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Daniel Dunaief

From left, scientist Lin Yang at the LiX beamline demonstrates how the beam hits the sample to high school teachers James Ripka, Mary Kroll, Fred Feraco, Janet Kaczmarek and Jocelyn Handley-Pendleton. Photo from BNL

By Daniel Dunaief

He helped build it and now a range of researchers are coming.

Lin Yang helped create the LiX beamline at the National Synchrotron Light Source II at Brookhaven National Laboratory, which is attracting researchers eager to study the fine structure and function of everything from proteins to steel.

The lead scientist for the LiX beamline at the NSLS-II at BNL, Yang was the control account manager for the construction of the beamline and was the spokesperson for a team that wrote the original beamline development proposal.

“In our case, the scattering from the sample is sensitive to the underlying structure” of materials, Yang said. “That’s why people want to use scattering to study their samples.”

Like the other beamlines at the NSLS-II, the LiX enables scientists to use sophisticated equipment to search for links between structures and function. Each beamline has a three-letter acronym. In the case of LiX, the “Li” stands for life sciences, while the “X” represents X-ray scattering.

When they designed the beamline, LiX researchers were seeking optics that were capable of producing a beam to conform to the specifications required for different types of measurements. They then designed an experimental station that is suitable for handling biological samples. Specifically, that involved developing an automated sample handler for measurements on protein molecules in solution.

“With atomic resolution structures and functional assays, we do get new insights [about] important ions such as calcium,” which are involved in signaling and physiology, Qun Liu, a principal investigator in the Biology Department at BNL, described in an email. “LiX will be essential to allow us [to see] the transport process in real time and space.” Liu wrote that Yang is an “outstanding X-ray beamline scientist” who is also well known for his pioneering work on membrane diffraction.

The ability to perform measurements using a beam of a few microns is “pretty unique right now,” which also attracted researchers working with steel samples, Yang said. “When we designed the instrument, our focus [was] on the biological structure” but the beamline is “versatile enough” that it has found other uses, Yang said.

Researchers working with steel realized that the same diffraction-based approach to finding underlying structures in living tissue could also shed light on the structures of their samples.

In everyday life, diffraction is visible from the wavelengths of light that form the hologram on a credit card. Scientists working with steel have been applying for time on the LiX beamline, too, creating a competitive environment for researchers working in both fields.

Lynne Ecker, the deputy department chair in the Nuclear Science and Technology Department at Brookhaven National Laboratory, has used the beamline to study the effect of neutrons and ions on steel.

“Ions will only damage steel so far,” Ecker said. The LiX is “perfect” to study the degree of the damage. Ecker said she’s tried this kind of analysis in other places, but the LiX provides better spatial resolution. The LiX scientists are working on improving the degree of automation for sample handling and data processing.

“We are about to install a six-axis robot, which is typically seen in industrial automation, to help realize unattended overnight measurements on protein solution samples,” Yang said. The robot is already at the facility and Yang and his team will be installing the support structure to mount the robot in the experimental station this month. “The more challenging task is to put the software in place so that the beamline can control the robot,” he explained in an email.

The LiX beamline uses lenses made from beryllium, which are transparent to X-rays. For X-rays at the wavelength of about one angstrom, about 93 percent can pass through about a millimeter of beryllium. That compares favorably to aluminum, which allows about 2 percent to pass through at the same thickness.

The LiX beamline can run at 500 frames per second, which produces a wealth of data. In practice, it may take up to a second for the detector to accumulate enough signal from the sample. Still, the beamline can generate enough data that the experimenter may not be able to examine it frame by frame, which makes automated data processing more important.

Scientists have used the beamline to explore the structure of plants. These researchers mainly want to understand how materials like cellulose are organized within different parts of the plant and in different plants.

In bones, researchers can differentiate between organic matter like collagen and inorganic matter. Not only can they determine where they are, but they can also explore their orientation in a sample. Bones are easy samples since collagen and minerals in bone have distinctive scattering and diffraction patterns, Yang said. Researchers “like to look at how biological molecules change their shape as they interact with their functional partners,” Yang said.

A resident of East Setauket, Yang lives with his wife Mian Wang, who is an architect in Farmingdale, and their two daughters. A fan of tennis, Yang plays as often as he can during the summer at the Three Village Tennis Club.

Yang grew up in Yunnan province in the southwest of China. Trained as a physicist, Yang picked up knowledge of molecular biology from his years of working with other scientists. In his work, he gets to combine his talents in engineering, programming and molecular biology.

“We learn new things when we interact with our users/guest researchers since we first need to learn about their problems before we can help solve them,” he described in an email. Yang hopes the research he and the team at the LiX support will result in high-impact publications. “As more researchers know about us and our capabilities, I expect more people will want to perform experiments at our beamline,” he said.

Above, Alesi, the skull of the new extinct ape species Nyanzapithecus alesi. Photo by Fred Spoor

By Daniel Dunaief

They were in a terrible mood. They had spent an entire day searching for clues about creatures that walked the Earth millions of years ago and had come up empty.

“We were not finding even a single bone, nothing,” recalled Isaiah Nengo, who will be an associate director of the Turkana Basin Institute and an assistant research professor at Stony Brook University this fall.

Alesi after attached sandstone rock was partially removed at the Turkana Basin Institute, near Lodwar, Kenya. Photo by Christopher Kiarie

One of the fossil hunters in the group, John Ekusi, started rolling a cigarette. Nengo told him to move away from them so that they didn’t inhale second-hand smoke. Walking ahead, Ekusi made a spectacular discovery that Nengo called a “freak of a fossil.” Ekusi pointed out a bone sticking out of the ground that looked like the femur of a large animal. When they got closer, they could see that it had brow ridges. Pushing aside dirt, they saw the outline of a primate skull.

“We knew we had found something unique and we started celebrating right there,” Nengo said. “We were dancing and high-fiving. The thrill was unimaginable.”

Nengo and his team discovered the fossil on Sept. 4, 2014, in northern Kenya. This week, a team of researchers from the United States, France and England are unveiling three years worth of research into this remarkable find in the prestigious research journal Nature.

For starters, the researchers had to confirm the date of their fossil, which was about the size of a lemon. Rutgers University geologists Craig Feibel and Sara Mana studied the matrix around the fossil and the area around it.

