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Power of 3

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Gábor Balázsi. Photo by Dmitry Nevozhay

By Daniel Dunaief

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

Similarly, genes in yeast respond to changes in temperature.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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Francis Alexander. Photo from BNL

By Daniel Dunaief

Now what? It’s a question that affects everyone from the quarterback who wins the Super Bowl — who often says something about visiting a Disney facility — to the student who earns a college degree, to the researcher who has published a paper sharing results with the scientific community.

For some, the path forward is akin to following footsteps in the snow, moving ever closer to a destination for which a path is clear. For others, particularly those developing new technology, looking to unlock mysteries, the path is more like trudging through unfamiliar terrain.

The technology at facilities like Brookhaven National Laboratory, which includes the powerful National Synchrotron Light Source II and the Center for Functional Nanomaterials, among others, enables scientists to see processes at incredibly fine scales.

While these sites offer the promise of providing a greater ability to address questions such as what causes some batteries to die sooner than others, they also cost considerable money to use, putting pressure on researchers to ask the most fruitful question or pursue research that has the greatest chance for success.

Francis Alexander. Photo from BNL

That’s where people like Francis Alexander, the deputy director of Brookhaven National Laboratory’s Computational Science Initiative, and his team at BNL can add considerable value. Alexander takes what researchers have discovered, couples it with other knowledge, and helps guide his fellow laboratory scientists to the next steps in their work — even if he, himself, isn’t conducting these experiments.

“Given our theoretical understanding of what’s going on, as imperfect as that may be, we take that understanding — the theory plus the experimental data — and determine what experiments we should do next,” Alexander said. “That will get us to our goal more quickly with limited resources.”

This approach offers a mutually reinforcing feedback loop between discoveries and interpretations of those discoveries, helping researchers appreciate what their results might show, while directing them toward the next best experiment.

The experiments, in turn, can either reinforce the theory or can challenge previous ideas or results, forcing theoreticians like Alexander to use that data to reconstruct models that take a wide range of information into account.

Alexander is hoping to begin a project in which he works on developing products with specific properties. He plans to apply his knowledge of theoretical physics to polymers that will separate or grow into different structures. “We want to grow a structure with a [particular] function” that has specific properties, he said.

This work is in the early stages in which the first goal is to find the linkage between what is known about some materials and what scientists can extrapolate based on the available experiments and data.

Alexander said the aerospace industry has “models of everything they do.” They run “complex computer simulations [because] they want to know how they’d design something and which design to carry out.”

Alexander is currently the head of a co-design center, ExaLearn, that focuses on exascale, machine-learning technologies. The center is the sixth through the Exascale Computing Project. Growth in the amount of data and computational power is rapidly changing the world of machine learning and artificial intelligence. The applications for this type of technology range from computational and experimental science to engineering and the complex systems that support them.

Ultimately, the exascale project hopes to create a scalable and sustainable software framework for machine learning that links applied math and computer science communities to create designs for learning.

Alexander “brings to machine learning a strong background in science that is often lacking in the field,” Edward Dougherty, a distinguished professor in the Department of Electrical and Computer Engineering at Texas A&M, wrote in an email. He is an “excellent choice to lead the exascale machine learning effort at Brookhaven.”

Alexander is eager to lead an attempt he suggested would advance scientific and national security work at the Department of Energy. “There are eight national laboratories involved and all the labs are on an equal level,” he said. 

One of the goals of the exascale computing project is to build machines capable of 10 to the 18th operations per second. “There’s this enormous investment of DOE” in this project, Alexander said.

Once the project is completely operational, Alexander expects that this work will take about 30 percent of his time. About 20 percent of the time, he’ll spend on other projects, which leaves him with about half of his workweek dedicated to management.

The deputy director recognizes that he will be coordinating an effort that involves numerous scientists accustomed to setting their own agenda.

Dougherty suggested that Alexander’s connections would help ensure his success, adding that he has “established a strong network of contacts in important application areas such as health care and materials.

The national laboratories are akin to players in a professional sporting league. They compete against each other regularly, bidding for projects and working to be the first to make a new discovery. Extending the sports metaphor, members of these labs often collaborate on broad projects, like players on an all-star team competing against similar teams from other nations or continents.

Alexander grew up in Ohio and wound up working at Los Alamos National Laboratory in New Mexico  for over 20 years. He came to BNL in 2017 because he felt he “had the opportunity to build something almost from the ground up.” The program he had been leading at Los Alamos was large and well developed, even as it was still growing. 

The experimental scientists at BNL have been receptive to working with Alexander, which has helped him achieve some of his early goals.

Ultimately, Alexander hopes his work increases the efficiency of numerous basic and applied science efforts. He hopes to help experimental scientists understand “what technologies we should develop that will be feasible” and “what technologies would be most useful to carry experiments out.”

