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Power of Three

A collection of tools found in Grotte Mandrin of both Neanderthals and modern humans. The pointier tools were made by modern humans about 54,000 years ago. Image from Ludovic Slimak

By Daniel Dunaief

Two Stony Brook University researchers are helping a team of scientists rewrite the timeline of modern humans in Europe.

Prior to a ground breaking study conducted in the Rhône Valley in a cave called Grotte Mandrin in southern France, researchers had believed that homo sapiens — i.e. earlier versions of us — had arrived in Europe some time around 45,000 years ago.

Scientists had been studying the stone tools in this cave for close to 30 years that seemed inconsistent with the narrative that Neanderthals had exclusively occupied Europe at that point. Researchers found key evidence in this cave, including advanced tools and teeth that came from modern humans, that pushed the presence of modern humans back by about 10,000 years to about 56,800 years ago, while also indicating that the two types of humans interacted in the same place.

“This is a huge paradigm shift in our understanding of modern human origin expansion,” said Jason Lewis, a lecturer in the Department of Anthropology at Stony Brook University and Assistant Director at the Turkana Basin Institute in Kenya. “We can demonstrate that it was modern humans. We have a whole series of radiometric dates to shore that up 100 percent. Any method that was useful was applied” to confirm the arrival of homo sapiens in southern France.

Ludovic Slimak, CNRS researcher based at the University of Toulouse Jean Jaures, is the lead author on a 130-page paper that came out this week in Science Advances. Slimak has been exploring a site for 24 years that he describes as a kind of Neanderthalian Pompei, without the catastrophe of Mount Vesuvius erupting and preserving a record of the lives the volcano destroyed.

“This is a major turn, maybe one of the most important since a century,” Slimak explained in an email.

The early Homo sapiens travelers left behind clues about their presence in a rock shelter that alternately served as a home for Homo sapiens and Neanderthals in the same year.

“We demonstrate in our paper that there is less than a year, maybe a season (six months), maximal time between the last Neanderthal occupation in the cave and the first Sapiens settlement,” Slimak wrote. “This is a very, very short time!”

The scientists came to this conclusion after they developed a new way to analyze the soot deposits on the vault fragments of the cave roof, he added.

When modern humans arrived in the Rhône Valley, they likely turned to Neanderthals, who had occupied the area considerably longer, as scouts to guide them, Slimak suggested.

Homo sapiens likely traveled by boat to France at the same time that other Homo sapiens journeyed over the water to Australia, between 50,000 and 60,000 years ago.

“We know that when Mandrin groups reached western Europe, Eurasian populations perfectly master navigation at the other end of the continent,” Slimak explained in an email. “It is then very likely that these technologies were at this time period well known by all these populations.”

Different tools

In addition to fossils, scientists have focused on the tools that Homo sapiens produced and used. Homo sapiens likely used bows or spears with mechanical propulsion, while Neanderthals had heavy hand-cast spears, Slimak explained.

The modern human technology was “very impressive,” Slimak added. They are exactly the same technologies we found in the eastern Mediterranean at the very beginning of the Upper Paleolithic in the same chronology [as] the Grotte Mandrin.”

The tools were small and pointed and looked like the kind of arrowheads someone might find when hiking along trails on Long Island, Lewis described. “It’s never been suggested or demonstrated that Neanderthals made bows and arrows or complex projectiles,” he said.

Once they discovered teeth of Homo sapiens, the researchers found the conclusive fossil proof of “who was there doing this,” Lewis said. “Even on a baby tooth, you can distinguish Neanderthals from modern humans.”

While researchers have excavated other caves in the Middle Rhône Valley region, they have not used such stringent methods, Lewis explained. “Mandrin is truly unique for the vision it gives us into this period of the past,” he explained in an email. He described Mandrin as more of a rock shelter than a cave, which is about 10 meters wide and eight meters deep.

The importance of timing

With the importance of providing specific dates for these discoveries, scientists who specialize in ancient chronology, such as Marine Frouin, joined the team.

