At the March 3 Town Board meeting, Councilwoman Jane Bonner recognized a group of Rocky Point High School Technology students who created a prosthetic hand for Anun Suastika, a six-year-old Indonesian boy who was born with no fingers on his right hand. Anan’s father made a plea on a website called E-name for someone to help make a prosthetic hand for his boy.
Mr. Schumacher, passionate about teaching students the technology skills that they can use in many career fields, happened upon e-NABLE, an organization with volunteer members who use open-source technology and 3-D printers to provide free prosthetic hands for children and adults. He thought it would be a great way to blend technology and humanity into a project for his students and guided them as they built the prosthetic hand using the school’s 3-D printer.
The students worked during free periods and after school to design and assemble the 3-D parts into a Phoenix V-3 prosthetic hand. As traditional prosthetics normally cost thousands of dollars and need to be replaced as children grow, the production of a printed Phoenix V-3 prosthetic hand is much more inexpensive because of its design: It simply relies on a person’s functional wrist and uses the palm to push against the device so the fingers close when the wrist is bent.
“It is not every day that high school students can make such a big impact on a person’s life, but these students did just that. I thank Mr. Schumacher and his Technology class for taking on the challenge to improve Anun’s quality of life,” said Councilwoman Jane Bonner.
“We are grateful to Mr. Schumacher and these students for this project that will have a profound effect on a boy’s life,” Rocky Point School District Superintendent of Schools Dr. Scott O’Brien said. “The enthusiasm and passion shown by this committed group is inspiring to others in our school district, learning that in our classrooms they too can make a difference in the global community.
A team of researchers led by Nav Nidhi Rajput, PhD, at Stony Brook University, have found a way to computationally predict stable molecular species in liquid solutions. The new method, detailed in a paper in Nature Computational Science, introduces a fully automated high-throughput computational framework to predict stable species by computing their nuclear magnetic resonance (NMR) chemical shifts.
Liquid solutions are essential aspects of both materials science applications such as battery development, and biological applications such as drug discovery. However, to optimize the performance of liquid applications, an understanding of the structure and thermodynamic stability and transport of any chemical species in a solution is paramount. Rajput and colleagues used NMR as a powerful technique to develop an atomistic view to predict stable species.
“Elucidating the complex solvation environment in multi-component liquid solutions can be a daunting task, even by using advanced experimental and computational techniques,” explains Rajput, Assistant Professor in the Department of Materials Science and Chemical Engineering in the College of Engineering and Applied Sciences. “We combined density functional theory with classical molecular dynamics simulations to make our predictions via NMR.”
The researchers developed and tested a computational framework that through simulations robustly and efficiently calculates, analyses, and stores NMR chemical shifts from a variety of molecules in liquid solutions. They also say the framework addresses some of the most challenging aspects of computational NMR by eliminating intuition driven prediction of stable species in liquid solutions.
They add that data collected from this framework should provide fingerprints to guide future experimental investigations of liquid solutions that have optimal properties for material and science applications.
For more details and a further explanation of the research method and the implications of the work, see this research briefing.
The work also involved use of key computational resources at Stony Brook’s Institute for Advanced Computational Science (IACS).
An over-the-counter stomach-soothing medication may also relieve some of the symptoms of mild to moderate COVID-19.
Tobias Janowitz Photo courtesy of CSHL
In a study recently published in the journal Gut, Cold Spring Harbor Laboratory Assistant Professor Tobias Janowitz and a team of collaborators at CSHL and The Feinstein Institutes for Medical Research at Northwell Health demonstrated that Famotidine, the active ingredient in Pepcid, shortened the duration of symptoms for a diverse patient group of adults soon after developing COVID-19 symptoms.
In a placebo-controlled study, people taking 80 milligrams of Famotidine three times a day reported that symptoms such as headaches declined after 8.2 days, compared with 11.4 days for patients who were taking the placebo.
“We think that the results are preliminary, but encouraging,” Janowitz explained in an email.
The research, which included 55 volunteers, may offer health care providers another tool to help treat mild to moderate cases of COVID-19. In the clinical study, the use of Famotidine helped reduce a potentially overactive inflammatory response without suppressing the immune system’s efforts to ward off the virus.
Participants in the study received Famotidine or placebo pills along with a host of instruments they could use at home to gather clinical data about themselves, including a cellular activated Apple iPad, a scale, thermometer, fitness tracker, spirometer to measure air flow in and out of the lungs and a pulse oximeter, which measured oxygen levels by taking a reading over a person’s fingernails.
