys the normal function of the p53 gene.

The mutation she studies represents about 4.5 percent of all cancers. That amounts to 66,000 cancer patients in the United States each year.

More broadly, mutations in p53 in general, including those Moll didn’t study, are involved in half of all human cancers, Shroyer explained, which makes it the “single most common cancer mutation.”

Yusuf Hannun, director of the Stony Brook University Cancer Center, suggested that the work Moll did could have important clinical implications.“The deciphering of this mechanism clearly indicates new cancer therapy possibilities,” Hannun wrote in an email. The models she worked with are “quite promising.”

In addition to finding ways to stop the progression of cancer in mice with this damaged gene, Moll and her colleagues also used an Hsp90 inhibitor, which blocks a protein that protects the mutant protein from being degraded.

Inhibiting this protein has other positive effects, as the inhibitor eliminates other co-mutant proteins that could also drive tumors. “We are hitting multiple birds with one stone,” Moll said.

Hsp90 inhibitors are a “complicated story” in part because they have strong side effects in the liver and the retina. Researchers are working on the next generation of inhibitors.

A class of anti-cholesterol drugs called statins, which Moll called “one of the blockbuster drugs of medicine,” also has mutant p53 degrading effects, which work against some mutants, but not in others. The benefits are inconsistent and involve confounding variables, which makes interpreting their usefulness difficult, she added.

Moll said her recent article in Cancer Cell has triggered a number of email exchanges with a range of people, including with a patient whose cancer involved a different type of mutation. She has also had discussions with researchers on several other possible collaborations and has started one after she published her recent work.

The scientist is hopeful that her studies will continue to contribute to an understanding of the development and potential treatment of cancer.

Degrading mutant p53 has shown positive results for mice, which indicates “in principle” that such an approach could work down the road in humans, she suggested.

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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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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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Stephanie Maiolino. Photo by Elizabeth Anne Ferrer

By Daniel Dunaief

This one’s a head scratcher, literally.

For years, people assumed early primates — small creatures that lived 55 million years ago — had nails. That, however, is not the complete story, as Stony Brook University Assistant Professor Stephanie Maiolino and a team of researchers discovered.

In addition to nails, which lay flat on our fingers and which make it easy to scratch an itch after a mosquito bite, earlier primates had something called grooming claws. These claws, which were on the toes next to their big toes, allowed them to remove external parasites like ticks and lice, which likely helped them survive against an onslaught of various critters eager to steal, or even infect, some of their blood.

Maiolino, who is in the Department of Anatomical Sciences at SBU, teamed up with lead author Douglas Boyer, an associate professor in the Department of Evolutionary Anthropology at Duke University; Johnathan Bloch, the Florida Museum of Natural History curator of vertebrate paleontology at University of Florida; Patricia Holroyd, a senior museum scientist at UC-Berkeley’s  Museum of Paleontology; and Paul Morse, from the Florida Museum of Natural History at the University of Florida at Gainesville to report their results recently in the Journal of Human Evolution.

“It was generally assumed that only a certain type of primate had grooming claws,” Maiolino said. “Finding these structures was quite surprising.”

Maiolino spent considerable time during her doctoral work, which she conducted at SBU prior to becoming an instructor at the university, analyzing the differences in the bones of species that have nails, claws and grooming claws. By understanding the anatomical features of the phalanges — or fingers and toes — leading up to the claws or nails, Maiolino was able to go back into the fossil record to explore the prevalence of these digit protrusions.

Oftentimes, she suggested, researchers collect a bone, or even a fragment of a bone, in which a nail or claw is almost never preserved in the fossil record. Maiolino used her analysis to extrapolate the parts that extend beyond the remaining fossils.

While nails sit on the end of fingers, grooming claws stick up, which puts them in an ideal position for combing through hair, which would allow the primates to remove pests that could compromise their health or threaten their survival.

“From a functional standpoint, it’s often overlooked how important the need to remove these parasites [is],” she said. When people see lemurs whose ears are completely covered in ticks or they hear about dogs that have so many ticks on them that the dog is at risk of dying, they recognize that “having an adaptation to help you remove them is actually surprisingly a big deal.”

