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Power of 3

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0 2013
Mikala Egeblad with a blown-up image of a neutrophil extracellular trap, or NET. Photo from CSHL

By Daniel Dunaief

Mikala Egeblad couldn’t shake the feeling that the work she was doing with cancer might somehow have a link to coronavirus.

Egeblad, who is an Associate Professor and cancer biologist at Cold Spring Harbor Laboratory, recently saw ways to apply her expertise to the fight against the global pandemic.

She studies something called neutrophil extracellular traps, which are spider webs that develop when a part of the immune system triggered by neutrophil is trying to fight off a bacteria. When these NETs, as they are known, are abundant enough in the blood stream, they may contribute to the spread of cancers to other organs and may also cause blood clots, which are also a symptom of more severe versions of COVID-19, the disease caused by the coronavirus, which has now infected over two million people worldwide.

“I always felt an urgency about cancer, but this has an urgency on steroids,” Egeblad said.

Cold Spring Harbor Laboratory reached out to numerous other scientists who specialize in the study of NETs, sometimes picking up on the tweets of colleagues who wondered in the social networking world whether NETs could contribute or exacerbate the progression of Covid19.

Egeblad started by reaching out to two scientists who tweeted, “Nothing about NETs and Covid-19?” She then started reaching out to other researchers.

“A lot of us had come to this conclusion independently,” she said. “Being able to talk together validated that this was something worth studying as a group.”

Indeed, the group, which Egeblad is leading and includes scientists at the Feinstein Institutes for Medical Research and the Research Institute of the McGill University Health Centre, published a paper last week in the Journal of Experimental Medicine, in which they proposed a potential role for NETs.

“We are putting this out so the field doesn’t overlook NETs,” said Egeblad, who appreciated the support from Andrew Whiteley, who is the Vice President of Business Development and Technology Transfer at CSHL.

With a range of responses to the coronavirus infection, from people who have it but are asymptomatic all the way to those who are battling for their survival in the intensive care units of hospitals around the world, the biologist said the disease may involve vastly different levels of NETs. “The hypothesis is that in mild or asymptomatic cases, the NETs probably play little if any role,” she said.

In more severe cases, Egeblad and her colleagues would like to determine if NETs contribute or exacerbate the condition. If they do, the NETs could become a diagnostic tool or a target for therapies.

At this point, the researchers in this field have ways of measuring the NETs, but haven’t been able to do so through clinical grade assays. “That has to be developed,” Egeblad explained. “As a group, we are looking into whether the NETs could come up before or after symptoms and whether the symptoms would track” with their presence, she added.

To conduct the lab work at Cold Spring Harbor, Egeblad said her team is preparing to develop special procedures to handle blood samples that contain the virus. 

As the lead investigator on this project, Egeblad said she is organizing weekly conference calls and writing up the summaries of those discussions. She and the first author on the paper Betsy J. Barnes, who is a Professor at the Feinstein Institute, wrote much of the text for the paper. Some specific paragraphs were written by experts in those areas.

At this point, doctors are conducting clinical trials with drugs that would also likely limit NET formation. In the specific sub field of working with this immune-system related challenge, researchers haven’t found a drug that specifically targets these NETs. 

If the study of patient samples indicates that NETs play an important role in the progression of the disease, particularly among the most severe cases, the scientists will look for drugs that have been tried in humans and are already approved for other diseases. This would create the shortest path for clinical use.

Suppressing NETs might require careful management of potential bacterial infections. Egeblad suggested any bacterial invaders might be manageable with other antibiotics.

NETs forming in airways may make it easier to get bacterial infections because the bacteria likes to grow on the DNA.

Thus far, laboratory research studies on NETs in COVID-19 patients have involved taking samples from routine care that have been discarded from their daily routine analysis. While those are not as reliable as samples taken specifically for an analysis of the presence of these specific markers, researchers don’t want to burden a hospital system already stretched thin with a deluge of sick patients to provide samples for a hypothetical pathway.

Egeblad and her colleagues anticipate the NETs will likely be more prevalent among the sicker patients. As more information comes in, the researchers also hope to link comorbidities, or other medical conditions, to the severity of COVID-19, which may implicate specific mechanisms in the progression of the disease.

“There are so many different efforts” to understand what might cause the progression of the disease, Egeblad said. “Everybody’s attention is laser focused.” A measure that is easy to study, such as this hypothesis, could have an impact and “it wouldn’t take long to find out,” she added. Indeed, she expects the results of this analysis should be available within a matter of weeks.

Egeblad believes the NETs may drive mucus production in the lungs, which could make it harder to ventilate in severe cases. They also may activate platelets, which are part of the clotting process. If they did play such a role, they could contribute to the blood clotting some patients with coronavirus experience.

Egeblad recognizes that NETs, which she has been studying in the context of cancer, may not be involved in COVID-19, which researchers should know soon. “We need to know whether this is important.”

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From left, Kerstin Kleese van Dam, Brand Development Manager at BNL Diana Murphy, and John Hill at the Practical Quantum Computing Conference (Q2B) in San Jose, CA, Dec. 2019. Photo courtesy of Kerstin Kleese van Dam

By Daniel Dunaief

Brookhaven National Laboratory is putting its considerable human and technical resources behind the global effort to combat the coronavirus.

John Hill, the director of the National Synchrotron Lightsource II, is leading a working group to coordinate the lab’s COVID-19 science and technology initiatives. He is also working on a team to coordinate COVID-19 research across all the Department of Energy labs.

“We are proud that the tools we built at BNL, which include the NSLS II, which took 10 years to build and cost about a billion dollars,” will contribute to the public health effort, Hill said. “We feel that science will solve this problem, and hopefully soon. It’s great that BNL is a part of that fight.”

In addition to using high-technology equipment like the NSLS II to study the atomic structure of the virus and any possible treatments or vaccines, BNL is also engaging a team led by Kerstin Kleese van Dam, who is the director of BNL’s Computational Science Initiative.

According to Hill, the combination of the physical experiments and the computing expertise will provide a feedback loop that informs the efforts with each team. Kleese van Dam’s team is using supercomputers to run simulated experiments, matching up the atomic structure of the viral proteins with any potential drugs or small molecules that might interfere with its self-copying and life-destroying efforts.