The protocol for the study allowed volunteers to stay home, where they gathered results from the instruments and reported on their health and any symptoms they felt. Technicians came to the home of each volunteer on the first, seventh, 15th, and 28th days after entering the clinical trial.
Researchers and doctors involved in the analysis of the effectiveness of COVID believe this remote approach to participating in clinical trials could prove a safe and effective way to conduct research for other diseases.
“In today’s virtual world, our clinical trial strategy has significant implications for how to study new drugs in patients at home,” Dr. Kevin Tracey, president and CEO of the Feinstein Institutes, explained in a Cold Spring Harbor Laboratory news brief.
Janowitz added that other studies could also use testing protocols at home, including for other diseases. “We are looking forward to employing it to help develop better treatments for people with cancer,” which is the disease at the center of his research, he explained.
The CSHL Assistant Professor focuses on the whole body response to cancer, although many of the biological considerations are transferable to other diseases.
Pivot to COVID
According to Janowitz, “It was relatively easy for us to pivot to COVID research when it was a global area of unmet need.”
The researchers chose Famotidine because of encouraging studies and from a case series, Janowitz explained. They also found a potential mechanism of action where Famotidine blocked the H2 receptor, which encouraged them to move to a phase 2 randomized clinical trial.
The researchers were pleased that the participants in this small trial included people from a range of ages and ethnic groups. Nearly two thirds of patients, who were 18 years and older, were from black, mixed-race or Hispanic communities.
“Patients with different ancestry may have different responses to this disease,” Janowitz explained. “It helps to learn about the generalizability of the results.”
In a CSHL news brief, Nicole Jordan-Martin, executive director for New York City Health + Hospitals, added that “accessible, safe and low-cost outpatient treatment options are a priority in our global efforts to combat COVID-19.” Northwell and New York City Health + Hospitals provided care for the communities most in need of support for New York City, she added.
The collaborators were also encouraged by their teamwork.
“Our institutions worked extremely well together to face challenges the pandemic posed, like offering digital solutions and reaching populations who struggled for access to care,” Dr. Christina Brennan, vice president of clinical research at the Feinstein Institute and co-investigator of the trial, said in the news brief.
“From screening patients to organizing home delivery of the equipment and medication, this sets a new model for future trials and convenience for participants.”
Janowitz described the safety profile of Famotidine as “excellent” and said it “appears to have few interactions with other drugs and very few side effects in general.”
To be sure, Janowitz cautioned doctors and patients not to stock up on Famotidine before researchers conduct additional studies.
“Our trial is not conclusive and an early phase clinical trial (phase 1 or 2) is not sufficient to inform clinical practice,” he wrote.
Additionally without further study, researchers don’t know the best potential dose and dosing interval for this possible treatment. At this point, they know how long the drug stays in the blood and the strength of its binding to its receptor.
A dose of 20 milligrams per day or less may be too little to achieve an effect, but “we do not know this for certain,” Janowitz explained.
While researchers agreed that further studies were necessary to answer key questions, they believed that the results from this research could provide fodder for studies outside of the COVID world.
“It is possible that sustained inflammation contributes to illness in other contexts and changing this inflammation would be beneficial,” Janowitz wrote. “This will have to be explored separately. Importantly, the methods used in this trial are also transferrable, so we have learned a lot of important information” from this research.
The U.S. Department of Energy’s (DOE) Brookhaven National Laboratory has awarded a $61.8 million contract to Plainview, NY-based E.W. Howell to build the Lab‘s new Science and User Support Center (SUSC). This new facility is part of a larger effort to redevelop an existing on-site apartment area near BrookhavenLab‘s entryway. General contractor E.W. Howell will oversee SUSC construction, planned to start in the first quarter of 2022.
With approximately 75,000 gross square feet, the SUSC will serve as a welcome center for guests, researchers, and facility users arriving at BrookhavenLab. It will offer modern, configurable conference space for scientists to collaborate and office areas for Lab employees.
The future Science and User Support Center
The SUSC is the first building planned for Discovery Park, a new vision for the gateway to BrookhavenLab. The concept for Discovery Park includes the potential for additional development on approximately 60 acres of previously used, publicly accessible land. The Lab is working, in coordination with DOE, on a process for developers, collaborators, and entrepreneurs to propose, build, and operate new facilities in Discovery Park. Future occupants will complement the DOE and BrookhavenLab missions, leveraging opportunities that result from close proximity to the Laboratory. Discovery Park will offer a flexible platform to advance science and technology-based economic development for Long Island, New York State, and beyond.