Akai Ekes and John Ekusi watch as Isaiah Nengo lifts the sandstone block with Alesi after six hours of excavation. Photo from ​Isaiah Nengo

“There was no doubt that [the fossil] came from this deposit and hadn’t rolled in or washed in” during some later period, explained Ellen Miller, a professor of physical anthropology at Wake Forest University.

Next, they had to figure out what kind of primate they had: It could have been an ape or a monkey. Fred Spoor, a paleontologist at University College London, did an initial CT reading using a medical scanner. He found intact molars that were characteristic of apes.

The researchers wanted to do a more thorough analysis of the three-dimensional shape of the skull, so they called Paul Tafforeau, a paleoanthropologist specialist of X-ray imaging who works as a beamline scientist at the European Synchrotron Radiation Facility in Grenoble, France. Typically, such research centers require scientists to wait a year or more.

As soon as Tafforeau saw the photos, Nengo recalls, he said, “You can bring it in anytime.” Tafforeau used a technique called propagation phase contrast–X-ray synchrotron microtomography. In an email, Tafforeau described it as being close to a medical scanner, but 1,000 times more precise and sensitive.

Over the course of three or four days, Tafforeau analyzed the teeth that hadn’t erupted from this young primate, which indicated that this individual died when it was only 16 months old. The teeth also demonstrated that the toddler, whose gender is difficult to determine because of its age, belonged to a new species, called Nyanzapithecus alesi. The name Alesi comes from the Turkana word “ales,” which means ancestor.

Tafforeau said the thickness of the tooth enamel suggest a classic hominoid diet, which would be similar to that of a modern gibbon, and would consist mostly of fruits and leaves. Researchers estimate that an adult of this species would weigh about 20 pounds.

Turning their attention to the fantastic creature’s ears, the researchers found that it didn’t have a balance organ. That means it couldn’t move as rapidly through trees as a gibbon. The ears of this primate, however, did have fully developed bony ear tubes. These ear structures “absolutely confirmed that these were apes,” said Miller. “We had no specimens between 15 million and 10 million years ago.”

Field crew of the​ Stony Brook University-affiliated​ Turkana Basin Institute​ when Alesi​ ​was discovered​ ​at​ Napudet​ in September 2014. From​ ​left, Abdala Ekuon, John Ekus​i, Isaiah Nengo,​ ​Bernard Ewoi, Akai Ekes and Cyprian Nyete.​ Photo from Isaiah​ ​​​Nengo.

Scientists generally believe apes and humans diverged in their evolution about 7 million years ago. That means this toddler ape belongs to a species that is likely a common ancestor for other apes and humans.

Anthropologist Meave Leakey, a research professor in the Department of Anthropology and the Turkana Basin Institute, suggested that this fossil “gives us a picture for the first time of what the ancestor of apes and humans looked like 13 million years ago. It also suggests,” she continued in an email, “that the nyanzapiehecines were close to the origin of all living apes and humans.”

Leakey described the fossil as one of the most complete skulls of an ape ever found anywhere and indicated it was of an age that is poorly represented in the African fossil record.

The three years between the discovery of the fossil and its unveiling to the world in the Nature article is “actually very quick,” Leakey explained. The images captured through the synchrotron provide detailed pictures of structures that would otherwise be hidden by bone.

Gathering and interpreting these images meant traveling to Grenoble, which, she explained, “takes considerable time.”

Researchers involved in this study said this is just the beginning of the work they will conduct on this rare and detailed fossil. Nengo said they had already collected two terabytes worth of data from their scans. Much of the further study of this ape will involve a closer examination of all of that data.

“A paper coming out in Nature makes it seem like the end of the process,” Miller said. “This is just the beginning.” He is intrigued to learn more about the organization of the brain.

Nengo hopes to bring together researchers for a two- or three-day workshop in September or October at Stony Brook University to tackle the next phase of analysis for Alesi.

As it turns out, September will likely become an important anniversary for Nengo, as he recalls the memory of a day three years ago that didn’t start out particularly well, but that ended with a rare and thrilling fossil find.

Nengo recalled how excited he was to return to the Turkana Basin Institute to show Richard Leakey, the founder of the site, Meave Leakey and Lawrence Martin, the director of TBI. “I had photos on my iPad and they were absolutely thrilled,” said Nengo. “Everybody was beginning the guesswork of wondering what it is.”

Organizers of the 3rd annual Genome Engineering: The CRISPR-Cas Revolution event, from left, Maria Jasin, Jonathan Weissman, Jennifer Doudna and Stanley Qi. Photo courtesy of CSHL

By Daniel Dunaief

One day, the tool 375 people from 29 countries came to discuss in late July at Cold Spring Harbor Laboratory may help eradicate malaria, develop treatments for cancer and help understand the role various proteins play in turning on and off genes.

Eager to interact with colleagues about the technical advances and challenges, medical applications and model organisms, the participants in Cold Spring Harbor Laboratory’s third meeting on the CRISPR-Cas9 gene editing system filled the seats at Grace Auditorium.

Jason Sheltzer. Photo from CSHL

“It’s amazing all the ways that people are pushing the envelope with CRISPR-Cas9 technology,” said Jason Sheltzer, an independent fellow from Cold Spring Harbor Laboratory who presented his research on a breast cancer treatment.

The technology comes from a close study of the battle between bacteria and viruses. Constantly under assault from viruses bent on commandeering their genetic machinery, bacteria figured out a way of developing a memory of viruses, sending out enzymes that recognize and destroy familiar invaders.

By tapping into this evolutionary machinery, scientists have found that this system not only recognizes genes but can also be used to slice out and replace an errant code.

“This is a rapidly evolving field and we continue to see new research such as how Cas1 and Cas2 recognize their target, which opens the door for modification of the proteins themselves, and the recent discovery of anti-CRISPR proteins that decrease off-target effects by as much as a factor of four,” explained Jennifer Doudna, professor of chemistry and molecular and cell biology at the University of California at Berkeley and a meeting organizer for the last three years, in an email.

Austin Burt, a professor of evolutionary genetics at the Imperial College in London, has been working on ways to alter the genes of malaria-carrying mosquitoes, which cause over 430,000 deaths each year, primarily in Africa.