The computer simulations will enable researchers to narrow down the list of potential drug candidates to a more manageable number. Experimental scientists can then test the most likely  treatments the computer helped select.

Across the world, the scale of the science to which BNL is contributing is even larger than the Manhattan Project that led to the creation of the atomic bomb during World War II, said Hill.

In just three months since scientists in China produced the genetic sequence of the coronavirus, researchers around the world have produced over 15,000 research articles, some of which have been published in scientific journals, while researchers have self-published others to share their findings in real time.

Working with computer scientists from different fields at BNL, Kleese van Dam is helping researchers screen through the abundant current research on COVID-19. The number of papers is “accelerating at a rate no one can read,” Hill explained. 

Kleese van Dam and four of her scientists are setting up a natural language processing interface so scientists can type in what they want to find, such as a protein binding with a specific complex, and put it into a search engine. She is working on an initial service that she hopes to expand. Additionally, the computer science team is planning to start a project to look at epidemiological data to determine how various people might react to different treatment.

Kleese van Dam and her team are also working to build an archive in the United States that they hope will host at least the results of the Department of Energy funded projects in medical therapeutics. “[We are] convinced that this would provide a much better starting point for future outbreaks, as well as providing a near term clearing house of results,” she explained in an email.

As for the work at the synchrotron, Hill said that the high-energy x-rays can determine the specific atomic configuration of proteins in the virus.

The NSLS II, which was designed to study the structure of batteries, geology and plant cells, among other objects, can look at “small protein crystals better than anywhere else in the world.”

The virus relies on a docking mechanism that allows it to enter a cell and then insert its malevolent RNA to disrupt the cell’s normal function. Understanding how the pieces come together physically can allow researchers to look for small molecules or approved drugs that could interfere with the virus.

One of the many advantages of the synchrotron over protein crystallography is that the NSLS II doesn’t need as many copies of proteins to determine their atomic structure. Hill said protein crystallography needs samples that are about 100 to 200 microns in size, which is about the width of a human hair, which can take weeks to months to years to grow. This is a “bottleneck in the whole process” of solving protein structure, he said.

On the other hand, the NSLS II only requires samples of about a micron in size. This “greatly speeds up the process,” he added. Two different groups of researchers, from the pharmaceutical industry and from academia and national labs, are conducting experiments on the NSLS II.

Hill said he was receiving viral proteins scientists believe will bind with the virus from collaborators in the United Kingdom. The scientific process is as quick and collaborative as it’s ever been among researchers, he said. The proteins arrived recently.

That collaborative process would have “taken months to set up under normal circumstances,” Hill said. Instead, it only took a few days.

At the same time, BNL is constructing a cryo-electron microscope, which doesn’t have the same resolution as the NSLS II, but does not need crystals and can study individual proteins. Researchers need about 10,000 of them and can average the images together. The resolution is five to 10 times worse than x-rays.

BNL is accelerating the construction of the cryo EM and hope to have the first beam in mid-May. Commissioning will take some extra time, Hill said. The first structure of the coronavirus spike protein was determined by using an electron microscope.

For Hill and Kleese van Dam, who each have dedicated much of their time to these efforts, the opportunity to contribute to a project that could have implications for a public that is battling this disease is rewarding and offers reasons for optimism. 

“To be able to help at such a scale is indeed humbling and gratifying,” said Kleese van Dam. “Science is going to solve this problem,” added Hill. “That gives me comfort.”

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Daniel Mazzone. Photo courtesy of BNL

By Daniel Dunaief

Like many people who hunch down when they step into cold air, many materials shrink when exposed to the frigid temperatures.

That, however, is not the case for samarium sulfide when it has impurities such as yttrium sprinkled throughout. Indeed, the material goes through negative thermal expansion, in which cold air causes it to expand.

Daniel Mazzone, a post-doctoral fellow in Brookhaven National Laboratory’s Condensed Matter Physics and Materials Science Department who is joining the Paul Scherrer Institute in May, wanted to know how this happened.

Working with synchrotrons on three different continents, at the National Synchrotron Lightsource II at BNL, the Soleil synchrotron in France and the SPring-8 synchrotron in Japan, Mazzone and a team of scientists explored the properties of this metal.

The work that led to an understanding of the properties that made the metal expand in cold temperatures could have applications in a range of industries. Some companies use materials that balance between expansion and contraction to prevent the lower temperatures from altering their configuration. 

Mazzone said the expansion properties can be fine tuned by altering the mixture of materials. With these results, he and his colleagues “bring a new material class to the focus of the community,” he wrote in a recent email.

So, what is happening with this samarium sulfide mixed with yttrium particles?

In a paper in the journal Physics Review Letters, Mazzone and his partners, including Ignace Jarrige, who is the group leader of the Soft Inelastic X-ray Scattering Beamline, described the way mobile conduction electrons screen the samarium ions, causing a fractional transfer of an electron into the outermost electronic samarium shell. Quantum mechanical rules govern the process.

Using the Pair Distribution Function beamline at NSLS-II, the researchers performed diffraction experiments. The scientists determined how the x-rays bounced off the samarium sample at different temperatures. The sample was contained in a liquid helium cooled crysotat.

“We track how the x-rays bounce off the sample to identify the locations of atoms and the distances between them,” Milinda Abeykoon, the lead scientist of the PDF beamline, said in a press release. “Our results show that, as the temperature drops, the atoms of this material move farther apart, causing the entire material to expand up to three percent in volume.”

In France and Japan, the researchers also used x-rays to explore what electrons were doing as temperatures changed.

“These ‘x-ray absorption spectroscopy’ experiments can track whether electrons are moving into or out of the outermost ‘shell’ of electrons around the samarium atoms,” Jarrige explained in a press release.

The valence electrons in samarium, which are the outermost electrons, are in a shell that is under half full. That means that they are more reactive than they would be if they the shell was full, as it is with noble gases.

The researchers observed that a fractional part of the electrons are transferred from the conduction band in the outermost samarium shell. This causes the samarium to expand, as the outermost shell needs to accommodate an extra electron. When this happens for the numerous ions in the system, this can have an important effect.