BrookhavenLab‘s 5,321-acre site is located north of the Long Island Expressway near Exit 68 and east of the William Floyd Parkway. The SUSC and Discovery Park will be built off William Floyd Parkway along the access road leading to BrookhavenLab‘s main entrance.
The selection of E.W. Howell as general contractor follows DOE’s decision on Sept. 13, 2021, approving a total project cost of $86.2 million and awarding the Lab‘s SUSC project team with “Critical Decision Three” (CD-3). CD-3 is the fourth major milestone in DOE’s five-step project management process. The SUSC project team—comprising staff from BrookhavenLab and the DOE’s local Brookhaven Site Office—and E.W. Howell are targeting summer 2024 for SUSC construction to be completed.
The SUSC was designed by Burns & McDonnell and Gensler, two U.S.-based international firms.
Significant investment supporting science and technology
The Science and User Support Center will serve as a welcome center for guests, researchers, and facility users arriving at Brookhaven Lab. It will offer modern, configurable conference space for scientists to collaborate and office areas for Lab employees.
“The Department of Energy’s investment in the Science and User Support Center reflects our commitment to science and technology for the nation. It represents a significant step towards moving Brookhaven National Laboratory’s outwardly facing organizations closer and more accessible to the public. DOE continues to support the SUSC to improve researchers’ access to the experts and capabilities offered at BrookhavenLab,” said Robert Gordon, manager of DOE’s local Brookhaven Site Office.
“Awarding this contract marks a major milestone in BrookhavenLab‘s efforts to improve experiences for staff, guests, and users, to modernize infrastructure, and increase the Laboratory’s overall impact,” said Jack Anderson, Deputy Director for Operations at the Lab. “We’re excited for the facility and for the scientific collaborations it will help facilitate.”
Future first destination for thousands of visiting scientists
More than 5,000 guests traveled to BrookhavenLab annually in the years before the COVID-19 pandemic. The largest percentage came from institutions in New York State, but many came from across the country and around the world, attracted by the Lab‘s in-house experts and highly specialized research facilities for experiments. Those facilities include DOE Office of Science User Facilities such as the Relativistic Heavy Ion Collider, National Synchrotron Light Source II, and Center for Functional Nanomaterials. Guests also visited—sometimes hundreds at a time—for conferences, workshops, and other events to discuss scientific results and opportunities for future research.
Because of the ongoing pandemic, research collaborations are continuing with remote access and few guests traveling to BrookhavenLab. When it becomes safer for the Laboratory to return to more normal operations, many guests and facility users are expected to return to the Lab site. Upon completion, the SUSC will be their first destination on site upon arrival at the Laboratory.
The SUSC project is funded by the DOE Office of Science.
Brookhaven National Laboratory is supported by the Office of Science of the U.S. Department of Energy. The Office of Science is the single largest supporter of basic research in the physical sciences in the United States and is working to address some of the most pressing challenges of our time. For more information, visit science.energy.gov.
Stay connected! The Smithtown Historical Society hosts a Technology Savvy Seniors program at the Brush Barn, 211 E. Main St., Smithtown every other Friday including March 11 and 25 at 10 a.m. This free technology workshop is geared to help seniors with their cell phones, tablets, laptops and more. Topic will vary at each session. Call 631-265-6768 for further details.
Jose M. Adrover and Mikala Egeblad. Photo by Lijuan Sun
By Daniel Dunaief
Cold Spring Harbor Laboratory Professor Mikala Egeblad thought she saw something familiar at the beginning of the pandemic.
Mikala Egeblad. Photo from CSHL
Egeblad has focused on the way the immune system’s defenses can exacerbate cancer and other diseases. Specifically, she studies the way a type of white blood cell produces an abundance of neutrophil extracellular traps or NETs that can break down diseased and healthy cells indiscriminately. She thought potentially high concentrations of these NETs could have been playing a role in the worst cases of COVID.
“We got the idea that NETs were involved in COVID-19 from the early reports from China and Italy” that described how the sickest patients had severe lung damage, clotting events and damage to their kidneys, which was what she’d expect from overactive NETs, Egeblad explained in an email.