“To wipe out malaria would be a huge deal,” Bruce Conklin, a professor and senior investigator at the Gladstone Institute of Cardiovascular Disease at the University of California in San Francisco and a presenter at the conference, said in an interview. “It’s killed millions of people.”

Carolyn Brokowski. Photo by Eugene Brokowski

This approach is a part of an international effort called Target Malaria, which received support from the Bill and Melinda Gates Foundation.

To be sure, this effort needs considerable testing before scientists bring it to the field. “It is a promising approach but we must be mindful of the unintended consequences of altering species and impacting ecosystems,” Doudna cautioned.

In an email, Burt suggested that deploying CRISPR in mosquitoes across a country was “at least 10 years” away.

CSHL’s Sheltzer, meanwhile, used CRISPR to show that a drug treatment for breast cancer isn’t working as scientists had thought. Researchers believed a drug that inhibited the function of a protein called maternal embryonic leucine zipper kinase, or MELK, was halting the spread of cancer. When Sheltzer knocked out the gene for MELK, however, he discovered that breast cancer continued to grow or divide. While this doesn’t invalidate a drug that may be effective in halting cancer, it suggests that the mechanism researchers believed was involved was inaccurate.

Researchers recognize an array of unanswered questions. “It’s premature to tell just how predictable genome modification might be at certain levels in development and in certain kinds of diseases,” said Carolyn Brokowski, a bioethicist who will begin a position as research associate in the Emergency Medicine Department at the Yale School of Medicine next week. “In many cases, there is considerable uncertainty about the causal relationship between gene expression and modification.”

Brokowski suggested that policy makers need to appreciate the “serious reasons to consider limitations on nontherapeutic uses for CRISPR.”

Like so many other technologies, CRISPR presents opportunities to benefit mankind and to cause destruction. “We can’t be blind to the conditions in which we live,” said Brokowski.

Indeed, Doudna recently was one of seven recipients of a $65 million Defense Advanced Research Projects Agency award to improve the safety and accuracy of gene editing.

The funding, which is for $65 million over four years, supports a greater understanding of how gene editing technologies work and monitors health and security concerns for their intentional or accidental misuse. Doudna, who is credited with co-creating the CRISPR-Cas9 system with Emmanuelle Charpentier a scientific member and director of the Max Planck Institute for Infection Biology in Berlin, will explore safe gene editing tools to use in animal models and will specifically target Zika and Ebola viruses.

“Like most misunderstood disruptive technologies, CRISPR outpaced the necessary policy and regulatory discussions,” Doudna explained. The scientific community, however, “continued to advance the technology in a transparent manner, helping to build public awareness, trust and dialogue. As a result, CRISPR is becoming a mainstream topic and the public understanding that it can be a beneficial tool to help solve some of our most important challenges continues to grow.”

Visitors enjoyed a wine and cheese party on the Airslie lawn during the event. Photo from CSHL

Cold Spring Harbor Laboratory plans to host its fourth CRISPR meeting next August, when many of the same scientists hope to return. “It’s great that you can see how the field and scientific community as a whole is evolving,” Sheltzer said.

Doudna appreciates the history of Cold Spring Harbor Laboratory, including her own experiences. As a graduate student in 1987, Doudna came across an unassuming woman walking the campus in a tee-shirt: Nobel Prize winner Barbara McClintock. “I thought, ‘Oh my gosh, this is someone I revere,” Doudna recalled. “That’s what life is like” at the lab.

Brokowski also plans to attend the conference next year. “I’m very interested in learning about all the promises CRISPR will offer,” she said. She is curious to see “whether there might be more discussion about ethical and regulatory aspects of this technology.”

Michael Airola. Photo from SBU

By Daniel Dunaief

Numerous trucks arrive at a construction site, each doing their part to make a blueprint for a building into a reality. In a destructive way, molecules also come together in cancer to change cells that cause damage and can ultimately kill.

Researchers often know the participants in the cancer process, although the structure of each molecule can be a mystery. Determining how the parts of an enzyme work could allow scientists and, eventually, doctors to slow those cancer players down or inactivate them, stopping their cell-damaging or destroying processes.

Recently, Michael Airola, who started his own lab at Stony Brook University early this year and is an assistant professor of biochemistry and cell biology, published a paper in the Proceedings of the National Academy of Sciences in which he showed the structure of an important enzyme that contributes to cell growth regulation in cancer and other diseases, including Alzheimer’s disease.

Called neutral sphingomyelinase, this enzyme produces ceramide, which allows cancer cells to become metastatic. Finding the structure of an enzyme can enable scientists to figure out the way it operates, which can point to pharmacological agents that can inhibit or deactivate the enzyme.

“We are trying to understand the link between structure and function to try to get the first sort of snapshots or pictures of what these enzymes look like” in the on and off states, said Airola. In his research, he showed what this enzyme looked like in its off or inactive state.

Airola joined Stony Brook Cancer Center Director Yusuf Hannun’s lab as a postdoctoral researcher in 2010, when Hannun was working in Charleston, South Carolina, at the Medical University of South Carolina. When Hannun moved to SBU in March of 2012, Airola joined him, continuing his postdoctoral research.

Michael Airola in April in New Orleans aboard the steamboat Natchez on the Mississippi River with his family, wife Krystal Airola, four-year-old Harper and two-year-old Grady. Photo from Michael Airola

Airola conducted his research at Stony Brook and Brookhaven National Laboratory, where he used a technique called X-ray crystallography, which shows the structure of crystallized molecules. Getting this enzyme to crystallize took considerable effort, especially because it has what Airola described as a floppy segment between two rigid structures.

Those floppy pieces, which Airola said aren’t the active sites of the enzyme, can interfere with the structural analysis. To see the important regions, Airola had to cut those flexible parts out, while fusing the rest of the enzyme into a single structure.

The crystallization took almost three years and was a “very difficult process,” Airola recounted. “To get proteins to crystallize, you need to get them to pack together in an ordered fashion.” He said he needed to develop some biochemical tricks to delete a large part in the middle of the protein. “Once we found the right trick and the right region to delete, we were able to crystallize the protein in about three months.”

Airola said he took considerable care to make sure removing the floppy or flexible region didn’t disrupt the function of the enzyme. Hannun and Airola are co-mentoring Prajna Shanbhogue, a graduate student who is in the process of discovering molecules that activate and inhibit the enzyme.