By working with Maxim Dzero, who is a theoretical physicist at Kent State University, the scientists were able to apply the Kondo effect, which was named after solid-state physicist Jun Kondo. Back in the 1960s, Kondo explained how magnetic impurities encourage electron scattering at low temperatures, which not only increases the volume of the materials, but can also increase their electrical resistance.

In the Kondo effect, electrons align their spins in the opposite direction of the larger magnetic articles to cancel its magnetism. For the samarium material, the outer shell moves around the atomic core, creating the magnetic moment of the samarium ion. 

“For some elements, because of the way the outer shell fills up, it is more energetically favorable for electrons to move out of the shell,” Jarrige explained in a press release. “But for a couple of these materials, the electrons can move in, which leads to expansion.”

A phone call among several of the collaborators led them to believe the process involved with the samarium was akin to the one that causes water to expand when it freezes. As scientists build on this understanding, they will likely need to create or search for similar but alternative materials to samarium sulfide, Mazzone said. 

Samarium sulfide is incredibly expensive. Materials scientist will need to find the right elements that can “do the same job,” he explained. “The next step is to find the materials that are cheaper and optimize it.”

Mazzone, who is currently living in his home country of Switzerland, is preparing for his next job, which is expected to start next month.

He and his wife Fabienne, who is an economist at the ski producer Stöckli, enjoyed living on Long Island during his two year post-doctoral research experience.

“Switzerland is landlocked and surrounded by mountains,” said Mazzone, who speaks German, French, English and some Italian. “Having a beach at the front door [when they lived on Long Island] was beautiful.”

Dedicated climbers, the Mazzones traveled to the Shawangunk and Adirondack mountains while they lived on Long Island to find an outlet for their passion for rock climbing.

As for his future work, Mazzone anticipates remaining in academia where he would like to continue his research and teach. He plans to conduct additional experiments on the Kondo effect. These materials also feature properties such as unconventional superconductivity and other quantum phases that may help with quantum computing.

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Lijun Wu is the 17th recipient of this esteemed award. Photo courtesy of BNL

By Daniel Dunaief

Despite the pause New York and so many other states are taking to combat the coronavirus, the awards can, and will, go on.

The Microscopy Society of America gave Brookhaven National Laboratory’s Lijun Wu the 2020 Chuck Fiori Award. The Award, which started in 1993, recognizes the achievements of a technologist in the physical sciences who has made long-standing contributions in microscopy or microanalysis.

Wu is the second consecutive BNL staff member to win the Chuck Fiori award. Dmitri Zakharov took home the honors last year.

Lijun Wu during a trip to Alaska last summer. Photo from Jiangyan Fang

Wu is an engineer in the Electron Microscopy and Nanostructure Group in the Condensed Matter Physics and Materials Science Division. He works with transmission electron microscopy in quantum materials, batteries, catalysts, and other energy materials. Wu learned how to write software programs on his own. His first effort in this area involved a program that indexed electron diffraction patterns. He has also created programs for simulating microscopy images and diffraction patterns.

Wu, who is hoping to pick up the award at the Microscopy Society of America meeting in August if the meeting still takes place, said he was “excited” to receive this distinction and was pleased for the support throughout his career at BNL.

Wu “has made significant contributions to the field of electron microscopy, especially quantitative electron diffraction,” group leader and senior scientist Yimei Zhu, said in a statement. “Applying his expertise in the field and talents in computer programming, [he] has advanced electron microscopy for material characterization. He well deserves the award.”

One of the most important contributions Wu, who has been at BNL since 1996, has made was in developing an electron diffraction method for measuring valence electron distribution. The valence electrons are the ones in the outermost shell of any substance or material.

Wu worked with Zhu and Johan Taftø, a visiting scientist from the University of Oslo, to develop an electron diffraction–based method for measuring valence electron distribution.

He appreciates the support and encouragement he has received from Zhu since he arrived at BNL.

Transmission electron microscopes can provide atomic-resolution images and electron-energy loss spectroscopy, Wu suggested. Through this work, scientists can determine where atoms are and what kind of atoms are present.

He would like to measure the distribution of these valence electrons through a process called quantitative electron diffraction.

By understanding how atoms share or transfer electrons, researchers can determine the physical properties of materials. Electron diffraction measurements can describe valence electron distribution from the bonds among atoms.

Wu and his colleagues developed a method called parallel recording of dark-field images. Through this technique, the scientists focus a beam above the sample they are studying and record numerous reflections from the same area. This is like studying the partial reflection of objects visible in windows on a city street and putting together a composite, three-dimensional view. Instead of cars, people, traffic lights and dog walkers, though, Wu and his colleagues are studying the distribution of electrons.

The information the scientists collect allows them to measure the charge transfer and aspherical valence electron distribution, which they need to describe electron orbitals for objects like high-temperature superconductors.

Using an electron probe, the team developed the technique to measure the displacement of atoms in crystal lattices with one-thousandth-of-a-nanometer accuracy.

To learn how to write software, Wu used several resources.

“I used literature and read books for computer programming,” he said. “I spent many, many years” learning how to write programs that would be useful in his research. He also consulted with colleagues, who have written similar programs.

Wu explained that the calculations necessary for his work far exceeded the functionality of a calculator. He also needed a super computer to handle the amount of data he was generating and the types of calculations necessary.

“If we used the older computer technique, it would take days or weeks to get one result,” he said.

A native of Pingjing in Hunan Province in China, Wu said learning English was considerably more challenging than understanding computer programming.

The youngest of nine siblings, Wu is the only one in the family who attended college. When he began his studies at the prestigious Shanghai Jiao Tong University, he said he was interested in physics and computers.

The college, however, decided his major, which was materials science.“They assigned it to me,” Wu said. “I liked it.”

He and his wife Jiangyan Fang, who is an accountant, have a 25-year-old son David, who lives in Boston and works with computers.

Wu, who started out at BNL as a Visiting Scientist, said he is comfortable living on Long Island. He said Long Island is cooler than his home town in the middle of China, where it’s generally hotter and more humid. For a week or two each year, the temperature can climb above 104 degrees Fahrenheit.

As for his work, Wu said he looks at the atomic level of substances. His techniques can explore how a defect in something like a battery affects how ions, like lithium, get in and through that.

“When you charge or discharge a battery, [I consider] how an electron gets through a defect. I always think about it this way.”