Like any other adaptation, however, the development of these grooming digits comes with a cost. Instead of having that digit available for locomotion or grasping branches, it becomes more useful in removing unwanted insects. “There are significant pressures shaping the feet of these primates,” said Maiolino.

To provide some perspective on the importance of grooming claws, Maiolino highlighted how the primates from the fossil record were not much bigger than a mouse. Having less blood because they are smaller than current primates, and dealing with ticks that are closer to their size, suggests that the health consequences of an infestation are much greater.

As primates became more social — interacting with other members of their species and taking turns grooming each other — the pressure to have these grooming claws may have reduced.

Nonetheless, Maiolino said, a few primates that spend hours each day picking ticks off each other in a process called allogrooming still have these claws. “Some of the animals that do have [the claws] groom each other considerably,” she said, which suggests that there is still work to do to understand the evolution of these features.

When Maiolino and her collaborators first started exploring the claws versus nails discussion, they knew that researchers believed anthropoids didn’t have them.

“Now we know that anthropoids did,” she said. “We’re getting more of a sense of the distribution” of these claws.

From here, Maiolino would like to continue to explore the evolutionary trajectory from claw-bearing nonprimates to nail-bearing primates. There are a “lot of questions about why early primates ended up evolving nails in the first place,” she said.

William Jungers, a distinguished professor emeritus at Stony Brook University who was Maiolino’s doctoral thesis adviser, described her as “an outstanding and innovative young scientist with a very bright future as an educator and comparative anatomist.” He said Maiolino uses “cutting edge imaging methods to advance our understanding of primate origins and paleobiology, especially the evolution of unique aspects of primate hands and feet.”

Jungers explained that claws and nails are the “key features linked to both locomotion and social behavior.”

Maiolino, who currently lives in Port Jefferson, said when she visits zoos, she’s always on the lookout for the way primates and other mammals use their nails or claws. She also studies photographs and videos.

When she first started graduate school, Maiolino was much more interested in skulls than in nails. Once she linked nails and claws, however, to questions about primate origins, she became much more interested in them.

Outside of the lab, Maiolino said she enjoys watching horror movies. One of her favorites is the second “Aliens” film in the Signourney Weaver centered franchise. She is also a fountain pen enthusiast.

Back in high school in New Jersey, Maiolino  was especially interested in studying evolution. Embryology and embryological development appealed to her, as she was amazed by how growth in the womb affected what organisms became.

As for her work, a Holy Grail question for her would be to better understand why primates developed nails in the first place. She’s trying to understand the interplay between body size, behavior and other variables that affected these structures.

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Camila dos Santos speaks at the Pershing Square Research Alliance’s Fifth Annual Prize Dinner at the Park Avenue Armory on May 23 with Bill Ackman, co-founder of the Pershing Square Sohn Foundation and CEO of Pershing Square Capital Management, and Olivia Tournay Flatto, the President of the Pershing Square Foundation.

By Daniel Dunaief

They aren’t quite wonder twins, but some day the dedicated work of husband and wife scientists Christopher Vakoc and Camila dos Santos may help people batting against a range of cancers, from leukemia to breast cancer.

An assistant professor at Cold Spring Harbor Laboratory, dos Santos recently won the prestigious and highly coveted Pershing Square Sohn prize. Dos Santos, who studies breast cancer, will receive $200,000 in funds per year for the next three years. She won the same prize her husband, an associate professor at Cold Spring Harbor Laboratory, collected two years earlier for his work using the gene-editing technique CRISPR to study the molecular pathways involved in leukemia.

Dos Santos and Vakoc are the first family of prize winners in the Pershing Square Foundation’s five years of supporting research in the New York area.“The board was very much taken by how original her approach is and how thoughtful she is about it,” said Olivia Tournay Flatto, president of the foundation. “There was a lot of early stage data that would say that the observations she’s making are interesting to pursue, but that the National Institutes of Health would not fund. We felt this was something we wanted to be a part of.”

Dos Santos is studying so-called epigenetic changes that protect women from breast cancer if they become pregnant before they are 25. Women who have pregnancies before that cut-off age have a 30 to 40 percent decrease in breast cancer, even decades after their pregnancy.

Dos Santos has been digging into this process, looking at why some women who are pregnant before this age still develop breast cancer later in life.

