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Power of Three

From left, Brenna Henn and Meng Lin at a conference last year in New Orleans. Photo from Meng Lin

By Daniel Dunaief

The story of the genetics of skin pigmentation in humans may have even more layers than the skin itself, depending on how close people live to the equator. The conventional wisdom for skin pigmentation is that it is a relatively simple trait, with a small number of genes accounting for almost half of the variety of skin tones.

That, however, isn’t always the case. Pigmentation genetics likely becomes more complex in populations near the equator or with greater variation in pigmentation, like with the Khoisan living in southern Africa.

Above, Brenna Henn, right, with an elder in the Khomani San community who gave her a book on the language formerly spoken in the southern Kalahari Desert. Photo from Brenna Henn

“As you move further toward the equator, the distributions are wide,” Brenna Henn, an assistant professor in the Department of Ecology and Evolution at Stony Brook University, said about the results she, along with collaborators from her lab and from Stanford University, recently published in the journal Cell.

Exploring the genetic determination of skin can serve as a model to understand the broad implications for various genetic variations for different populations as they confront a range of health challenges.

Henn has also worked with tuberculosis studies in South Africa. About one in three people in the world has a latent tuberculosis infection. Researchers have conducted studies to see which genes might be responsible for the different reactions to this disease. Tuberculosis susceptibility studies indicate that different genes may be responsible for infection in different populations, in areas including Russia, West Africa and South Africa.

According to Henn, scientists need to study and understand the disease in different populations to identify, through gene interactions, who will benefit from specific treatments in a vaccination campaign.

When Henn, who is a native of California, started the pigmentation study seven years ago when she was a graduate student at Stanford University, she had considerably different expectations. “When I was a post doc at Stanford, I expected the project to be quick because the genetics of pigmentation in Europeans was relatively well understood,” she explained in an email. When she started analyzing the results, she found that her hypothesis “was not true at all. There are so many different things involved.”

Calling this analysis the “tip of the iceberg,” Henn said she discovered many new genes beyond the ones scientists already knew contributed to skin pigmentation. She estimates that there are 50 if not more genetic sequences involved in skin pigmentation near the equator.

The range of skin pigmentation in South African populations reflected this increased genetic blueprint, with people in these areas demonstrating about twice the variation as people might encounter in a western European population.

These studies require the analysis of considerable data, through a field called bioinformatics, in which researchers analyze and process information through programs that search for patterns. “There’s a huge computational component” to this work, Henn said. “We don’t know where the genes are. We have to sample the entire genome” for as many as 500 people. “This blows up into a computational problem.”

Above, from left, Meng Lin and Brenna Henn at Lin’s graduation ceremony where she earned her PhD. Photo from Brenna Henn

Meng Lin, who worked in Henn’s lab for four and a half years and recently earned her doctorate, performs just such analyses. “We were hoping we’d be able to find some signals that had never been found before, to demonstrate the difference” in the genetic architecture, said Lin, who is now applying for postdoctoral research positions. “Given the prior studies on skin pigmentation traits, the complexity of the genetic architecture we found out was unexpected.”

People near the equator would likely need to have pigmentation that balanced between producing vitamin D from sunlight with protecting their skin from too much exposure to ultraviolet light. In areas such as in Africa, the ultraviolet light can be so strong that “the primary selection factor would be to avoid the photo damage from the strong UV, which favors melanin enriched dark skin pigmentation for photo protection,” Lin explained in an email.

Generally, people further from the equator, such as Scandinavian populations, have lighter skin because they need to process the limited vitamin D they can get, particularly during the darker months. That, however, isn’t the case for the Inuit people, who have darker skin in an area that gets limited sunlight. “Anyone who lives there should be under pressure for light skin,” Lin said. The Inuit, however, are darker skinned, which might be because their diet includes fish and fish oil, which is a rich source of vitamin D. “That would relax the selection force on lighter skin color,” she said.

With people able to travel and live in a wide range of regions across the Earth, selection pressures might be harder to decipher in the modern world. “Travel across continents is a recent” phenomenon, Lin said. The history of such travel freedom is “way too short for changing the genetic components.” Selection pressure occurs over tens of thousands of years, she added.