Frouin, who started working in the Grotte Mandrin in 2014 when she was a post-doctoral fellow at the Luminescence Laboratory at the University of Oxford, looks for the presence of radioactive elements like potassium, thorium and uranium to determine the age of sediments. When these elements decay, they emit radiation, which the sediments accumulate.

Frouin likened the build up of radioactive elements in the grains to the process of charging a battery. Over time, the radioactive energy increases, providing a signal for the last time sunlight reached the sediment.

Indeed, when the sun reaches these grains, it eliminates the signal, which means that Frouin collected samples in lower light, transported them to a lab or facility in darkness, and then analyzed them in rooms that look like a photographer’s darkroom studio.

Frouin conducted the first of three approaches to determining the timing for these discoveries. She used luminescence on quartz, feldspar and flint and was the first one to obtain dates in 2014. Colleagues at the Université de Paris then conducted Thermoluminescence dating on burnt flint, while the lab of Andaine Seguin-Orlando at the University Paul Sabatier Toulouse 3 provided single grain dating.

The three labs “were able to combine all our results together and propose a very precise chronology for this site with very high confidence,” she explained in an email.

Frouin, who arrived at Stony Brook University in January of 2020, has designed and built her own lab, where she plans to study samples and advance the field of luminescence dating.

At this point, luminescence dating can provide the timing from a few hundred years ago to 600,000 years, beyond which the radioactive signal reaches its maximum brightness. Trained as a physicist, Frouin, however, is developing new techniques to find larger doses from grains that data at least over a million years old.

Journey to France

During this period of time on the Earth, the climate was especially cold. That, Lewis said, would favor the continued use of the cave by Neanderthals, who could have survived better under more challenging conditions.

At around 55,000 years ago, however, something may have shifted in the modern human population that allowed Homo sapiens to survive in a colder climate. These changes could include projectile weapons, more advanced clothing and/or social cooperation.

“These are all hypotheses we are dealing with,” Lewis said. “In this case, it seems like a tentative exploration by modern humans into Western Europe.”

The cave itself would have been especially appealing to Neanderthals or modern humans because of its geographic and topological features. For scientists, some of those same features also helped provide a chronological record to indicate when each of these groups lived in that space.

Near the cave, the Rhône River provides a way to travel. The cave itself is situated at a bottleneck through which groups of migrating animals such as horse, bison and deer traveled to follow their own food sources.

“It’s one of the most strategic points in Southern France,” Lewis said.

Indeed, Allied Forces during World War II recognized the importance of this site, landing in Provence on August 15, 1944. The progression into Europe mirrored the expansion of modern humans, said Lewis, who studies history and is particularly interested in WWII.

The site faces northwest in a part of the Rhône Valley in which the mistral wind, which is a cold and dry strong wind, can reach up to speeds of 60 miles per hour. During the glacial period, the wind blew dust that came off the tundra of northern Europe, filling the cave with fine grain sediment that helped preserve the site. Using that dust, scientists determined that Neanderthals had occupied that cave for almost 100,000 years. Around 55,000 years ago, modern humans showed up, who were replaced again by Neanderthals.

A resident of Stony Brook, Lewis lives with his wife Sonia Harmand, who is in the same department at Stony Brook and with whom he has collaborated on research, and their daughter Scarlett.

A native of Dover, Pennsylvania, Lewis decided to study evolution after reading a coffee table book at a friend’s house when he was 13 that included descriptions of the work of the late paleoanthropologist Richard Leakey. After reading that book, Lewis said evolution made sense to him and he was eager to participate in the search for evidence of the changes that led to modern humans.

His first field experience was in a Neanderthal site in France, where he also traveled to the Turkana basin in Kenya for a project directed by Rutgers University. Ultimately, he wound up working for Rutgers and has conducted considerable research in Kenya as well.

“After working at Rutgers, I came to Stony Brook to work for [Richard Leakey in a field school at [what would become] the Turkana Basin Institute,” he said. The combination of his earlier aspirations to join Leakey, his first research field experiences including time in France and Kenya, and his eventual work with Leakey and his role at TBI were a part of his “circle of life.”