Hannun was pleased with the work Airola did in his lab, which he suggested was a “challenging type of research. Getting to a structure of a protein or enzyme (a specific type of protein) can take several years and is never guaranteed of success, but the rewards can be tremendous,” Hannun explained in an email, adding that Airola was a “critical contributor” and introduced structural biology to his group.

While Airola will continue to work on this enzyme, he is exploring another enzyme, in a collaboration with Hannun and John Haley at Stony Brook, that is involved in colon cancer.

Airola, two graduate students and three undergraduates in his lab are focusing considerable energy on an enzyme involved in the production of triglycerides.

Airola recently received a three-year, $231,000 grant from the American Heart Association to study lipins, a class of enzyme that plays a role both in heart disease and in diabetes. As he did with the enzyme that makes ceramide, Airola is developing a way to understand the structure and function of the triglyceride enzyme. He’d like to find out how this enzyme is regulated. “We’re trying to see if we can inhibit that enzyme, too,” he said.

Airola has “some creative ideas about using information from lipin proteins in plants and fungi, which have a less complex protein structure than mammalian lipins but catalyze the same biochemical reaction,” Karen Reue, a professor in the Department of Human Genetics, David Geffen School of Medicine at UCLA and a collaborator with Airola, explained in an email.

Reue’s lab will complement Airola’s work by conducting physiological analyses of the various “minimal” lipin proteins in processes that the mammalian proteins perform, including triglyceride biosynthesis.

While lipin proteins are necessary for metabolic homeostasis, Reue said a reasonable but still challenging goal might be to modulate the enzyme’s activity for partial inhibition in areas such as adipose tissue, while allowing the triglycerides to perform other important tasks.

Airola lives in East Setauket with his wife Krystal Airola, who is doing her residency in radiology at SBU, and their two children, four-year-old Harper and two-year-old Grady. The couple, who is expecting a third child next month, enjoy living in East Setauket, where they appreciate that they have a forest in their backyard and they can enjoy the water in Port Jefferson and West Meadow Beach.

When Airola’s postdoctoral position ended, he did a broad, national search for his next position and was delighted that he could remain at Stony Brook. “We love the area,” he said. “The research and science here are fantastic.” Airola’s collaborators are optimistic about the prospects for his research.

He is an “up and coming structural biologist that has already made important contributions to the field of lipid biology” Reue said and is a “creative and rigorous scientist with a bright future.”

Alexander Krasnitz. Photo from CSHL

By Daniel Dunaief

If homeowners could find insects in their home, confirm that they were termites and locate nests before the termites damaged a house, they’d save themselves numerous problems. The same holds true for cancer.

Using the latest molecular biology techniques, researchers at Cold Spring Harbor Laboratory including Associate Professor Alexander Krasnitz and Professor Michael Wigler have explored ways to detect cancer earlier.

Unlike other scientists, who have created tests that reveal the genetic probability of developing cancer, Krasnitz and Wigler developed a blood test to reveal the presence of a tumor that might be hard to spot. Such a test could be particularly valuable for cancers such as ovarian and pancreatic cancer, which can be inoperable by the time they present clinical symptoms.

Urging what Wigler described as a “call to arms,” Krasnitz said they created a blood test, called copy number variation, that they hope will be economically feasible. In copy number variation, sections of genes are repeated. While healthy cells have copy number variation, cancer cells use them like a Jack Nicholson mantra in “The Shining,” where the repetition of “all work and no play makes Jack a dull boy” becomes a calling card for a killing spree.

In cancer, chromosomes or chromosome arms are duplicated or deleted. Sometimes, a narrow region of the genome undergoes amplification, creating multiple copies of the region. Other times, a region of the genome may be lost. Genome-wide copy number variation is a hallmark of cancer. Copy number variation occurs often amid the disruption of DNA repair mechanisms and the breakdown in the way DNA separates into daughter cells during division.

In a recent article in Trends in Molecular Medicine, Krasnitz, Jude Kendall, Joan Alexander, Dan Levy and Wigler — all scientists at CSHL — suggest the potential for single-cell genomic analysis that searches for the presence of copy number variations could raise the alert level for cancer, signaling the need to search more closely for developing tumors.

In most massive cancers in the population, including breast, ovarian and prostate cancer, copy number variation is “ubiquitous,” Krasnitz said. Screening for these changes could provide “evidence for the presence of something abnormal,” which can be validated through other tests, Krasnitz said.

Copy number variation, on its own, is not sufficient to detect cancer, Krasnitz said. Researchers need evidence of similar abnormal copy number profiles in multiple cells. For this test to have clinical relevance, it would need to minimize false positives, which could create alarm and lead to future tests that might not be warranted, while also avoiding false negatives, which would miss the presence of cancer.

The main sources of false positives could come from copy number variation that’s already in cells in the blood that randomly look like a tumor. Cells with partially degraded DNA can have high copy number variation, which the researchers have observed. These profiles, however, arise from random processes and typically look different from each other. Cells from a cancer clone, however, have similar copy number profile.

Cancers with low copy number variation were a minority among the 11 cancers the scientists studied and include a type of colorectal cancer called microsatellite-unstable. If these CSHL researchers developed a preclinical test, they would look for additional ways to detect such cancers.

While numerous technological innovations required for the test exist, including copy number profiling of single cells and methods to enrich specimens from blood for suspected tumors, Krasnitz explained that considerable work remains before its clinical use, including establishing tumor cell counts in the blood of early patients, making single-cell profiling cheaper and finding optimal ways to identify the tissue of origin.

They are planning to study newly diagnosed patients to observe the presence of circulating cells from tumors. Once the scientists prove that the test has some predictive value, they need to ensure that it is economical and that they can follow up with patients to find tumors.

At this point, it’s unclear what the presence of copy number variation might reveal about the type of tumor, which could be a slowly growing or an aggressive type. Additionally, an abnormal indication from this type of analysis wouldn’t reveal anything about the type of cancer. Further tests, including on RNA, would help direct doctors to a specific organ or system.

Apart from his work with Wigler, Krasnitz also has numerous collaborations, including one with CSHL Cancer Center Director David Tuveson.

In his work with Tuveson, Krasnitz is ensuring that the organoid models Tuveson’s lab creates, which are living replicas of tumors taken from patients, faithfully reflect the genetic make up of the tumors. That, Tuveson said, is a significant undertaking because it can validate the organoid model for exploring the biology of tumors.