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Above, Brian Colle, who enjoys surf fishing, with a false albacore that he caught at the Shinnecock Inlet. Photo by B. Colle

By Daniel Dunaief

In August of 2014, Islip experienced record rainfall, with over 13 inches coming down in a 24-hour stretch — more than the typical rainfall for an entire summer and a single day record for New York state. The rain required emergency rescues for motorists whose cars suddenly died after more than 5 inches of rain fell in a single hour.

What if, however, that rain had fallen just 50 miles west, in Manhattan, where the population density is much higher and where people travel to and from work on subways that can become flooded from storms that carry less precipitation?

An image of an ice crystal Colle examined during a Nor’easter. Image from B. Colle

Brian Colle, professor of atmospheric sciences and director of the Institute for Terrestrial and Planetary Atmospheres at the School of Marine and Atmospheric Sciences at Stony Brook University, is part of a group that is studying flood risks in the New York metro area during extreme storms that could bring heavy rains, storm surge or both. The team is exploring mitigation strategies that may help reduce flooding.

“The risk for an Islip event for somewhere in the NYC-Long Island area may be about one in 100 years (but this is being further quantified in this project), and this event illustrates that it is not a matter of whether it will occur in NYC, but a matter of when,” Colle explained in a recent interview.

The group, which is led by Brooklyn College, received $1.8 million in funding from New York City’s Department of Environmental Protection and the Mayor’s Office of Recovery & Resiliency. It also includes experts from The New School, the Stevens Institute of Technology and Colorado State University.

The co-principal investigators are Assistant Professor Brianne Smith and Professor Jennifer Cherrier, who are in the Department of Earth and Environmental Sciences at Brooklyn College–CUNY.

Smith, who had worked with Colle in the past, had recruited him to join this effort. They had “been wanting to do studies of flooding for New York City for a long time,” Smith said. “When the city came out with this” funding for research, Colle was “the first person I thought of.”

Malcolm Bowman, a distinguished service professor at Stony Brook University, holds his colleague, whom he has known for a dozen years, in high regard. Colle is “a leading meteorologist on regional weather patterns,” he wrote in an email. 

Colle is interested in the atmospheric processes that produce rainfall of 2 or 3 inches per hour. “It takes a unique part of the atmosphere to do that,” he said. The three main ingredients are lots of moisture, lift along a wind boundary, and an unstable atmosphere that allows air parcels, or a volume of air, to rise, condense and produce precipitation.

Representatives from the local airports, the subway systems and response units have been eager to get these predictions, so they can prepare mitigation efforts.

Brooklyn College – CUNY project co-leads Brianne Smith (left) and Jennifer Cherrier at Grand Army Plaza in Brooklyn in early September. Photo by John Mara

This group has taken an ambitious approach to understanding and predicting the course of future storms. Typically, scientists analyze storms using 100- to 200-kilometer grid spacing. In extreme rainfall events during coastal storms, scientists and city planners, however, need regional spacing of 20 kilometers. Looking at storms in finer detail may offer a more realistic assessment of local precipitation.

Researchers are anticipating more heavy rainfall events, akin to the one that recently caused flooding in Port Jefferson.

A warmer climate will create conditions for more heavy rains. Water vapor increases about 6 to 7 percent for every degree increase in Celsius. If the climate rises two to four degrees as expected by the end of the century, this would increase water vapor by 13 to 25 percent, Colle said.

The group includes experts from several disciplines. “Each of the scientists is highly aware of how integrative the research is,” Cherrier said. The researchers are asking, “How can we provide the best scientific foundation for the decisions” officials need to make. If, as predicted, the storms become more severe, there will be some “hard decisions to make.”

Smith suggested that a visible project led by women can encourage the next generation of students. Women undergraduates can appreciate the opportunity their female professors have to lead “cool projects,” she said. 

Raised from the time he was 4 in Ohio, Colle said he was a “typical weather geek” during his childhood. The blizzard of 1978 fascinated him. After moving to Long Island in 1999, Colle used to sit in a weather shed and collect ice crystals during nor’easters. He would study how the shape of these crystals changed during storms. An avid surf fisherman, Colle said there is “not a better place to observe weather” than standing near the water and fishing for striped bass, fluke, bluefish and false albacore. A resident of Mount Sinai, Colle lives with his wife Jennifer, their 16-year-old son Justin and their 13-year-old son Andrew.

As for his work on flood risks around the New York metro area, Colle said the group is producing monthly reports. The effort will end in December. “The urgency is definitely there,” he acknowledged. Heavy rainfall has increased the need to understand rain, particularly when combined with surge flooding.

A transportation study written over a decade ago describes storm surge and rainfall risk. That study, however, included a prediction of 1 to 2 inches of rainfall an hour, which is far less than the 5 inches an hour that hit Long Island in 2014.

“Once you start seeing that, there’s a lot of people who are nervous about that risk and want to get a best estimate of what could happen,” Colle said.

Cherrier described New York City as being “quite progressive” in gathering information and formulating data. “The city wants to be prepared as soon as possible.”

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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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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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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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