Wu has been working with Zhu and visiting scientist Qingping Meng from Shanghai Jiao Tong University, where Wu earned his Bachelor’s of Science and his Master’s in Science, on an initiative that advances the ability to determine valence electron distribution.

Wu is preparing a new publication. “I’m writing the manuscript and will introduce the method we are developing,” he said.

 

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SBU team member Steve Forrest scales the rock face as chinstrap penguins look on. Photo by Christian Åslund

By Daniel Dunaief

The canary in the Arctic coal mines, chinstrap penguins need more ice. These multitudinous flightless birds also depend on the survival and abundance of the krill that feed on the plankton that live under the ice.

With global warming causing the volume of ice in the Antarctic to decline precipitously, the krill that form the majority of the diet of the chinstrap penguin have either declined or shifted their distribution further south, which has put pressure on the chinstrap penguins.

Indeed, at the end of December, a team of three graduate students (PhD students in Ecology and Evolution Alex Borowicz and Michael Wethington and MS student in Marine Science Noah Strycker) from the lab of Heather Lynch, who recently was promoted to the inaugural IACS Endowed Chair of Ecology & Evolution at Stony Brook University, joined Greenpeace on a five week mission to the Antarctic to catalog, for the first time in about 50 years, the reduction in the number of this specific penguin species.

The team boarded Greenpeace’s ship, the Esperanza, for a five week mission. Photo by Christian Åslund

The group, which included  private contractor Steve Forrest and two graduate students from Northeastern University, “saw a shocking 55 percent decline in the chinstrap on Elephant Island,” Lynch said. That drop is “commensurate with declines elsewhere on the peninsula.”

Elephant Island and Low Island were the targets for this expedition. The scientific team surveyed about 99 percent of Elephant Island, which was last visited by the Joint Services Expedition in 1970-1971.

The decline on Elephant Island is surprising given that the conditions in the area are close to the ideal conditions for chinstraps.

In some colonies in the Antarctic, the declines were as much as 80 percent to 90 percent, with several small chinstrap colonies disappearing entirely.

“We had hoped that Elephant Island would be spared,” Lynch said. “In fact, that’s not at all the case.”

While many indications suggest that global warming is affecting krill, the amount of fishing in the area could also have some impact. It’s difficult to determine how much fishing contributes to this reduction, Lynch said, because the scientists don’t have enough information to understand the magnitude of that contribution.

The chinstrap is a picky eater. The only place the bird breeds is the Antarctic peninsula, Elephant Island and places associated with the peninsula. The concern is that it has few alternatives if krill declines or shifts further south.

“Chinstraps have been under-studied in the last few decades, in part because so much attention has been focused on the other species and in part because they nest in such remote and challenging places,” Lynch explained in an email. “I hope our findings raise awareness of the chinstraps as being in serious trouble, and that will encourage everyone to help keep an eye on them.”

While these declines over 50 years is enormous, they don’t immediately put the flightless waterfowl that tends to mate with the same partner each year on the list of endangered species because millions of the sea birds that feel warm and soft to the touch are still waddling around the Antarctic.

Researchers believe that the biggest declines may have occurred in the 1980s and early 1990s, in part because areas with more regular monitoring showed reductions during those times.

Still, where there are more recent counts to use as a standard of comparison, the declines “show no signs of abating,” Lynch explained.

The evidence of warming in the Antarctic has been abundant this year. On Valentine’s Day, the Antarctic had its hottest day on record, reaching 69.35 degrees Fahrenheit. The high in Stony Brook that day was a much cooler 56 degrees.

“What’s more concerning is the long term trends in air temperature, which have been inching up steadily on the Antarctic Peninsula since at the least the 1940’s,” Lynch wrote in an email.

At the same time, other penguin species may be preparing to expand their range. King penguins started moving into the area several years ago, which represents a major range expansion. “It’s almost inevitable that they will eventually be able to raise chicks in this region,” Lynch suggested.

The northern part of the Antarctic is becoming much more like the sub Antarctic, which encourages other species to extend their range.

Among many other environmental and conservation organizations, Greenpeace is calling on the United Nation to protect 30 percent of the world’s oceans by 2030. The Antarctic was the last stop on a pole to pole cruise to raise awareness, Lynch said.

One of the many advantages of traveling with Greenpeace was that the ship was prepared to remove trash.

“We pulled up containers labeled poison,” Lynch said. Debris of all kinds had washed up on the hard-to-reach islands.

“People are not polluting the ocean in Antarctica, but pollution finds its way down there on a regular basis,” she added. “If people knew more about [the garbage and pollution that goes in the ocean], they’d be horrified. It is spoiling otherwise pristine places.”

Lynch appreciated that Greenpeace provided the opportunity to conduct scientific research without steering the results in any way or affecting her interpretation of the data.

“We were able to do our science unimpeded,” she said.

Counting penguins on the rocky islands required a combination of counting birds and nests in the more accessible areas and deploying drones in the areas that were harder to reach. One of Lynch’s partners Hanumant Singh, a Professor Mechanical and Industrial Engineering at Northeastern University, flew the drones over distant chinstrap colonies. The researchers launched the drones from land and from the small zodiac boats.

The next step in this research is to figure out where the penguins are going when they are not in the colony. “Using satellite tags to track penguins at sea is something I’d like to get into over the next few years, as it will answer some big questions for us about where penguins, including chinstraps, are trying to find food,” Lynch said.

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Above, from left, Kenneth Kaushansky, Dean of the Renaissance School of Medicine; Anissa Abi-Dargham; Henry Tannous; Ute Moll; and Michael Bernstein, Interim President of SBU.

By Daniel Dunaief

A heart and lung doctor, a researcher who works on imaging for schizophrenia and a scientist working with a mutation that affects cancer last month received endowed inaugural chair positions at Stony Brook University.

Ute Moll is the Renaissance Endowed Professor in Cancer Biology, Anissa Abi-Dargham is the Lourie Endowed Chair in Psychiatry and Henry Tannous is the General Ting Feng Cheng Endowed Chair in Cardiothoracic Surgery.

In addition to adding the prestigious titles and winning support from local benefactors and philanthropists, the three researchers will each receive annual financial support from their positions that will sustain their research and education efforts. TBR News Media is highlighting the research from each of these standout scientists.