“This is a deliverable that many people are waiting for,” Tuveson said. The researchers want to make sure “what we grew is what the patient had in the first place.” So far, Tuveson said, the data looks good and the scientists don’t have any examples of the genetics of the organoids differing from that of the tumor.

Krasnitz also attempts to predict an organoid’s response to drugs that haven’t been tested yet based on the organoid’s reaction to other drugs. Tuveson reached out to Krasnitz to work with his group. He said Krasnitz is “a major player” and is “very skilled” in the type of analysis of big data his group generates through the genome, the transcriptome and drug screens. “He’s able to look at those three types of information and make sense of it,” Tuveson said.

Krasnitz is grateful for the support of the Simons Foundation, the National Institutes of Health and the Breast Cancer Research Foundation for his work with Wigler. The most recent article with Wigler is an “invitation for the [research] community to join in the effort,” Krasnitz said. “We want collaborators and more competition in this area.”

Elizabeth Boon, back row, center, with graduate students from her lab at Stony Brook University. Photo from Elizabeth Boon

By Daniel Dunaief

It was in the back of Elizabeth Boon’s mind for the last decade. How, she wondered, could the switch that is so critical to life not be there and yet still allow for normal functioning? She suspected that there had to be another switch, so the associate professor in the Department of Chemistry at Stony Brook University, spent the last five years looking for it.

Sure enough, she and graduate students including Sajjad Hossain, found it.

Bacteria, like so many other living creatures, need to have a way of detecting nitric oxide gas. At a high enough concentration, this gas can kill them and, indeed, can kill other living creatures as well, including humans.

Nitric oxide is “toxic to any organism at a high enough concentration,” Boon said. “Most organisms have ways of detecting high concentrations … to avoid toxic consequences.” Other research had found a way other bacteria detect this toxic gas through a system called H-NOX, for heme nitric oxide/ oxygen binding protein.

When bacteria live together in colonies called biofilms, many of them typically rely on a signal about the presence of nitric oxide from the H-NOX protein. And yet, some bacteria survived without this seemingly critical protein. “We and others have shown that H-NOX detection of nitric oxide allows bacteria to regulate biofilm formation,” Boon explained.

Elizabeth Boon with her family, from left, Sheridan, 3, Cannon, 7, Beckett, 1, with her husband Isaac Carrico, who is also an Associate Professor in the Chemistry Department at Stony Brook University. Photo by Alfreda James

Named the nitric oxide sensing protein, or NosP, Boon and her team discovered this alternative signaling system that has some of the same functional group as the original mechanism. When activated in one bacteria, the Pseudomonas aeruginosa, this signaling mechanism causes biofilm bacteria to react in the same way as they would when an H-NOX system was alerted, by breaking up the colony into individuals. Using a flagella, an individual bacteria can move to try to escape from an environment containing the toxic gas.

Nicole Sampson, a professor of chemistry at Stony Brook University, suggested that this work was groundbreaking. While some biofilms are benign or even beneficial to humans, including a biofilm in the human gut, many of them, including those involved in hospital-borne infections, can cause illness or exacerbate diseases, particularly for people who are immunocompromised. Bacteria in biofilm are difficult to eradicate through drugs or antibiotics. When they are separated into individuals, however, they don’t have the same rigid defenses.

“They are resistant to most forms of treatment” when they are in biofilms, Boon said. “If we could get the bacteria to disperse, it’d be much easier to kill them. One of the hopes is that we could develop some sort of molecule that might loosen up the film and then we could come in with an antibiotic and kill the bacteria.”

Boon and her team published their results on the cover of the magazine ACS Infectious Disease, where they presented evidence of what they describe as a novel nitric oxide response pathway that regulates biofilm in the bacteria P. aeruginosa, which lack the H-NOX gene. The day the lab discovered this other protein, they celebrated with a trip for frozen yogurt at Sweet Frog.

In an email, Sampson said that finding the mechanism through which bacteria responds to nitric oxide “is important for developing therapies that target biofilms.”

While Boon is pleased that her lab found an alternative nitric oxide signaling system that answered a long-standing question about how some bacteria could respond to an environmental signal that suggested a threat to the biofilm, she said the answer to the question, as so many others do in the world of science, has led to numerous other questions.

For starters, the lab doesn’t yet know the structure of the NosP. “Not all proteins are immediately willing to crystallize,” Boon said. “We’re hopeful we’ll have a structure soon.” She knows it has a heme group, which includes an iron ion in the middle of an organic compound. That’s where the nitric oxide binds.

“We’d like to have the structure to piece together how that signal is relayed out to the end of the protein and how that gets transferred to other proteins that cause changes in behavior,” she said. The NosP is longer than the H-NOX protein, although they appear to have the same function.

Boon has also found that some bacteria have both the H-NOX and the NosP, which raises questions about why there might be an apparent redundancy. In organisms that have both proteins, it’s tempting to conclude that these bacteria live in a broader range of environments, which might suggest that the two systems react to the gas under different conditions. At this point, however, it’s too early to conclude that the additional sensing system developed to enable the bacteria to respond in a wider range of conditions.

Boon believes the nitric oxide system could be a master regulator of bacterial biofilms. “Detecting nitric oxide might be one of the first things that happen” to protect a bacteria, she said. The reason for that is that bacteria, like humans, use iron proteins in respiration. If those proteins are blocked by nitric oxide, any organism could suffocate.

Boon believes a multistep therapeutic approach might work down the road. She believes breaking up the biofilm would be an important first step in making the bacteria vulnerable to attack by antibiotics. She and her graduate students work with bacteria in the lab that generally only cause human disease in people who are already immunocompromised. Even so, her staff takes safety precautions, including working in a hood and wearing protective equipment.

Boon and her husband Isaac Carrico, who is an associate professor in the Department of Chemistry at Stony Brook University, have a 7-year-old son Cannon, a 3-year-old daughter Sheridan and a 1-year-old son Beckett. Boon said she and her husband are equal partners in raising their three children.

In her work, Boon is excited by the possibility of addressing new questions in this nitric oxide mechanism. “We’re trying to cover as much ground as fast as possible,” she said.