Recently, she, her post doctoral researcher Jose M. Adrover and collaborators at Weill Cornell Medical College and the Icahn School of Medicine at Mt. Sinai proved that this hypothesis had merit. They showed in hamsters infected with COVID and in mice with acute lung injuries that disabling these NETs improved the health of these rodents, which strongly suggested that NETs are playing a role in COVID-19.
“It was very exciting to go from forming a hypothesis to showing it was correct in the context of a complete new disease and within a relatively short time period,” Egeblad wrote.
Egeblad, Andover and their collaborators recently published their work in the Journal of Clinical Investigation Insight.
Importantly, reducing the NETs did not alter how much virus was in the lungs of the hamsters, which suggests that reducing NETs didn’t weaken the immune system’s response to the virus.
Additional experiments would be necessary to prove this is true for people battling the worst symptoms of COVID-19, Egeblad added.
While the research is in the early stages, it advances the understanding of the importance of NETs and offers a potential approach to treating COVID-19.
An unexpected direction
Jose Adrover. Photo from CSHL
When Adrover arrived from Spain, where he had earned his PhD from the Universidad Complutense de Madrid and had conducted research as a post doctoral fellow at the Spanish Center for Cardiovascular Research in March of 2020, he expected to do immune-related cancer research.
Within weeks, however, the world changed. Like other researchers at CSHL and around the world, Egeblad and Adrover redirected their efforts towards combating COVID.
Egeblad and Andover “were thinking about the virus and what was going on and we thought about trying to do something,” Adrover said.
Egeblad and Adrover weren’t trying to fight the virus but rather the danger from overactive NETs in the immune system.
Finding an approved drug
Even though they were searching for a way to calm an immune system responding to a new threat, Egeblad and Adrover hoped to find a drug that was already approved.
After all, the process of developing a drug, testing its safety, and getting Food and Drug Administration approval is costly and time-consuming.
That’s where Juliane Daßler-Plenker, also a postdoctoral fellow in Egeblad’s lab, came in. Daßler-Plenker conducted a literature search and found disulfiram, a drug approved in the 1950’s to treat alcohol use disorder. Specifically, she found a preprint reporting that disulfuram can target a key molecule in macrophages, which are another immune cell. Since the researchers knew this was important for the formation of NETs, Daßler-Plenker proposed that the lab test it.
Working with Weill Cornell Medical College and the Icahn School of Medicine at Mt. Sinai, Adrover explored the effect of disulfiram, among several other possible treatments, on NET production.
Using purified neutrophils from mice and from humans, Adrover discovered that disulfiram was the most effective treatment to block the formation of NETs.
He, Assistant Professor Robert Schwartz’s staff at Weill Cornell and Professor Benjamin tenOever at Mt. Sinai tried disulfiram on hamsters infected with SARS-Cov-2. The drug blocked net production and reduced lung injury.
The two experiments were “useful in my opinion as it strengthens our results, since we blocked NETs and injury in two independent models, one of infection and the other of sterile injury,” Adrover said. “Disulfuram worked in both models.”
More work needed
While encouraged by the results, Egeblad cautioned that this work started before the availability of vaccines. The lab is currently investigating how neutrophils in vaccinated people respond to COVID-19.
Still, this research offered potential promise for additional work on NETs with some COVID patients and with people whose battles with other diseases could involve some of the same immune-triggered damage.
“Beyond COVID, we are thinking about whether it would be possible to use disulfiram for acute respiratory distress syndrome,” Egeblad said. She thinks the research community has focused more attention on NETs.
“A lot more clinicians are aware of NETs and NETs’ role in diseases, COVID-19 and beyond,” she said. Researchers have developed an “appreciation that they are an important part of the immune response and inflammatory response.”
While researchers currently have methods to test the concentration of NETs in the blood, these tests are not standardized yet for routine clinical use. Egeblad is “sensing that there is more interest in figuring out how and when to target NETs” among companies hoping to discover treatments for COVID and other diseases.
The CSHL researcher said the initial race to gather information has proven that NETs are a potentially important target. Down the road, additional research will address a wide range of questions, including what causes some patients to develop different levels of NETs in response to infections.
Esther S. Takeuchi, PhD, Distinguished Professor and the William and Jane Knapp Chair at Stony Brook University is being honored by the National Academy of Sciences (NAS) and will receive the Award in Chemical Sciences. This award is in recognition of her breakthrough contributions in the understanding of electrochemical energy storage.