Ute Moll

Ute Moll

A native of Germany, Ute Moll, who is studying the six most common mutated forms of the highly researched p53 gene, is grateful for the donors, the funds and the recognition. “It’s pretty prestigious to have an endowed chair or professorship attached to your name or title,” she said 

Moll described the p53 mutations as the “most common mutation in cancer.” She has been working with a mouse model. The p53 R248 hotspot is the single most common variant in all p53 altered tumor types, which occurs in about 66,000 newly diagnosed cancer patients in the United States each year.

If these mice also have a gene called Myc, they get either liver or colon cancer. By receiving an estrogen derivative drug called Tamoxifen, which is used in breast cancer, the active, mutated version of the p53 gene is turned off when another gene called Cre recombinase is activated. By removing the p53 gene, the mice live two to three times longer than they would have.

In a typical mouse, cancer can cause over 100 tumor nodules, leaving almost no normal liver. When Moll and her colleagues turned off the mutant gene, the size of the cancer is much more limited, with only a few remaining nodules.

One particular mouse lived for more than two months, eventually dying of an unrelated lymphoma. The liver, however, which had an infection across the entire organ, didn’t show a single trace of a tumor. It was completely normal, despite the ubiquitous tumor nodules before treatment.

Thus far, targeting this mutated p53 is a concept Moll and her colleagues have developed in pre-clinical mouse models of lymphoma, colon and liver cancer, but it doesn’t yet have a clinical application. 

Liver cancer used to be relatively rare in the population, driven largely by infection from hepatitis B and hepatitis C, as well as through alcoholism. Amid an epidemic of obesity, people are developing a chronically inflammatory liver condition, which increases the incidence of liver cancer.

Anissa Abi-Dargham

Anissa Abi-Dargham

A specialist in Positron Emission Tomography (or PET) imaging for schizophrenia, Anissa Abi-Dargham is pleased with the opportunity to deploy the funds for her work at her discretion.

“The beauty of these funds is that they are totally flexible,” she explained, adding that she plans to use the funds to pursue new research ideas that might not otherwise get funding until she can use data to prove a concept or principal. 

“This is really a great honor because it means that the institution believes in you and wants to invest and retain you,” she said.

In her work, Abi-Dargham has been using imaging to see what is causing dopamine dis-regulation, either with too much or too little of the neurotransmitter. 

She is looking at two systems that may explain the imbalance: the cholinergic system and the kappa opioid system.

Abi-Dargham had been at Columbia University for 20 years before joining Stony Brook over three years ago. She appreciates the school investing in a state-of-the-art imaging center. “The people in charge of this imaging center are very much investing in promoting imaging for neuroscience and psychiatry,” she said.

Based on her findings in schizophrenia, other investigators in the United Kingdom have documented dopamine levels before schizophrenia symptoms begin.

She hopes her research discovers biomarkers that can be used to predict who is going to convert to having schizophrenia.

Patients do better when the onset of symptoms is later in their lives because their more mature brain has fostered better organized life, skill sets, and relationships.

She is also testing whether other markers, such as a neuromelanin, which is a metabolite of dopamine and binds iron-like materials, will show up on a Magnetic Resonance Imaging scan before the disease.

Henry Tannous

Henry Tannous

Henry Tannous joined Stony Brook University in 2016 and is excited to be a part of the current team and to help shape the future of clinical practice and research.

Tannous called the endowed chair position an “absolute honor.” It will not only allow him to continue with his current work, but it’s also going to enable him to expand his research. He will also use some of the funds to provide continuing education for his staff.

The financial support will allow him to hire research assistants and access national databases. Tannous and his research team of cardiothoracic and lung scientists use registries from the New York State Department of Health registry and the Society of Thoracic Surgeons, each of which provides the data for a price.

With his lung work, Tannous focuses on state 1 lung cancer. Traditionally, he said, people have received a diagnosis late in the development of the disease. Over the past few years, doctors have diagnosed patients at an earlier point.

Earlier diagnoses became more prevalent after Medicare approved lung cancer screening in 2015, which picked up more cases while patients were still in the earlier stages, when the cancer might otherwise be asymptomatic.

“We would like to know more about how the disease affects [patients] and their quality of life,” Tannous said. His lab has a collaboration with Mount Sinai Hospital to learn more about the effect of the disease on the lives of the patients.

With his heart research, he’s focusing on aortic disease and is testing the limits of the Trans Catheter Aortic Valve Replacement.

Photos courtesy of SBU

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ARM instrument mentor Janek Uin in front of Polarstern
The icebreaker Polarstern
Containers on the Polarstern
A polar bear with a cub
ARM/BNL Instrument Mentors Matt Boyer, Janek Uin and Tom Watson in front of the AMF2 AOS
ARM/BNL Instrument Mentors Matt Boyer, Janek Uin and Tom Watson in front of the AMF2 AOS
Last look on Polarstern while waiting for helicopter ride to Akademik Fedorov
BNL's Matt Boyer and Janek Uin
Preparing to launch a helicopter from Akademik Fedorov
Lifting equipment onto ice
ARM technician Vagner Castro and ARM Instrument Mentor Matt Boyer
A curious polar bear
Polarstern trapped in the ice
Snowman on Akademik Fedorov

By Daniel Dunaief

Two researchers from Brookhaven National Laboratory were stuck on a ship trapped in ice near the North Pole — and they couldn’t have been happier.

In fact, one of them, Matt Boyer, an Atmospheric Scientist at BNL, is returning to the German ship Polarstern for six of the next seven months. The Polarstern is part of a 20-nation effort that will gather information about the Arctic to understand climate change. The scientific collaboration, called MOSAiC (Multidisciplinary Drifting Observatory for the Study of Arctic Climate), started in September and will involve collecting data for a full year.

The scientists are measuring aerosols, cloud particles, and other data through conditions that are among the most challenging on the planet. Researchers aboard the Polarstern regularly endure cold temperatures, fierce winds, minimal to no sunlight and the threat of polar bears unafraid of humans.

Janek Uin, an Associate Atmospheric Scientist at BNL, is working with instruments that measure properties of atmospheric aerosol particles such as their size, the concentration of particles per unit volume of air, how the particles are affected by water vapor and how much light the particles scatter, which affects the sunlight that reaches the Earth’s surface.