Standing near one of the X-ray scattering instruments, Kevin Yager holds a collection of samples, including a self-assembling polymer film. Photo courtesy of BNL

By Daniel Dunaief

Throw a batch of LEGOs in a closed container and shake it up. When the lid is opened, the LEGOs will likely be spread out randomly across the container, with pieces facing different directions. Chances are few, if any, of the pieces will stick together. Attaching strong magnets to those pieces could change the result, with some of the LEGOs binding together. On a much smaller scale and with pieces made from other parts, this is what researchers who study the world of self-assembled materials do.

Scientists at the Center for Functional Nanomaterials and at the National Synchrotron Light Source II at Brookhaven National Laboratory experiment with small parts that will come together in particular ways based on their energy landscapes through a process called self-assembly.

Every so often, however, a combination of steps will alter the pathway through the energy landscape, causing molecules to end up in a different final configuration. For many scientists, these so-called nonequilibrium states are a nuisance.

Above, Kevin Yager listens to sonified data. When data is sonified, it is translated into sound. Photo by Margaret Schedel

For Kevin Yager, they are an opportunity. A group leader at the CFN who works closely with the NSLS-II, the McGill University-educated Yager wants to understand how the order of these steps can change the final self-assembled product. “In the energy landscape, you have these peaks and valleys and you can take advantage of that to move into a particular state you want,” Yager said. “The high level goal is that, if we understand the fundamentals well enough, we can have a set of design rules for any structure we can dream up.”

At the CFN, Yager manages a nanofabrication facility that uses electron-beam lithography and other techniques to make nanostructures. He would like to fabricate model batteries to show the power of nanomaterials. He is also determined to understand the rules of the road in the self-assembly process, creating the equivalent of an instruction manual for miniature parts.

In future years, this awareness of nonequilibrium self-assembly may lead to revolutionary innovations, enabling the manufacture of parts for electronics, drugs to treat disease and deliver medicine to specific locations in a cell and monitors for the detection of traces of radioactivity or toxins in the environment, among many other possibilities.

Yager’s colleagues saw considerable opportunities for advancement from his work. Nonequilibrium self-assembly has “significant potential for a broad range of nanodevices and materials due to its ability to create complex structures with ease,” Oleg Gang, a group leader in Soft and Bio Nanomaterials at the CFN, explained in an email. Yager is an “excellent scientist” who produces “outstanding results.”

One of the things Yager hopes his research can develop is a way to “trick self-assembly into making structures they don’t natively want to make” by using the order of steps to control the final result.

As an example, Yager said he developed a sequence of steps in which nanoscale cylinders pack hexagonal lattices into a plane. These lattices tend to point in random directions as the cylinders form. By following several steps, including sheer aligning a plane and then thermal processing, the cylinders flip from horizontal to vertical as they inherit the alignment of the sheered surface. Flipping these cylinders, in turn, causes the hexagons all to point in the same direction. When Yager conducted these steps in a different order, he produced a different structure.

Broadly speaking, Yager is working on stacking self-assembling layers. In his case, however, the layers aren’t like turkey and swiss cheese on a sandwich, in which the order is irrelevant to the desired final product. Each layer has a hand in directing the way the subsequent layers stack themselves. Choosing the sequence in which he stacks the materials controls their structure.

Yager is working with Esther Takeuchi and Amy Marschilok at Stony Brook University to develop an understanding of the nanostructure of batteries. Gang suggested that Yager’s expertise is “invaluable for many scientists who are coming to the CFN to characterize nanomaterials using synchtrotron methods. In many cases, it would probably be impossible to achieve such quantitative understanding without [Yager’s] input.”

Yager and his wife Margaret Schedel, an associate professor in the Department of Music at Stony Brook University who is a cellist and a composer, live in East Setauket. The couple combined their talents when they sought ways to turn the data produced by the CFN, the NSLS and the NSLS-II into sound.

Scientists typically convert their information into visual images, but there’s “no reason we can’t do that with sound,” Yager said. “When you listen to data, you sometimes pick up features you wouldn’t have seen.”

One of the benefits of turning the data into sound is that researchers can work on something else and listen to the collection of data in the background, he said. If anything unexpected happens, or there is a problem with a sample or piece of equipment, they might hear it and take measures more rapidly to correct the process. “This started as a fun collaboration,” Yager said, “but it is useful.”

Schedel is working on sonifying penguin data as well. She also sonified wave data on Long Island. “By listening to the tides quickly, larger patterns emerge,” she said, adding that Yager thought the idea was theoretically interesting until he listened to misaligned data and then he recognized its benefit.

Schedel’s goal is to see this sonification effort spread from one beamline to all of them and then to the Fermilab near Chicago and elsewhere. She wants sonification to become “an ear worm in the science community.”

While Schedel introduced Yager to the world of sound in his research, he introduced her to sailing, an activity he enjoyed while growing up in the suburbs of Montreal. When she sails with him, they are “half in and half out of the boat,” Schedel said. It’s like two people “flying a kite, but you are the kite. You have to learn how to counterbalance” the boat. They hike out so they can take turns faster without tipping over, she said.

HXN team members, from left, Evgeny Nazaretski, Ken Lauer, Sebastian Kalbfleisch, Xiaojing Huang, Yong Chu, Nathalie Bouet and Hanfei Yan. Photo courtesy of BNL

By Daniel Dunaief

There’s precision in measurements and then there’s the world of Yong Chu. The head of a beamline that’s housed off to the side in a separate, concrete structure from similar efforts at Brookhaven National Laboratory, Chu led the design, construction and commissioning of a sophisticated beamline with a resolution of as low as 3 nanometers, which he hopes will get down to 1 nanometer within a year.

Just as a measure of contrast, a human hair is about 80,000 nanometers wide. Why so fine a resolution? For starters, seeing objects or processes at that high level can offer insights into how they function, how to improve their manufacture or how to counteract the effects of harmful processes.

With a battery, for example, the Hard X-ray Nanoprobe, or HXN beamline, could help reveal structural weaknesses in the nanostructure that could cause safety issues. In biology, numerous functions involve sub-cellular organelles that respond to proteins. Proteins are typically smaller than the HXN beamline can image, although researchers can tag the proteins with metals, which allows Chu, his colleagues and visiting scientists to see an aggregate of these proteins.