Takeuchi, who holds a joint appointment at Department of Energy’s (DOE) Brookhaven National Laboratory, is an internationally recognized inventor, researcher, and educator in the fields of materials science, chemistry and renewable energy. She will be honored in a ceremony during the NAS 159th annual meeting on May 1 and will receive a medal and prize of $15,000 sponsored by the Merck Company Foundation.
The award cites Takeuchi’s contributions “to the materials and mechanistic understanding relevant to electrochemical energy storage, using chemical insight to address issues of critical importance.”
“I am sincerely honored to receive the National Academy of Science Award for Chemical Sciences,” said Takeuchi, also the Knapp Chair Professor of Energy and the Environment in the Department of Materials Science and Chemical Engineering “The fundamental chemistry of electrochemical energy storage is complex and the subsequent development of viable energy storage devices is made even more challenging by the unique demands of each application.”
Takeuchi’s research has been instrumental in energy storage improvements that meet societal needs and can be applied to electric vehicles, medical devices, and batteries that back up the power grid. Among her numerous and notable inventions is a compact lithium/silver vanadium oxide battery that increased the lifespan of implantable cardiac defibrillators, a solution that reduced the number of surgeries patients needed to undergo to replace the devices that detect and correct irregular, potentially fatal, heart rhythms.
Takeuchi was recently elected a member of the American Academy of Arts and Sciences. She has also been inducted into the National Academy of Engineering and selected as a Fellow of the American Institute for Medical and Biological Engineering and the American Association for the Advancement of Science. She was selected as the 2013 recipient of the E.V. Murphree Award in Industrial and Engineering Chemistry from the American Chemical Society. She was inducted into the National Inventors Hall of Fame in 2011. In 2009, President Obama presented Takeuchi with the National Medal of Technology and Innovation, the highest honor possible for technological achievement in the United States.
Ostrich eggshell beads found at the Mlambalasi site. These beads are examples of Later Stone Age cultural objects that people created and traded as they traveled the continent. Photo by Jennifer Miller
Ancient DNA from the remains of nearly three dozen African foragers—groups associated with hunting, gathering, and fishing—sheds new light on how groups across sub-Saharan Africa lived, traveled and settled prior to the spread of herding and farming. The study involved an international team of 44 researchers including experts from Stony Brook University. The findings, to be published in Nature, produced the earliest DNA of humans on the continent, at some 5,000 to 18,000 years old.
View of the Mlambalasi Rock Shelter in Tanzania, where one of the newly DNA sequenced individuals was recovered by Elizabeth Sawchuk in 2010. Radiocarbon dates suggest that this individual lived approximately 18,000 years ago, making their DNA the oldest currently known in Africa. Photo by Katie Biittner
The new genetic findings add weight to archeological, skeletal and linguistic evidence for changes in how people were moving and interacting across Africa toward the end of the Ice Ages. Around 50,000 years ago, distinct groups of foragers began exhibiting similar cultural traditions, hinting at the development of exchange networks and interregional connections. The reason for this shift, which archaeologists refer to as the Later Stone Age transition, has remained a mystery.
“We demonstrated for the first time that a major archeological transition some 50,000 years ago associated with profound shifts in technology, symbolism, and so-called ‘modern behavior’ in fact coincided with major demographic changes,” said Elizabeth Sawchuk, PhD, Co-First Author, Research Assistant Professor at Stony Brook University and a Banting Postdoctoral Fellow at the University of Alberta. “We found that ancient foragers across eastern and south-central Africa are a mix of eastern, southern, and central African ancestry, showing there was widespread movement and mixing across sub-Saharan Africa coinciding with the transition from the Middle to Later Stone Age.”
Previous research proposed a genetic cline (or gradient) of variation among ancient African foragers extending from eastern to southern Africa. To the research team’s surprise, this new analysis indicates a three-way cline instead of a two-way cline that includes a central African ancestry – a significant point of future investigation because there has been less archeological research in central Africa than other parts of the continent.
“By associating archaeological artifacts with ancient DNA, the researchers have created a remarkable framework for exploring the prehistory of humans in Africa,” says Archaeology and Archaeometry program director John Yellen of the U.S. National Science Foundation, one of the funders behind this project. “This insight is charting a new way forward to understanding humanity and our complex shared history.”
Sawchuk and Stony Brook colleague and Co-Author Jason Lewis, PhD, presented ancient DNA (aDNA) from six individuals from the Late Pleistocene and early Holocene from five sites in Tanzania, Zambia, and Malawi
These six individuals have now yielded the oldest human DNA from sub-Saharan Africa.