Diversity and the intake of vitamin D interact closely with each other. They can have impacts on the balance point. Using vitamin supplements could relax the selection on lighter skin, so the balance might shift to a darker population, Lin explained. Other modern lifestyles, such as wearing clothes, staying indoors and consuming vitamin D could complicate this and relax the strength of selection in the future, she added.

A native of China, Lin lives in Port Jefferson Station and enjoys applying math and computer skills to biology. “It’s great fun to solve the questions we have by developing and applying computational methods to existing data,” she said.

After five years at Stony Brook, Henn is transitioning to a position at the University of California at Davis, where she hopes to continue this ongoing work. “We want to follow up on how quickly these selective events occur,” Henn said. She’d like to discover how long it takes for the genetic average of the population to shift.

From left, Yuxin Xia, Luke Papazian, Manuela Corcho, Johnny Donza and their thesis advisor Harold Walker. Photo from Johnny Donza

By Daniel Dunaief

Yuxin Xia and Johnny Donza

Johnny Donza wants to use the training he’s received as an engineering undergraduate at Stony Brook University to help people 8,600 miles and another continent away in Madagascar.

The group leader of a senior project, Donza is working with Yuxin Xia, Luke Papazian and Manuela Corcho to design and hopefully help build a bridge that will cross a stream on the outskirts of the village of Mandrivany. People living in that village had been walking across a log that has broken to buy and sell food or get to a hospital.

“I wanted to be involved in something that would make an impact,” said Donza, who is studying civil engineering with a concentration in structural engineering. This project presented an opportunity to help “people on the opposite side of the world. I thought that was pretty cool.”

Donza’s project is one of 15 senior design efforts that arose from a collaboration between Stony Brook and a group called BeLocal. The company sent Stony Brook graduates Acacia Leakey and Leila Esmailzada to collect video footage this summer in Madagascar. They hoped to return with the kind of information about the needs and resources of the people they met.

“These projects create the perfect opportunity for students to manage a real engineering project,” Harold Walker, professor and chair of the Department of Civil Engineering, explained in an email. Walker is Donza’s senior advisor on the project. “The experience the students have with these projects will be invaluable as they start their engineering careers.”

Acacia Leakey, on left

Walker said he initially expected to have one team of four to five students work with BeLocal in Civil Engineering. Instead, 13 students signed up. Walker spoke with Leakey and they decided to divide the students into three teams, each of which is working on different types of bridges. “If the bridge design can be implemented locally in Madagascar, this will improve the safety of river crossings and also provide the community [with] greater access to education and other opportunities,” he continued. “A bridge may seem like a simple thing but it can really be transformative.”

In addition to the bridge project Donza and his teammates are developing, Stony Brook teams are working on projects including rice storage, rat control, rice processing and briquette manufacturing.

Eric Bergerson, one of the three founders of BeLocal along with Mickie and Jeff Nagel of Laurel Hollow, said the group was thrilled with the range and scope of the projects. The response is “overwhelming,” Bergerson said, and “we couldn’t be happier.” Bergerson is the director of research at the social data intelligence company TickerTags.

For their project, Donza’s group is exploring the use of bamboo to create the bridge. “Deforestation in the region is a major problem,” which reduces the ability to find and use hardwood, Donza said. “Bamboo grows rampantly, so there’s plenty of bamboo we can use.”

To gather information about the structural details about this material, Donza and his team are testing bamboo they harvested from the Stony Brook campus. Leakey, who is earning her master’s at SBU after she did a Madagascar senior design project last year, said using bamboo creates a useful supply chain. “It’s such a sustainable resource,” said Leakey, who speaks regularly with Donza and other project managers who are seeking additional information about how to use local resources to meet a demonstrated need in Madagascar.

The Stony Brook team is working to model its structure after the Rainbow Bridge, which is an ancient Chinese bridge. The Rainbow Bridge has a longer span and has a more exaggerated arch than the one Donza and his classmates are designing. The group plans to build a structure that will hold several people at the same time. During monsoon season, the stream below the bridge also floods. The design may need to include nails or bolts, creating a durable, longer-lasting bond between pieces of bamboo.