The Cold Spring Harbor scientist is exploring how infections block the protective effects of pregnancy. She hasn’t defined the panel of infections that could influence cancer risk before or after pregnancy. The hypothesis in her work is that “the whole process that is fighting inflammation could change the breast cells,” which could “take away the advantage that pregnancy brings.”

If she proves her theory — that changes to inflammation could take away benefits of an early pregnancy — she could define changes to proteins and genes as biomarkers to predict the risk of breast cancer, even in the event of an early pregnancy. One of the challenges in the three-step application process for this prize was to explain to a group of experts how what she’s doing was different from what others are pursuing. Her approach is to look at cells before and during the process of turning into cancer cells. That strategy led to the current hypothesis, which was the basis for her application for this prize.

To study breast cancer, dos Santos recently developed a mouse model in her lab, to see how pregnancy changes pre-malignant lesions. When the mice they are studying have a gene that would turn into cancer, some of them don’t develop cancer if they’ve already been pregnant. Those mice that haven’t been pregnant develop cancer. She uses this mouse model to ask questions about how pregnancy changes a cell such that oncogenes cannot operate to change a cell into a cancer.

“We are not only investigating how prevention works, but we are also learning what signals break that prevention,” dos Santos said.

Dos Santos has used the mouse model experiments to test an unusual element to human breast cancer resistance. Women who reach their second trimester before 25, but don’t give birth to a child, have the same resistance, decades later, to breast cancer. Mice whose pregnancies last through the equivalent of the second trimester also experience similar epigenetic benefits.

She has tested mice who have a pseudo-pregnancy —who have higher pregnancy hormone levels without being pregnant — to see if a similar pregnancy environment would convey the same resistance. “Even in those cases, with no fetus, no embryo, no birth and no nursing, we see that the epigenetics changes,” dos Santos said. The scientist plans to use the funds from this award to perform high-tech experiments, such as single-cell, multiple mouse models and human tissue analysis that she wouldn’t have been able to tackle without the funding.

Dos Santos is grateful for the funding, which she said she wouldn’t have been able to secure through other means based on “the stage we are right now,” she said. The work is “risky” and “provocative,” but it’s also “outside of the box ideas and experiments and approaches.”

When she puts all the variants together, the risky outcome could be beneficial, leading to a better understanding of how to copy or, perhaps, understand nature to try to cure or prevent cancer.

Dos Santos said she learned about the award when she was on a train on the way to Jamaica, where she was catching a flight to Washington, D.C. She said she turned into a “texting machine,” sharing the good news with everyone, including her husband Vakoc, who called her as soon as he saw the news. “He was super happy,” she recalled.

She said Vakoc was particularly helpful in discussing the work and in watching their sons Lucas and Marcus who are 8 and 5, respectively. She also received some unexpected help from him before an extensive seven- to eight-minute finalist screening process.

She asked him about the interview, and he remembered that there were five people in the audience and that he didn’t get that many questions. When she appeared for her interview, she saw about 25 people in the audience and received numerous questions. In a way, she said, his memory of his experience may have helped her, because she didn’t have time to worry about the size of the audience or the number of questions.

Dos Santos said their sons are proud of their parents for winning awards for their work on cancer.

When her sons are upset with dos Santos, they sometimes warn, reflecting their parents’ threat to take away TV, that they’re going to “take your epigenetics away.”

Dos Santos said the couple maintains a healthy work-life balance. She is grateful for her husband’s support, as well as for the environment and expertise at Cold Spring Harbor Laboratory.

“Here at the lab, we not only have the technology to move this forward, but we also have a pretty outstanding body of scientists that are very collaborative,” she said.

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By Daniel Dunaief

Replacing batteries in a flashlight or an alarm clock requires simple effort and generally doesn’t carry any risk for the device. The same, however, can’t be said for battery-operated systems that go in human bodies and save lives, such as the implantable cardiac defibrillator, or ICD.

Earlier versions of these life-saving devices that restore a normal heart rhythm were large and clunky and required a change of battery every 12 to 18 months, which meant additional surgeries to get to the device.