The six individuals were analyzed with 28 previously published ancient persons associated with foraging and/or Later Stone Age material culture. The research team also generated higher coverage data for fifteen of these individuals which permitted a more in-depth look at their DNA.
Lewis co-led a team reanalyzing the history of work and collections from the ancient Tanzanian rockshelter site of Kisese II, particularly in the context and dating of the human remains, allowing the collection to be included in the present study. The skeletons from the site were originally excavated in the 1960s but remained unstudied until recently.
“The work is a great example of the unexpected and important results that can come from going back to old museum collections to take another look with new approaches and technologies, in this case using aDNA methods,” said Lewis.
Ancient DNA and archaeological data now both point toward a demographic transition across Africa around the time that beads, pigments, and symbolic art became more widespread. Sawchuk, Lewis and colleagues note that while scientists have proposed shifts in social networks and perhaps changes in populations sizes played a role, such hypotheses have remained difficult to test.
“We’ve never been able to directly explore proposed demographic shifts until now,” explains Sawchuk. “It has been difficult to reconstruct events in our deeper past using the DNA of people living today, and artifacts can’t tell the whole story. The DNA from people who lived around this time provides the missing piece of the puzzle, offering an unprecedented view of population structures among ancient foragers.”
While this three-way population structure can only be explained by widespread movement and mixing in the past, the researchers also note that the traveling and mixing didn’t last.
Individuals in this study were most genetically similar to their geographic neighbors, which suggests that by 20,000 years ago, people had already stopped moving as much. The authors explain this coincides with archaeological evidence for “regionalization” toward the end of the Ice Ages when Later Stone Age industries began to diversity and take on distinctive local attributes. So while stone and beads continued moving through exchange networks, people themselves began living more locally.
Mary Prendergast, the study’s co-Senior Author and Associate Professor of Anthropology at Rice University, said there are arguments that the development and expansion of long-distance trade networks around these ancient times helped humans weather the last Ice Age.
“Humans began relying on each other in new ways,” she said. “And this shift in how people interacted with one another may have been what allowed people to thrive.
“The work also helps address the global imbalance of research, as there are around 30 times more published ancient DNA sequences from Europe than from Africa,” she added. “Given that Africa harbors the greatest human genetic diversity on the plant, we have much more to learn.”
The entire research team included scholars from the United States, Canada, Kenya, Malawi, Tanzania, Zambia and several other countries. Critical contributions to the study came from curators and co-authors from African museums who are responsible for protecting and preserving the remains.
Diseases like cancer take the normal raw materials of a cell and make them a part of a pernicious process that often threatens a person’s health.
Ideally, when researchers find the raw materials cancers need to survive, they discover specific proteins that are necessary for cancer, but aren’t critical for healthy cells.
That appears to have happened recently in the lab of Cold Spring Harbor Laboratory Professor Chris Vakoc in the study of the blood disease Acute Myeloid Leukemia, or AML.
Vakoc’s former graduate student Sofya Polyanskaya, who now works in a pharmaceutical company in Germany, discovered the importance of an understudied protein called SCP4, which removes phosphate groups from other proteins, in some forms of AML. This protein acts as an enzyme, which makes it a particularly appealing target.
In his lab, Vakoc said he and his researchers take “genes and the proteins they encode and [try to] publish the first paper linking them to cancer,” Vakoc said.
Polyanskaya and Vakoc recently published their findings in the journal Cell Reports.
These scientists disabled proteins in a host of diverse cancer types, looking for dependencies that were unique to each cancer. After determining that SCP4 was only needed in leukemia and not other cancers, they inactivated the protein in normal, healthy blood cells and found that it wasn’t needed.
“Leukemia cells are super sensitive to the loss of this enzyme,” Vakoc said.
Vakoc praised the work of Polyanskaya, who he said conducted the “inspiring work” that led to this conclusion. “It’s not easy for a brand new scientist entering the field to write the first cancer paper on a target.”
Polyanskaya surveyed hundreds of these enzymes to find a potential new protein that cancer, specifically, might need. The CRISPR technology, which didn’t exist nine years ago, provides a way of altering a large number of potential enzymes to find the ones that are critical for cancer’s survival.
Ideally, this kind of analysis enables researchers like Polyanskaya and Vakoc to focus in on the ones that are critical to cancer, but that don’t perform any important function in normal cells.
One of the other benefits of this work is that it validates the importance of targets that have become the focus of other research projects.