The team is also waiting to collect information about the soil around the stream, so they know what kind of foundation they can construct. In their design, they are trying to account for a likely increase in the population and future windy conditions.

Donza said he and his team are excited to make a meaningful contribution to life in Madagascar. “We’re not just doing this to graduate,” he said. “We’re doing this because we have a chance to help people. They need this bridge.”

Leila Esmailzada

The BeLocal approach to the collaborations with Stony Brook involves learning what people need by observing and interacting with them, rather than by imposing expectations based on experiences elsewhere. Esmailzada said they spoke with women about various materials because women were the ones using the charcoal and firewood.

At some point, BeLocal may also foster an exchange that allows students from Madagascar to come to Stony Brook to learn from their American counterparts while also sharing first-hand information about what might work in Madagascar. “It’d be great if we could get people to come” to Stony Brook, Bergerson said. “We’re just developing relationships with universities now.”

Leakey said Stony Brook students have shown genuine interest in life in Madagascar and, as a result, have found some surprises. People across various disciplines assume incorrectly that developing nations progress along the same technological path that America did, which leads them to the inaccurate expectation that Madagascar is 100 years behind the United States. When engineering students learned that “people in Madagascar have smartphones” with Twitter and Facebook accounts, “their jaws fall. It’s important to recognize that so you can realize it isn’t a simple story that you’re innovating for and that there is this mixture of technology that’s familiar in a lifestyle that’s unfamiliar.”

Even while these projects are still in the formative stages, with students continuing to gather information and refine their projects, Walker suggested they have already provided value to engineering students. “The students have already learned a great deal,” Walker explained. They appreciate how their classroom skills “can really transform the lives of people across the world.”

From left, BNL Staff Scientist Lihua Zhang, former postdoctoral researcher Vitor Manfrinato and BNL Senior Scientist Aaron Stein. Photo courtesy of BNL

By Daniel Dunaief

It took a village to build this particular village or, more precisely, a pattern so small it could fit thousands of times over on the head of a pin.

Working at Brookhaven National Laboratory’s Center for Functional Nanomaterials, a team of researchers wanted to exceed the boundaries of creating small patterns with finely honed features. The group included Aaron Stein, a senior scientist at CFN, Charles Black, the head of CFN, Vitor Manfrinato, a former postdoctoral researcher at BNL and several other key members of the BNL team. The team added a pattern generator that allowed them to control a microscope to create a pattern that set a record for drawing at the 1-nanometer scale.

Just for reference, the width of a human hair is about 80,000 to 100,000 nanometers. The size of the pattern is a breakthrough as standard tools and processes generally produce patterns on a scale of 10 nanometers. “We were able to push that by a factor of five or 10 below,” Stein said. “When you get to those small size scales, that’s pretty significant.”

In this case, the novelty that enabled this resolution originated with the idea of employing the scanning transmission electron microscope, which isn’t typically used for patterning to create these images. The scanning transmission electron microscope has an extraordinarily high resolution, while the pattern generator allowed them to control the patterns they drew and other aspects of the exposure.

Researchers at CFN are focusing on this spectacularly small world to manipulate properties such as chemical reactivity, electrical conductivity and light interactions. “This new development is exciting because it will allow other researchers to create nanomaterials at previously impossible size scales,” Kevin Yager, a group leader at CFN explained in an email. “There are numerous predictions about how materials should behave differently at a size scale at 1 to 3 nanometers. With this patterning capability, we can finally test some of those hypotheses,” he said.

Stein and the research team were able to create this pattern on a simple polymer, polymethyl methacrylate, or PMMA for short. “It’s surprising to us that you don’t need fancy materials to create these kinds of features,” said Stein. “PMMA is a common polymer. It’s Plexiglas. It’s kind of exciting to do something that is beyond what people have done” up until now.

One of the many possible next steps, now that the researchers have developed this proof of principle, is to apply this technique to a substance that might have commercial use. Taking the same approach with silicon, for example, could lead to innovations in electronics. “We can make them with a high clarity of patterns and sharp corners, which we can’t do with other techniques,” Stein said.