Esther Takeuchi with Michaëlle Jean, the secretary general of the Organisation Internationale de la Francophonie, and moderator Fernando Tiberini at the award ceremony in Paris on June 7. Photo courtesy of European Patent Office

That’s where Esther Takeuchi, who is now Stony Brook University’s William and Jane Knapp Endowed Chair in Energy and the Environment and the chief scientist of the Energy Sciences Directorate at Brookhaven National Laboratory, has made her mark. In the 1980s, working at a company called Greatbatch, Takeuchi designed a battery that was much smaller and that lasted as long as five years. The battery she designed was a million times higher power than a pacemaker battery.

For her breakthrough work on this battery, Takeuchi has received numerous awards. Recently, the European Patent Office honored her with the 2018 innovation prize at a ceremony in Paris. Numerous high-level scientists and public officials attended the award presentation, including former French Minister of the Economy Thierry Breton, who is currently the CEO of Atos, and the Secretary General of the International Organisation of Francophony Michaëlle Jean. 

Takeuchi was the only American to win this innovation award this year.

Takeuchi’s work is “the epitome of innovation, as demonstrated in this breakthrough translational research for which she was recognized,” Dr. Samuel L. Stanley Jr., the president of Stony Brook and board chair of Brookhaven Science Associates, which manages Brookhaven National Laboratory. “Her star keeps getting brighter, and I’m proud that she is part of the Stony Brook University family.”

As a winner of this award, Takeuchi joins the ranks of other celebrated scientists, including Shuji Nakamura, who won the European Inventor Award in 2007 and went on to win the Nobel Prize in physics, and Stefan Hell from Germany, whose European Inventor Award predated a Nobel Prize in chemistry. 

Among the over 170 innovators who have won the award, some have worked on gluten substitutes from corn, some have developed drugs against multi-drug-resistant tuberculosis, and some have developed soft close furniture hinges.

“The previous recipients have had substantial impact on the world and how we live,” Takeuchi explained in an email. “It is incredible to be considered among that group.” Nominated for the award by a patent examiner from the European Patent Office, she described the award as an “honor” for the global recognition.

The inventor award is a symbolic prize in which the recipients receive attention for their work, explained Rainer Osterwalder, the director of media relations at the European Patent Office.

Takeuchi was one of four women to receive the award this year — the largest such class of women innovators.

“It was very meaningful to see so many accomplished women be recognized for their contributions,” she explained. “I was delighted to meet them and make some additional contacts with female innovators as well.”

About half the researchers in her lab, which currently includes three postdoctoral researchers and usually has about 12 to 16 graduate students, are women. Takeuchi has said that she likes being a role model for women and that she hopes they can see how it is possible to succeed as a scientist.

Implantable cardiac defibrillators are so common in the United States that an estimated 10,000 people receive them each month.

Indeed, while she was at the reception for an awards ceremony attended by over 600 people, Takeuchi said she met someone who had an ICD.

“It is very rewarding to know that they are alive due to technology and my contributions to the technology,” she explained.

Takeuchi said that many people contributed to the battery project for the ICD over the years who were employed at Greatbach. These collaborators were involved in engineering, manufacturing, quality and customer interactions, with each aspect contributing to the final product.

The battery innovation stacks alternating layers of anodes and cathodes and uses lithium silver vanadium oxide. The silver is used for high current, while the vanadium provides long life and high voltage.

Takeuchi, who earned her bachelor’s degree from the University of Pennsylvania and her doctorate from Ohio State University, has received over 150 patents. The daughter of Latvian emigrants, she received the presidential level National Medal of Technology and Innovation from Barack Obama and has been inducted into the National Inventors Hall of Fame.

Takeuchi continues to push the envelope in her energy research. “We are now involved in thinking about larger scale batteries for cars and ultimately for the grid,” she wrote in an email. “Further, we have demonstrated methods that allow battery components to be regenerated to extend their use. This could potentially minimize batteries going into land fills in the future.”

Takeuchi is one of a growing field of scientists who are using the high-tech capabilities of the National Synchrotron Light Source II at BNL, which allows her to see inside batteries as they are working.

“We recently published a paper where we were able to detect the onset of parasitic reactions,” she suggested, which is “an important question for battery lifetime.”

In the big picture, the scientist said she is balancing between power and energy content in her battery research.

“Usually, when cells need to deliver high power, the energy content goes down,” she said. “The goal is to have high energy and high power simultaneously.”

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