“Part of what we’re doing is making sure that our processes more broadly in the field are robust,” Vakoc said. “We are more confident in other targets we didn’t discover” but that play a role in the progression of leukemia.
To be sure, the discovery of the SCP4 target is the first step in a series of questions that may require considerable time and resources to ensure a reliable and safe clinical benefit.
As with many cancers, leukemia may have the equivalent of a back up plan, in case this seemingly important enzyme is unavailable. Indeed, the battle against cancer and other diseases involves moves and counter moves by pharmaceutical and biotechnology companies and the diseases they battle.
Additionally, researchers like Vakoc need to discover the reason cells produce this enzyme in the first place. Mice lacking SCP4 are born, but develop metabolic stress after birth.
“The important experiment in the future will be to determine what the consequences of targeting SCP4 are in normal tissue much later after birth,” Vakoc explained in an email.
Like other cancers, leukemia is a heterogeneous disease, which is another way of saying that not everyone with the disease has the same symptoms and prognosis and not everyone would respond to the same treatment in the same way.
Vakoc would like to figure out for “which subset of patients with leukemia is this protein the most important. Down the road, that could help determine who might benefit from an SCP4 inhibitor.
“We want to personalize therapy as much as possible,” he said.
In his follow up research, Vakoc hopes to learn more about the three-dimensional structure of the protein complex.
Vakoc’s interest in leukemia stems from his interest in studying blood. When he conducted his PhD training at the University of Pennsylvania, he studied normal blood development.
He was particularly interested in pediatric cancer. While AML is on of the cancers that children can develop, it is far more common in elderly people.
The lab has a strong focus on leukemia.
Vakoc, whose lab is next door to CSHL Cancer Center Director David Tuveson, has also starting searching for potential therapeutic targets in pancreatic cancer.
He is excited about the potential to bring attention to a possible candidate that may provide a therapeutic benefit for patients at some point.
“It feels good to put a new target on the map,” he said.
The CSHL scientist recognizes that cancer can and often does develop resistance to a treatment that tackles any one enzyme or protein. Still, he said treating cancer with any new and effective therapy could extend life by several months, which are often “very valuable to patients.”
Vakoc suggested that any potential new treatment for leukemia would likely involve several drugs working together to stay ahead of cancer.
“The real hope and optimism is that, if you had a copule of targets like this that are not needed in healthy cells, you could add 10 or 20 years of high quality life. You could keep the disease in a chronic, latent state.”
Members of the research team include: Daniel Mazzone (formerly of Brookhaven Lab, now at the Paul Scherrer Institut in Switzerland), Yao Shen (Brookhaven Lab), Gilberto Fabbris (Argonne National Laboratory), Hidemaro Suwa (University of Tokyo and University of Tennessee), Hu Miao (Oak Ridge National Laboratory—ORNL), Jennifer Sears* (Brookhaven Lab), Jian Liu (U Tennessee), Christian Batista (U Tennessee and ORNL), and Mark Dean (Brookhaven Lab). *Photo Credit: DESY, Marta Mayer
Scientists identify a long-sought magnetic state predicted 60 years ago
Scientists at the U.S. Department of Energy’s Brookhaven National Laboratory have discovered a long-predicted magnetic state of matter called an “antiferromagnetic excitonic insulator.”
“Broadly speaking, this is a novel type of magnet,” said Brookhaven Lab physicist Mark Dean, senior author on a paper describing the research just published in Nature Communications. “Since magnetic materials lie at the heart of much of the technology around us, new types of magnets are both fundamentally fascinating and promising for future applications.”
The new magnetic state involves strong magnetic attraction between electrons in a layered material that make the electrons want to arrange their magnetic moments, or “spins,” into a regular up-down “antiferromagnetic” pattern. The idea that such antiferromagnetism could be driven by quirky electron coupling in an insulating material was first predicted in the 1960s as physicists explored the differing properties of metals, semiconductors, and insulators.
“Sixty years ago, physicists were just starting to consider how the rules of quantum mechanics apply to the electronic properties of materials,” said Daniel Mazzone, a former Brookhaven Lab physicist who led the study and is now at the Paul Scherrer Institut in Switzerland. “They were trying to work out what happens as you make the electronic ‘energy gap’ between an insulator and a conductor smaller and smaller. Do you just change a simple insulator into a simple metal where the electrons can move freely, or does something more interesting happen?”
The prediction was that, under certain conditions, you could get something more interesting: namely, the “antiferromagnetic excitonic insulator” just discovered by the Brookhaven team.