The BNL research team would “like to apply this to real world research,” which could include electronics and transistors, as well as photonics and plasmonics, he added. This project arose out of a doctoral thesis that Manfrinato was conducting. He is one of the many scientists who came to BNL, which isa Department of Energy funded user facility that provides tools to conduct research for scientists from around the world.

Manfrinato was a doctoral student in Professor Karl Berggren’s group at the Massachusetts Institute of Technology. In an email, Manfrinato explained that he was interested in pushing the resolution limits of e-beam lithography. “BNL has state of the art facilities and expert staff, so our collaboration was a great fit, starting in 2011,” he explained.

Other scientists thought it was worthwhile to continue to pursue this effort, encouraging him to “come here and work on this. It’s a home grown project,” Stein said. Manfrinato worked on his doctorate from 2011 to 2015, at which point he became a postdoctoral researcher at BNL. His efforts involved several groups, all within the Center for Functional Nanomaterials at BNL. Stein, Manfrinato and Black worked on the lithography part of the project, while Lihua Zhang and Eric Stach developed the microscopy. Yager helped the team to understand the processes by which they could pattern PMMA at such small scale lengths.

“No one or two of us could have made this happen,” Stein said. “That’s really the joy of working in a place like this: There are [so many] permutations for collaborating.” Indeed, the other scientists involved in this study were Yager; Zhang, a staff scientist in electron microscopy; Stach, the electron microscopy group leader at CFN; and Chang-Yong Nam, who assisted with the pattern transfer.

Manfrinato, who is now a research and development engineer at a startup company in the San Francisco Bay area, explained that this lithographic technique has numerous possible applications. Other researchers could create prototypes of their devices at a level below the 10-nanometer scale at CFN. Manfrinato interacts with the BNL team a few times a month and he has “exciting results to be further analyzed, explored and published,” he wrote in an email.

Stein said BNL would like to offer this patterning device for other users who come to BNL. Ultimately, researchers use materials at this scale to find properties that may vary when the materials are larger. Sometimes, the properties such as color, chemical reactivity, electrical conductivity and light interactions change enough to create opportunities for new products, innovations or more efficient designs.

A resident of Huntington, Stein and his wife Sasha Abraham, who works in the planning department for the Town of Huntington, have a 15-year-old daughter Lily and a 13-year-old son Henry.

As for his work, Stein said he’s interested in continuing to push the limits of understanding various properties of nanomaterials. “My career has been using the e-beam lithography to make all sorts of structures,” he said. “We’re in a regime where people have not been there before. Finding the bottom is very interesting. Figuring out the limits of this technique is, in and of itself” an incredible opportunity.

Priya Sridevi with her golden doodle Henry. Photo by Ullas Pedmale

By Daniel Dunaief

Priya Sridevi started out working with plants but has since branched out to study human cancer. Indeed, the research investigator in Cold Spring Harbor Laboratory Cancer Center Director David Tuveson’s lab recently became the project manager for an ambitious effort coordinating cancer research among labs in three countries.

The National Cancer Institute is funding the creation of a Cancer Model Development Center, which supports the establishment of cancer models for pancreatic, breast, colorectal, lung, liver and other upper-gastrointestinal cancers. The models will be available to other interested researchers. Tuveson is leading the collaboration and CSHL Research Director David Spector is a co-principal investigator.

The team plans to create a biobank of organoids, which are three-dimensional models derived from human cancers and which mirror the genetic and cellular characteristics of tumors. Over the next 18 months, labs in Italy, the Netherlands and the United States, at Cold Spring Harbor Laboratory, expect to produce up to 150 organoid models.

The project officially started in January and the labs have been setting up the process through June. Sridevi is working with Hans Clevers of the Hubrecht Institute, who pioneered the development of organoids, and with Vincenzo Corbo and Aldo Scarpa at the University and Hospital Trust of Verona.