Arthur Sedlacek, an atmospheric chemist with the Environmental & Climate Sciences Department at BNL, is one of a host of scientists collecting data from the Polarstern. Indeed, Sedlacek traveled to Tromsø Norway when the ship departed, where he prepared to measure the accumulation of black carbon in the Arctic. 

Caused by burning fossil fuels, emissions from distant wildfires, among other things, black carbon can cause polar ice to melt. When there is sun, the black carbon prevents the reflection of the light, which further darkens the white surface, either through exposure of the underlying ground or previously deposited black carbon.

Sedlacek, who did not travel aboard the Polarstern, said scientists around the world are “itching to see the data” from this ambitious mission. The data collection is “so unique and so important that it will not only help us better understand the current (pristine) state of the cryosphere, but it will also [allow scientists] to better understand (and quantify) how the Arctic is responding to climate change.”

Uin, who is an instrument mentor for about 30 instruments worldwide, recalled how he went out for a fire drill. Following his designated path and waiting for the signal to return, Uin decided to snap some pictures of a frozen and uneven landscape that appeared blue during much of the day, when the faint rays of the sun barely made it over the horizon. Unable to maneuver the camera to his satisfaction, Uin took off his gloves. His exposed fingers became numb in the wind. After he put his gloves back on, it took about 10 minutes for the feeling to return to his hands.

Boyer, meanwhile, who spent more of his time working outside than Uin, helped set up the meteorological site about 1 kilometer away from the ship and is monitoring the size and concentration of organic and inorganic aerosol particles.

The size and concentration of the particles determines how they behave in atmospheric processes, Boyer explained. The size of the particle influences its light scattering ability, how long it stays in the atmosphere, the human health impact and its ability to form clouds, among other properties.

The process of working near the North Pole requires a high level of patience. A task that might take two hours in a lab, for example, might require as long as four days to complete in Arctic conditions.

Boyer described how the moisture from his own breath sometimes froze in his face. “I prefer not to wear goggles” because they fog up, he explained. When he exhaled, the water vapor in his breath caused his eyelids to freeze shut. “You have to constantly close your eyes and pull the ice off your eyelids.”

Boyer had to hold onto a piece of metal when it was well below 0 degrees Fahrenheit and windy. Placing the bolts, nuts and screws into a hole with a glove on is “almost impossible,” Boyer said, although once those items are in place, holding a wrench with gloves on is manageable

Each time people work outside, polar bear guards constantly watch the horizon to make sure the carnivorous creatures don’t approach scientists. While the ship is not a cruise vessel, it offers pleasant amenities, including a small pool, a sauna, an exercise room and nourishment Uin and Boyer, who were roommates aboard the Polarstern, appreciated.

“The food was excellent,” Uin said. “Working long hours in extreme conditions in close quarters, the food has to be good. If it’s bad, morale plummets.” The scientist has been on three ice breakers and the food has always been high quality. 

Uin appreciated the opportunity to take the journey and to conduct the scientific research. “I am reminded how lucky I am that people trust me to do this,” he said.

Uin enjoys the opportunity to look at the ice, which appears blue because of the low light. “People think it’s all white,” he said. “There’s a constant twilight and an all-encompassing blue.” He is excited to look at the information the instruments collect and is “certain that the data will help to bring new insights into the very complex processes governing Earth’s climate and help better predict future trends.”

Boyer, who plans to leave BNL this month to pursue his PhD at the University of Helsinki, said he appreciated the opportunity to be a part of a multi-national team. “I’m one of the luckier people on the planet,” Boyer said. “Not many people will see the Arctic and the Antarctic and I’ve seen both,” adding that there is a satisfaction at being involved with something that is “much larger than myself. I’m a part of a community that works together towards a common goal. It’s nice to be a part of an international team working with people from places and countries who put aside their differences.”

All photos from Janek Uin

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Maureen O’Leary. Photo courtesy of SBU

By Daniel Dunaief

Like the great white shark that needs to keep swimming to stay alive, scientific databases that provide resources to researchers from all over the world can’t stay still or they risk losing their usefulness and reliability.

The directors of these resources need to find funds that will ensure that the data remains accessible and that users, who range from high school students conducting work for a class to the chairman of research departments at colleges, can benefit from the availability of information.

Maureen O’Leary. Photo from SBU

Maureen O’Leary, a Professor and Graduate Program Director at the Department of Anatomical Sciences at the Renaissance School of Medicine at Stony Brook University, is looking to ensure that Morphobank, a web application and database that allows scientists around the world to share raw data on the structure of various organisms to help determine their evolutionary links, receives funds that sustain its mission.

O’Leary helped start MorphoBank in 2000 to encourage researchers to share data and propel science forward and is currently the director. By making observations of the structures of organisms available in one place online, she hoped to help advance the field of phylogenetics — the relationships among organisms in a family tree — while cutting down on the need to reproduce data from the same fossils at museums or other sites.

Up to this point, O’Leary has found financial support for the effort through grants from the National Science Foundation, the American Museum of Natural History and the National Oceanographic and Atmospheric Administration.

Looking to the future, however, O’Leary wanted to create a financial plan that would ensure ongoing funding for a database that has not only helped researchers explore data, but has also enabled collaborators to share information privately in a non-public area of MorphoBank.

O’Leary has been working with Phoenix Bioinformatics, a nonprofit group based in Fremont, California that has developed funding models for databases. Phoenix started its operations in 2013 after the staff of TAIR, a curated database for plant genome information, lost its grant funding.

The business is in the early stages of helping O’Leary with Morphobank, said Eva Huala, the Executive Director of Phoenix and a founding member of TAIR.

Phoenix has helped construct a financial model that is similar to the way university libraries and scientists pay for subscriptions to journals. The prices vary depending on the database the library subscribes to and the amount of usage of that database from the university. 

Huala said Phoenix is providing software that helps recruit members. The company is also enabling users to see whether their institution is supporting MorphoBank. So far, the Executive Director is “encouraged by the response. We know that this often takes several months or longer for libraries to decide” to lend financial support, she said.

The cost of running MorphoBank is connected to the time people spend curating as well as fixing bugs or managing computer-related challenges. Without software patches and fixes, the databases can run into problems.