Why is this material so exotic and interesting? To understand, let’s dive into those terms and explore how this new state of matter forms.
In an antiferromagnet, the electrons on adjacent atoms have their axes of magnetic polarization (spins) aligned in alternating directions: up, down, up, down and so on. On the scale of the entire material those alternating internal magnetic orientations cancel one another out, resulting in no net magnetism of the overall material. Such materials can be switched quickly between different states. They’re also resistant to information being lost due to interference from external magnetic fields. These properties make antiferromagnetic materials attractive for modern communication technologies.
Next we have excitonic. Excitons arise when certain conditions allow electrons to move around and interact strongly with one another to form bound states. Electrons can also form bound states with “holes,” the vacancies left behind when electrons jump to a different position or energy level in a material. In the case of electron-electron interactions, the binding is driven by magnetic attractions that are strong enough to overcome the repulsive force between the two like-charged particles. In the case of electron-hole interactions, the attraction must be strong enough to overcome the material’s “energy gap,” a characteristic of an insulator.
“An insulator is the opposite of a metal; it’s a material that doesn’t conduct electricity,” said Dean. Electrons in the material generally stay in a low, or “ground,” energy state. “The electrons are all jammed in place, like people in a filled amphitheater; they can’t move around,” he said. To get the electrons to move, you have to give them a boost in energy that’s big enough to overcome a characteristic gap between the ground state and a higher energy level.
An artist’s impression of how the team identified this historic phase of matter. The researchers used x-rays to measure how spins (blue arrows) move when they are disturbed and were able to show that they oscillate in length in the pattern illustrated above. This special behavior occurs because the amount of electrical charge at each site (shown as yellow disks) can also vary and is the fingerprint used to pin down the novel behavior.
In very special circumstances, the energy gain from magnetic electron-hole interactions can outweigh the energy cost of electrons jumping across the energy gap.
Now, thanks to advanced techniques, physicists can explore those special circumstances to learn how the antiferromagnetic excitonic insulator state emerges.
A collaborative team worked with a material called strontium iridium oxide (Sr3Ir2O7), which is only barely insulating at high temperature. Daniel Mazzone, Yao Shen (Brookhaven Lab), Gilberto Fabbris (Argonne National Laboratory), and Jennifer Sears (Brookhaven Lab) used x-rays at the Advanced Photon Source—a DOE Office of Science user facility at Argonne National Laboratory—to measure the magnetic interactions and associated energy cost of moving electrons. Jian Liu and Junyi Yang from the University of Tennessee and Argonne scientists Mary Upton and Diego Casa also made important contributions.
The team started their investigation at high temperature and gradually cooled the material. With cooling, the energy gap gradually narrowed. At 285 Kelvin (about 53 degrees Fahrenheit), electrons started jumping between the magnetic layers of the material but immediately formed bound pairs with the holes they’d left behind, simultaneously triggering the antiferromagnetic alignment of adjacent electron spins. Hidemaro Suwa and Christian Batista of the University of Tennessee performed calculations to develop a model using the concept of the predicted antiferromagnetic excitonic insulator, and showed that this model comprehensively explains the experimental results.
“Using x-rays we observed that the binding triggered by the attraction between electrons and holes actually gives back more energy than when the electron jumped over the band gap,” explained Yao Shen. “Because energy is saved by this process, all the electrons want to do this. Then, after all electrons have accomplished the transition, the material looks different from the high-temperature state in terms of the overall arrangement of electrons and spins. The new configuration involves the electron spins being ordered in an antiferromagnetic pattern while the bound pairs create a ‘locked-in’ insulating state.”
The identification of the antiferromagnetic excitonic insulator completes a long journey exploring the fascinating ways electrons choose to arrange themselves in materials. In the future, understanding the connections between spin and charge in such materials could have potential for realizing new technologies.
Brookhaven Lab’s role in this research was funded by the DOE Office of Science, with collaborators receiving funding from a range of additional sources noted in the paper. The scientists also used computational resources of the Oak Ridge Leadership Computing Facility, a DOE Office of Science user facility at Oak Ridge National Laboratory.
Brookhaven National Laboratory is supported by the Office of Science of the U.S. Department of Energy. The Office of Science is the single largest supporter of basic research in the physical sciences in the United States and is working to address some of the most pressing challenges of our time. For more information, visit science.energy.gov. [https://www.energy.gov/science/]