Sridevi’s former doctoral advisor Stephen Alexander, a professor of biological sciences at the University of Missouri, said Sridevi has had responsibilities beyond her own research. She was in charge of day-to-day operations in his lab, like ordering and regulatory reporting on radioactive material storage and usage, while he and his wife Hannah Alexander, who was Sridevi’s co-advisor, were on sabbatical. “She is hard working and determined,” said Alexander. “She knows how to get things done.”

In total, the project will likely include 25 people in the three centers. CSHL will hire an additional two or three scientists, including a postdoctoral researcher and a technician, while the Italian and Netherlands groups will also likely add another few scientists to each of their groups.

Each lab will be responsible for specific organoids. Tuveson’s lab, which has done considerable work in creating pancreatic cancer organoids, will create colorectal tumors and a few pancreatic cancer models, while Spector’s lab will create breast cancer organoids.

Clevers’ lab, meanwhile, will be responsible for creating breast and colorectal organoids, and the Italian team will create pancreatic cancer organoids. In addition, each of the teams will try to create organoids for other model systems, in areas like lung, cholangiocarcinomas, stomach cancer, neuroendocrine tumors and other cancers of the gastrointestinal tract.

For those additional cancers, there are no standard operating procedures, so technicians will need to develop new procedures to generate these models, Sridevi said. “We’ll be learning so much more” through those processes, Sridevi added. They might also learn about the dependencies of these cancers during the process of culturing them.

Sridevi was particularly grateful to the patients who donated their cells to these efforts. These patients are making significant contributions to medical research even though they, themselves, likely won’t benefit from these efforts, she said. In the United States, the patient samples will come from Northwell Health and the Tissue Donation Program of Northwell’s Feinstein Institute of Medical Research. “It’s remarkable that so many people are willing to do this,” Sridevi said. “Without them, there is no cancer model.”

Sridevi also appreciates the support of the philanthropists and foundations that provide funds to back these projects. Sridevi came to Tuveson’s lab last year, when she was seeking opportunities to contribute to translational efforts to help patients. She was involved in making drought and salinity resistant rice and transgenic tomato plants in her native India before earning her doctorate at the University of Missouri in Columbia.

Alexander recalled how Sridevi, who was recruited to join another department at the University of Missouri, showed up in his office unannounced and said she wanted to work in his lab. He said his lab was full and that she would have to be a teaching assistant to earn a stipend. He also suggested this wasn’t the optimal way to conduct research for a doctorate in molecular biology, which is a labor-intensive effort. “She was intelligent and determined,” Alexander marveled, adding that she was a teaching assistant seven times and obtained a wealth of knowledge about cell biology.

Sridevi, who lives on campus at CSHL with her husband Ullas Pedmale, an assistant professor at CSHL who studies the mechanisms involved in the response of plants to the environment, said the transition to Long Island was initially difficult after living for six years in San Diego.

“The weather spoiled us,” she said, although they and their goldendoodle Henry have become accustomed to life on Long Island. She appreciates the “wonderful colleagues” she works with who have made the couple feel welcome.

Sridevi believes the efforts she is involved with will play a role in understanding the biology of cancer and therapeutic opportunities researchers can pursue, which is one of the reasons she shifted her attention from plants. In Tuveson’s lab, she said she “feels more closely connected to patients” and is more “directly impacting their therapy.” She said the lab members don’t get to know the patients, but they hope to be involved in designing personalized therapy for them. In the Cancer Model Development Center, the scientists won a subcontract from Leidos Biomedical Research. If the study progresses as the scientists believe it should, it can be extended for another 18 months.

As for her work, Sridevi doesn’t look back on her decision to shift from plants to people. While she enjoyed her initial studies, she said she is “glad she made this transition” to modeling and understanding cancer.

Front row, from left, Liliana Dávalos, Heather Lynch and Christine O’Connell; back row, from left, Robert Harrison, IACS director and STRIDE PI, Arie Kaufman, and Janet Nye. Photo from Stony Brook University

By Daniel Dunaief

If Stony Brook University has its way, the university will stand out not only for the quality of the research its graduate students produce but also for the way those budding scientists present, explain and interpret their results to the public and to policy makers.