Universities often require their researchers to make sure the data they collect is available to the scientific community, Huala explained, adding that MorphoBank can give scientists a way to “demonstrate the impact of their research” by offering download and viewing statistics for their data.

Mike D’Emic, an Assistant Professor in Biology at Adelphi University and a member of the Executive Committee of MorphoBank, has used the database for over seven years.

D’Emic suggested that MorphoBank “saves people from reinventing the wheel in doing science” by providing free, raw data. Scientists don’t have to travel to museums or other sites to gather the same information.

An early career researcher or student might have a small grant to visit three or four museums. These scientists can “supplement that data set with information from MorphoBank that’s multiple times the value of a grant they would have gotten,” D’Emic noted.

Scientists can freely use data from MorphoBank that would have taken tens of thousands of dollars to acquire. This includes photographs of a dinosaur skull from distant countries or CT scans that can be expensive to produce.

D’Emic, who helped convince the Adelphi library to provide financial support for the database, said MorphoBank addresses bug reports quickly, fixing problems with a few days.

Prior to O’Leary’s effort to start MorphoBank, a researcher might need to search through the appendices or the published reports from other scientists in their field to access raw data for tree building, sometimes retyping by hand large spreadsheets of numerical scores.

MorphoBank has been “invaluable and transformative in terms of the way people access and replicate science,” D’Emic said.

Some journals have started urging authors to publish their data online. The Journal of Vertebrate Paleontology strongly recommends uploading dataset, character descriptions and images to an online repository.

“For not too much money, MorphoBank has a huge impact on science,” D’Emic said, who said it was a cost effective boost to evolutionary biology and related fields

Scientists have changed significantly in their approach to sharing information. Around 30 years ago, some researchers wouldn’t always share their raw data. Other scientists would then have to spend thousands of dollars to travel to places like Thailand, Australian and Madagascar.

“People have come around” and are more comfortable exchanging data, sometimes as they produce it, D’Emic said. “MorphoBank has been an integral venue for convincing people you should share.”

O’Leary believes researchers have evolved in the way they think about the information they collect as a part of their studies.“We have reached a social transition where scientists get used to not only writing a paper and walking away, but making sure the data content is in a digitally reusable format,” she said.

O’Leary feels fortunate to have received funding for over two decades for MorphoBank. She plans to remain the director when MorphoBank moves to Phoenix. It’s an “important and dynamic tool” and she feels a “responsibility to allow its continuity.”

 

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Members of the team at Brookhaven Lab’s Accelerator Test Facility from left, Mark Palmer, Dejan Trbojevic, Stephen Brooks, George Mahler, Steven Trabocchi, Thomas Roser, and Mikhail Fedurin. Photo from BNL

By Daniel Dunaief

Scientists at Brookhaven National Laboratory and Cornell University have tested and developed a new “green” accelerator. Capturing and reusing the energy from electrons that are decelerating, the newly designed model, called CBETA, will have uses in everything from computer chip manufacture to medicine to missile defense to basic science.

Employing permanent magnets, which require no energy to operate, and superconducting material, these researchers brought to fruition an idea first formulated in 1965 by Maury Tigner, professor emeritus at Cornell University.

“It was talked about for many years,” said Thomas Roser, who just completed his 10th year as chairman of the Collider-Accelerator Department at Brookhaven National Laboratory. “To put everything together in an energy efficient way could have a significant impact for the future.”

Indeed, the new design could lower the energy needs of a future facility like the Electron Ion Collider, which BNL plans to complete in 2030.

“We all have a responsibility to contribute to the well-being” of the planet, including in efforts to reduce the energy consumption of devices used to unlock the mysteries of the universe and produce future technology, said Roser.

Schematic of the Cornell-BNL
ERL Test Accelerator.
Image courtesy of Cornell University

One of the many advantages of the new accelerator design, which was tested in the early morning hours of Dec. 24 at Cornell, is that it captures and reuses the energy in a multi-turn particle accelerator. The idea of the accelerator was to enable beams of different energy to travel through the same magnets on slightly different paths in an oblong structure. 

The design is akin to a relay race on a running track. Each lane has runners that move at their own speeds. When it is time for one of the runners to slow down and leave the track, she shares the energy from her sprint with an intermediary, which drives the next runner forward at a rapid pace, while she decelerates in a nearby loop.

In the case of the accelerator, the intermediary is a superconducting radio frequency cavity.

A key design feature is that multiple beams recirculate in these cavities four times. This cuts down on future construction costs and reduces the size of an accelerator from about a football field to a single experimental hall, according to information from Cornell.

A fresh electron beam allows researchers to get a better quality beam than in the traditional way of operating an accelerator, in a ring that would circulate continuously. 

“The beam is always refreshed, and what gets recirculated is the energy,” Roser said.

The high quality, bright beam creates bright lasers that companies may be able to use to manufacture new chips for computer or phone technology. These accelerators could also make infrared lasers that could melt objects. This type of application could help with defense department efforts to thwart an incoming missile. While BNL is taking steps to work on applications in other areas, the Department of Energy laboratory is not involved in such missile defense applications.

In the medical arena, this kind of accelerator could enable the construction of smaller, simpler and lighter devices for proton therapy to treat cancer. The multi-energy beam transport of CBETA would allow the building of more compact and less expensive gantries that deliver beams to the patient.

Using different energies at the same time, doctors could “treat cancers at different depths inside the body,” Roser said. “That’s an application for this unique transport.” Proton therapy could become cheaper and available in more hospitals with this approach, he asserted.

For Dejan Trbojevic, the principal investigator on the CBETA project and a senior physicist from BNL, the successful test of the concept was a validation of over 20 years of work.

“You can do a lot of simulations assuming realistic errors,” but the actual experiment demonstrating the concept “makes a big difference,” he explained in an email.

The BNL scientist was at Cornell in late December, where he and his colleagues celebrated the results with champagne.

Trbojevic, who had developed the concept of using a single beamline instead of multiple beamlines, hopes to use the new design to create a less expensive design to proton therapy treatment for cancer

“I’m trying to make this cheaper so more hospitals can have it,” Trbojevic said. He has already made contact with companies and a professor in Europe who hopes to use the design concept. He has also requested funding from the Department of Energy.