The HXN beamline can also help explore environmental problems, such as how plants transport harmful nanoparticles to their fruits or how artificial compounds absorb nuclear waste. Imaging beamlines that use micro-focused beams typically offer spatial resolution of 10 microns, 1 micron or even 100 nanometers, according to Ryan Tappero, the head scientist at the X-ray Fluorescence Microprobe at BNL, who has used the HXN for his research. Using the NSLS II source properties and a new x-ray optics development routinely offers resolution of 10 nanometers, which pushes the spatial resolution down by another factor of 10, which makes the HXN, according to Tappero, a “game changer.”

Tappero described Chu as a “rock star” and suggested he was an “exceptional beamline scientist” who is “very knowledgeable about X-ray optics.”

BNL houses 19 beamlines at the National Synchrotron Light Source II, a state-of-the-art facility large enough that scientists ride adult tricycles inside it to travel from one beamline to another and to transport supplies around the facility. BNL is building another nine beamlines that it hopes to have operational within the next 18 months. Each of these beamlines offers a different way to explore the world of matter. Some beamlines do not use a focused beam, while others produce beams with high angular or high energy resolution. Imaging beamlines such as the HXN produce a small beam size.

The HXN beamline has the highest spatial resolution of any beamline at the NSLS-II. Scientists building the HXN grew a nanofocusing lens with a dedicated deposition system that was constructed at the NSLS-II Research and Development lab. The system grew a nanofocusing lens a layer at a time, alternating materials and controlling the thickness at better than 1 nanometer, Chu explained.

The beamline where Chu works has padded walls, a door separating it from the rest of the light source and a monitor that records the temperature to the thousandths of a degree. “We are constantly monitoring the temperature around the X-ray microscope and inside of the X-ray microscope chamber,” he said. Around the microscope, he can keep the temperature stable within 0.03 degree Celsius. In the chamber, the scientists maintain the temperature at better than 0.003 degree Celsius.

So, now that Chu and his colleagues built their beamline, have the scientists come? Indeed, the interest in using the HXN has been well above the available time slots. For the three cycles each year, BNL receives about four requests for each available time. This reflects the unique qualities of the instrument, Chu said, adding that he doesn’t expect the rate to drop considerably, even as the HXN continues to operate, because of the ongoing demand.

Researchers have to go through a peer review process, where their ideas are graded for the likelihood of success and for the opportunity to learn from the experiments. All beam time proposals are reviewed by external expert panels, which examine the scientific merit, appropriateness of use of the facility, capability of proposers and quality of prior performance and the research plan and technical feasibility.

Chu fields about 10 calls per month from scientists who want to speak with him about the feasibility of their ideas. He may suggest another station at the NSLS-II or at the Advanced Photon Source at Argonne National Laboratory in Chicago, where he was a beamline scientist starting in 1999.

“I know many of the beamlines” at the Advanced Photon Source, he said. “I recommend some of the potential users to perform experiments at the APS first before coming to the HXN.” By the time scientists arrive at his beamline, Chu said he’s gotten to know them through numerous discussions. He considers them “as a guest” at the HXN hotel. “We try to make sure the experimental needs for the users are met as much as possible,” he said.

The HXN beamline has three staff scientists and two postdoctoral fellows who remain in contact with scientists who use the facility. “For most of the users, at least one of us is working throughout the weekends and late evenings,” said Chu.

Not just a staff scientist, Chu is also a user of the HXN, with currently one active general user proposal through a peer review process in which he is collaborating with Stony Brook University and BNL scientist Esther Takeuchi to explore the nanostructure of metal atoms during phase separation in batteries.

Chu and his wife Youngkyu Park, who works at Cold Spring Harbor Laboratory as a research investigator in basic and preclinical cancer research, live in Northport. The couple’s 22-year-old son Luke is attending Nassau Community College and is planning to transfer to Stony Brook this fall to study engineering. Their daughter Joyce is 18 and is enrolled in the Parsons School of Design in New York.

Chu grew up in Seoul, South Korea, and came to the United States when he was 18. He attended Caltech. While Chu’s parents wanted him to become a doctor, he was more inspired by a cartoon called Astro Boy, in which a scientist, Dr. Tenma, is a hero solving problems. As for the work of the scientists who visit his beamline, Chu said the “success of individual users is the success of the beamline.”

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By Daniel Dunaief

Hurry, hurry, hurry! You’ve got five minutes to get to the high school before your daughter’s graduation. It usually takes six. You might have to go faster than the speed limit, but you’ve done it before.

Your daughter looks great and she’s so calm. You push on the accelerator on the straight road ahead. Your daughter takes a deep breath.

OK, just a little faster and you’ll make it. Oh, no, no, no, a small car pulls in front of you. It’s being driven at 25 mph in a 35 mph zone. Why do cars pull in front of you and then go slowly? “Come on!” you implore, flicking your fingers forward as if you were trying to scratch a chalkboard from the bottom up.

“Dad, it’s OK,” your daughter insists. “I don’t want you to be late,” you say.

You drive carefully around a curve and head for another straight part of the road. You reach a stop sign, where a BMW misses an opening to go. It was a small one, but you’ve got to make your own openings in this town. That’s what you’d tell everyone today if you were giving the speech your daughter won the right to deliver.

Your daughter did better in school than you did. That makes you proud, but you don’t have time to be proud. All these people are slowing you down. You just have a few more turns.

A Girl Scout troop crosses the road in front of you. Your daughter was in Girl Scouts years ago, but you don’t like them now. They’re making you late for such an important day for the family.

Then the Girl Scouts, whose uniforms make you think of those mint cookies, cross the street. You’re a block from the school and a sedan takes forever to park.

You grind your teeth and lift your hand to touch the horn. Your daughter puts her hand firmly on yours and shakes her head slowly.

The woman with streaks of gray in her hair and a green suit looks vaguely familiar as she gets out of a car.

Finally, you park, get in the school and, shockingly, your daughter’s friends have reserved you great seats.

You pick up your phone to start recording your daughter’s speech. The camera’s out of memory. You grind your teeth as you try to delete enough old pictures to record this magic moment.

“Good morning,” your daughter’s voice offers the room. Your wife tells you to stop fiddling with your phone and look up. After your daughter shares memories of high school, she wants to offer advice to her class.

“I want you to remember to leave some margin for error,” she urges. Right, you smile. Your daughter, who made so many fewer errors than you did, is talking to the other people about their mistakes. You nod to the other people.