Pulling together faculty from numerous departments across the campus, Robert Harrison, the director of the Institute for Advanced Computational Science, created a program that will teach graduate students how to use big data sets to inform difficult decisions.

The institute recently received a $3 million grant from the National Science Foundation Research Traineeship for this effort, called Science Training & Research to Inform DEcisions, or STRIDE. The grant will be used for students in the departments of Applied Mathematics and Statistics, Biomedical Informatics, Computer Science, Ecology and Evolution and the schools of Journalism and Marine and Atmospheric Sciences.

“This is unique,” said Arie Kaufman, a distinguished professor and chair of the Department Computer Science at Stony Brook. “It’s a new kind of approach to training and adding value to Ph.D. students.” Indeed, the students who complete the STRIDE training will earn their doctorates and will also receive a certificate for their participation in this program. Students in the participating departments will need to apply for one of the 10 positions available in the program next year. The partners involved in this program expect it to expand to 30 students within five years.

Kaufman said what enabled this collaboration was the range of skill sets across Stony Brook, including the Alan Alda Center for Communicating Science, which is a growing program that already offers the type of training more typical for an actor studying improvisation techniques than for a scientist studying neurotransmitters or DNA.

The Alda Center is “creating a new course,” said Christine O’Connell, an associate director at the center and assistant professor in the School of Journalism. She is currently working on developing the course description, which will include communicating to decision makers. O’Connell, who has a doctorate in marine and atmospheric sciences, sees her work with the Alda Center and with STRIDE as the “perfect combination in bringing the decision making piece to work with scientists to help them talk about their research.”

Scientists who take courses at the Alda Center with STRIDE learn how to understand their audience through various role-playing scenarios. They will also develop their abilities to present their goals or messages in a visual way and not just talk about their work.

Heather Lynch, an associate professor in the Department of Ecology and Evolution who is also a co-principal investigator on the STRIDE grant, will help design the program, mentor students and develop courses. She’s been involved with this proposal since its inception, over three years ago. “In many ways,” she explained in an email, “my interest stems from my own difficulties communicating effectively with policy makers, and finding tools and visualizations that are compelling to a non-scientist.” Lynch recounted her frustration with presenting science to help a policy making body, such as a committee, with the kind of analysis she believed they were seeking. After she did her best to answer the question, the committee sometimes dismissed her work as not being what they wanted. “That’s frustrating because that means I failed at the outset to define the science question and that’s what I hope we can teach students to do better,” Lynch explained.

Lynch said she wishes she had the training these students will be getting. For scientists, computers are an invaluable tool that can help delve into greater breadth and depth in analyzing, interpreting and collecting information. The STRIDE effort includes a greater awareness of the way computers can inform political or social science. Researchers generate “tremendous amounts of data that can be used to analyze trends or detect diseases,” Kaufman said. “The data science is tremendous in every discipline.”

The faculty who are a part of this program said they have already benefited from the interactions they’ve had with each other as they’ve developed the curriculum. “I know a few people in Ecology and Evolution and I know more people in Marine Sciences, but these particular individuals were new to me,” said Kaufman. “We have already been communicating about ideas for how to use the Reality Deck for other projects.”

Completed in late 2012, the Reality Deck is a $2 million rectangular room in the Center of Excellence in Information Technology building. The room has hundreds of monitors that cover the wall from floor to ceiling and provides a way for researchers to study images in exquisite detail.

Other scientists in the program include Liliano Dávalos, an associate professor in the Department of Ecology and Evolution, Janet Nye, an assistant professor in the School of Marine and Atmospheric Sciences, Joel Saltz, the founding chair of the Depatment of Biomedical Informatics, Erez Zadok, a professor in the Department of Computer Science and Mighua Zhang, a professor in the School of Marine and Atmospheric Sciences.

Lynch said the program will bring in people who are working on real-world problems, including those in government, industry and nongovernmental organizations who are “in a position to take science and use it for practical purposes.” As a part of the program, the scientists will monitor the progress of the STRIDE candidates, O’Connell said.

The evaluations will check to see if “they become better communicators and better at interpreting their data for different audiences,” O’Connell said. “The evaluation piece built in will help us assess the program.”

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