Beyond the excitement of the recent collaboration with Cornell on the new accelerator design, Roser reflected on his first decade as chairman of the Collider-Accelerator Department.

The BNL department is leading the world in many accelerator technologies and is collaborating closely with CERN, which was founded in Europe seven years after BNL.

Indeed, this year marks numerous celebrations for the department. The Relativistic Heavy Ion Collider, or RHIC, has been operating for 20 years and will become a part of the new Electron Ion Collider. At the same time, the Alternating Gradient Synchrotron, where research for three Nobel Prizes was conducted, marks its 60th year of generating scientific results.

And, to top off the historical trifecta, Ernest Courant, a former BNL Scientist who teamed up with Stanley Livingston and Hartland Snyder to create the strong focusing principle, turns 100 in March. Courant, who worked with Trbojevic on a paper describing the single beamline concept in 1999, helped provide a critical step for modern particle accelerators.

As it did 10 years ago, the department is rolling these three celebrations into one in June.

Courant can’t attend the event because he lives in a retirement home in Ann Arbor, Michigan near his son. BNL will likely show photos and video from Ernest’s birthday at the celebration.

As for the recently completed collaboration with Cornell, Roser believes the work is an important step.

“It’s a new concept and a new type” of accelerator, Roser said. “That doesn’t come around very often. There are cyclotrons and there are linear accelerators. This is a combination of a circular and linear accelerator put together in a new way.”

 

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Lingbo Zhang Photo from CSHL

By Daniel Dunaief

In the span of a few months, Lingbo Zhang, a Cold Spring Harbor Laboratory fellow, has made discoveries involving two deadly blood cancers.

In September, Zhang, collaborating with researchers from Memorial Sloan Kettering Cancer Center and the National Institute of Diabetes and Digestive and Kidney Diseases, found a drug target that might eventually lead to a new treatment for myelodysplastic syndrome, which is a common form of blood cancer. The scientists published their work in the journal Science Translational Medicine.

In January, Zhang published work that analyzed the genes that are active in acute myeloid leukemia, which has a five-year survival rate of only 33 percent. 

By studying 230 genes, Zhang found that this form of blood cancer is addicted to higher concentrations of vitamin B6, creating a potential target for future therapy. The CSHL scientist published this work in the journal Cancer Cell.

“We feel humbled that we found a target” for a future AML therapy, Zhang said of his latest discovery. “My lab partners and I think one day we can potentially translate our knowledge into a real therapy. The translational part gives us the energy and encouragement to work hard.”

Indeed, Zhang explained that his work broadly focuses on blood cancer, in which he looks for questions of medical importance. With MDS, he started with the view that many patients with this disease do not respond to the typical treatment using a hormone called erythropoietin, or EPO.

Lingbo Zhang

People with MDS typically have too few red blood cells, which are made in bone marrow. The hormone EPO converts progenitor immature versions of red blood cells into the ones that function in the body. A small percentage of MDS patients, however, respond to EPO. This occurs because people with this disease have a smaller pool of progenitor cells.

Zhang and his colleagues went upstream of those progenitor cells, searching for defective processes earlier in the pathway. They found that a protein receptor, CHRM4, decreases the production of cells that might become red blood cells. 

By inhibiting that receptor, they hoped to restore the red blood cell making process. In mice that have the same blood features as human MDS, this approach worked, restoring the machinery that leads to the production of red blood cells.

With both the MDS and the leukemia studies, these discoveries might lead to a future treatment, but are not necessarily the final step between understanding molecular signals and developing treatments. These findings are transitioning from basic discoveries into the preclinical development of novel therapies, Zhang said.

For MDS, the treatment may be effective with the inhibitor itself, while for AML, it will potentially be effective as part of a therapy in combination with other treatments.

In his work on leukemia, Zhang said the research went through several phases, each of which took several months. For starters, he screened all the potential target genes. Once he performed the initial work, he conducted a validation study, exploring each gene, one by one. Finally, he worked to validate the study.

After all that work, he discovered the role that the gene that makes PDXK, the enzyme that helps cells use vitamin B6, plays in contributing to cancer. Normal, healthy cells use vitamin B6 during metabolism to produce energy and grow. As with most cancers, leukemia involves more cell division than in a healthy cell, which means that the PDXK enzyme is more active.

Scott Lowe, a collaborator on the research and former CSHL fellow who is now the chair of Cancer Biology and Genetics at Memorial Sloan Kettering, expressed surprised at the finding. “While the action of certain vitamins has previously been linked to cancer, the specific links between vitamin B6 identified here were unexpected,” he said in a press release.

A postdoctoral researcher in Zhang’s lab who has been working on the project for two years, Bo Li plans to continue this research and hopes to find a more mechanistic understanding of the discovery.

While this vitamin contributes to cancer, people with leukemia shouldn’t reduce their consumption of B6, which is necessary in healthy cells. If normal and cancer cells both need this vitamin, how could this be a target for drugs?

The difference, Zhang explained, is in the concentration of the enzyme and, as a result, the B6.

PDXK is higher in leukemia. Reducing its activity by inhibiting this activity could affect the disease.

Working with a collaborator at Memorial Sloan Kettering, Zhang is hoping to develop a better chemical compound with the right property to target the activity of this gene and enzyme.

To conduct research into different diseases and pathways, Zhang works with a group of “very talented and hard working people,” in his lab, which includes a few postdoctoral researchers, a doctoral student, a few undergraduates and a technician, bringing his lab’s staff to eight people. “We also have very good collaborators at other institutes and we are able to manage several projects in parallel,” he said.

Zhang said he likes basic and translational science. The basic science brings “beautiful new theories that identify a detail nature created.” He also feels driven to “translate some of these basic discoveries into a potential treatment,” he said. He is working with a foundation and the hospital and receives patient information from them, which encourages him to work hard to seek ways to “benefit them.”

Down the road, he hopes to understand the hierarchical process that leads from stem cells to mature blood cells. By identifying a majority of the players or the regulators, he may be able to understand the different processes involved in the course of numerous diseases.

As for his current work, Zhang is pleased with the potential translational benefit of both discoveries. “I feel very happy that we can identify a target for leukemia and MDS,” he said.

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