“If we need to do something, to be somewhere or to accomplish anything, we need to accept that the route might include detours or unexpected obstacles,” she offers, sharing that crooked smile she developed in middle school. “It’s not anyone else’s fault. If it’s important, don’t blame the obstacles. Be prepared for them. Planning means understanding them and giving yourself some extra time to reach your goals.”

You take a deep breath, the way she did so many times while she waited for you at the entrance to the house. You look around the room to see if anyone else knows she’s talking to you. You now recognize the woman on stage with streaks of gray in her hair and a green suit; she’s the superintendent of schools.

You realize how much smarter your daughter is than you.

SBU graduate student and grand niece of world renowned anthropologist Richard Leakey, Acacia Leakey, draws a sketch of huts in the village of Ambodiaviavy, Madagascar as the children look on. Photo from Mickie Nagel

By Daniel Dunaief

 

Mickie Nagel recently returned from the island nation of Madagascar, and she’s filled with ideas, inspiration, observations and opportunities. One of the three founders of a new nongovernmental organization called BeLocal, the Laurel Hollow resident spent several weeks with Stony Brook University graduate students Leila Esmailzada and Acacia Leakey taking videos and gathering information about life in Madagascar.

The goal of the new organization is to share this footage and insight with undergraduate engineers at SBU, who might come up with innovations that could enhance the quality of life for the Malagasy people.

In one village, a man showed her a three-inch lump on his shoulder, which he got by dragging a long stick with bunches of bananas that weigh over 100 pounds along a clay footpath out of the forest. People also carry rice that weighs over 150 pounds on their heads, while many others haul buckets of water from rivers and streams to their homes while walking barefoot.

In addition to transportation, Nagel also found that villagers around Centre ValBio, a Stony Brook research station, had basic food and water needs. Over 17 years ago, another group had installed four water pumps in a village to provide access to water. Only one pump now works.

SBU graduate student Leila Esmailzada helps villagers in Ambodiaviavy, Madagascar, clean rice. The job is usually delegated to the children who pound the rice for 30 minutes. Photo by Mickie Nagel

As for food, some villagers in Madagascar spend hours preparing rice, including beating off the husks and drying the rice. They store this hard-earned food in huts that are often infiltrated with rats, who consume their rice and leave their feces, which spreads disease.

Traveling with Esmailzada and Leakey, Nagel not only helped document life in these villages but also searched for information about available resources to drive engineering innovations, while Leakey gathered information about an invasive species of guava.

“Ideally, if any projects require wood, then they should incorporate guava sticks into their design, as opposed to planks from forest trees,” explained Leakey in an email sent from Madagascar. The graduate student, who recently earned her bachelor’s degree at Stony Brook, will be recording the average thickness of the stems, the average length of a straight piece and the load capacity of the branches. Leakey plans to return from the African continent in the beginning of August.

Leakey also visited metalworkers to explore the local capacity. The raw materials come from scrap metal dealers, who often get them from old car parts.

Nagel started BeLocal with her husband Jeff Nagel and a classmate of his from their days as undergraduates at Carnegie Mellon University, Eric Bergerson. Indeed, BeLocal fulfills a long-standing goal of Jeff Nagel’s. Before freshman year in college, Nagel told Bergerson that he wanted to do something that had a positive impact on the world.

While the founders have contributed through their work, their jobs and their families, they found that partnering with Stony Brook University and Distinguished Professor Patricia Wright in Madagascar presented a chance to have a meaningful impact on life on the island nation.

Nagel, whose background is in marketing, visited Madagascar over two years ago, where she traveled for over a hundred hours on a bus through the country. “You just see people living below the poverty line and you see how that plays out in normal day-to-day activities,” she said. “You see a young mom carrying a child on her back and one on her front, with heavy produce on her head and you just think, ‘Wow, there has to be an easier way for some of this.’”

Mickie Nagel, far right, on an earlier trip to Central ValBio with her daughters Gabrielle, far left, and Lauren, center. when they first visited Centre ValBio. Photo by Heidi Hutner

When Nagel returned from her initial trip to Madagascar with her daughters Gabrielle, 18, and Lauren, 17, she and her husband thought people around the world would likely want to help but that not everyone could afford to travel that far.

Nagel recalls Bergerson, who is the director of research at the social data intelligence company Tickertags, telling her that they “don’t have to travel there. You can videotape the daily challenges and crowd source” innovations.

That’s exactly what Leakey and Esmailzada did for the last few weeks. Leakey said she is looking forward to working with senior design students as they go through their projects at Stony Brook and is eager to see how they understand the situation “through the footage and pictures we collect.”

The BeLocal approach isn’t limited to Madagascar, the BeLocal founders suggested. Indeed, given the distance to an island famous for its lemurs, animated movies and an Imax film that features primates with personality, BeLocal could have started in a Central American country like Belize.

Mickie Nagel, however, urged them to start at a location where they would immediately have the trust of local residents. That, she suggested, came from the over quarter of a century of work from Wright, an award-winning scientist who has not only helped preserve Ranomafana [National Park in Madagascar] but has also helped bring health care and education to the villages around the CVB research station. Wright and the Malagasy people have a “mutual respect for each other,” Nagel said.

“People have been exceptionally warm and welcoming,” Leakey said. Getting people accustomed to the presence of cameras hasn’t been straightforward, as people sometimes stop what they are doing, but the guides have helped make the villagers more comfortable.

Jeff Nagel, who works at a private equity firm in New York City, explained that Madagascar is the first step for BeLocal. This effort “can be expanded to other countries or other areas,” Nagel said. “It doesn’t have to be engineers and universities,” but can be instituted by creative people everywhere.

At this point, BeLocal is not looking for any additional funding but might consider expanding the effort at this time next year. Nagel said this fall, they will look for professional engineers to advise on projects. “We would like people who are interested in participating or just keeping up with developments to come and register on our website, www.BeLocalgrp.com,” she suggested.

The site, which the group is upgrading, is up and running. Bergerson explained that they have a “lot of infrastructure to build on” to create the crowd sourcing platform.

Jeff Nagel suggested that this effort is designed to use technology constructively. “Technology’s job, first and foremost, is to help humanity,” he said. “This is a chance to use it in a way that matters to people.”