Lewis is thrilled to be a part of the ongoing effort to share information discovered in a cave he called a “magical place. The satisfaction at being there is high.”

For Slimak, the years of work at the site have been personally and professionally transformational. After taking necessary breaks from the rigors of excavating on the cave floor, he is now more comfortable sleeping on a hard floor than on a soft mattress.

Professionally, Slimak described this paper as the culmination of 32 years of continuous scientific efforts, which includes a “huge amount of very important unpublished data” that include social, cultural, economic and historical organization of these populations.

The current paper represents “only the visible part of the iceberg and many important enlightenment and other fascinating discoveries from my team will be made available in the coming months and years.”

A tough beginning

A native of Bordeaux, France, Frouin had a tough start to her work at Stony Brook. She arrived two months before the pandemic shut down many businesses and services, including driving schools and social security offices.

When she arrived, she didn’t have a driver’s permit or a credit history, which meant that she relied on the kindness and support of her colleagues and transportation from car services to pick up necessities like groceries.

A resident of Port Jefferson, Frouin, who enjoys playing electric guitar and does oil painting when she’s not studying sediments, said it took just under a year to get her American driver’s license.

Frouin, who has an undergraduate and a graduate student in her lab and is expecting to add another graduate student soon, appreciates the opportunity to explore the differences between the north and south shore of Long Island. 

As for her contribution to this work, she said this effort was “extremely exciting. I’m doing what I wanted to do since I was a kid. We were able to answer many questions that maybe 20 years ago, we weren’t able to answer.”

Martyna Sroka. Photo by Sofya Polyanskaya

By Daniel Dunaief

Part 1:

A group of people may prove to be the guardian angels for the children of couples who haven’t even met yet.

After suffering unimaginable losses to a form of cancer that can claim the lives of children, several families, their foundations, and passionate scientists have teamed up to find weaknesses and vulnerabilities in cancers including rhabdomyosarcoma and Ewing sarcoma.

Rhabdomyosarcoma affects about 400 to 500 people each year in the United States, with more than half of those patients receiving the diagnosis before their 10th birthday. Patients who receive diagnoses for these cancers typically receive medicines designed to combat other diseases.

 

Christopher Vakoc. Photo from CSHL

A group of passionate people banded together using a different approach to funding and research to develop tools for a different outcome. Six years after the Christina Renna Foundation and others funded a Banbury meeting at Cold Spring Harbor Laboratory, the grass roots funders and dedicated scientists are finding reasons for optimism.

“I wish I could run up to the top of a hill and scream it out: ‘I’m more hopeful than I’ve ever been,’” said Phil Renna, director of operations, communications department at CSHL and the co-founder of the Christina Renna Foundation. “I’m really excited” about the progress the foundation and the aligned group supporting the Sarcoma Initiative at the lab has made.

Renna and his wife Rene started the foundation after their daughter Christina died at the age of 16 in 2007 from rhabdomyosarcoma. Renna’s optimism stems from work Cold Spring Harbor Laboratory’s Christopher Vakoc, a professor and Cancer Center co-director and his research team, including PhD candidate Martyna Sroka have performed.

The cause for optimism comes from the approach Vakoc has taken to cancers, including leukemia.

Vakoc has developed a way to screen the effects of genetic changes on the course of cancer.

“Usually, when you hear about a CRISPR screen, you think of taking out a function and the cell either dies or doesn’t care,” Sroka said, referring to the tool of genetic editing. Sroka is not asking whether the cell dies, but whether the genetic change nudges the cellular processes in a different direction.

“We are asking whether a loss of a gene changes the biology of a cell to undergo a fate change; in our case, whether cancer cells stop growing and differentiate down the muscle lineage,” she explained.

In the case of sarcoma, researchers believe immature muscle cells continue to grow and divide, turning into cancer, rather than differentiating to a final stage in which they function as normal cells.

Through genetic changes, however, Sroka and Vakoc’s lab are hoping to restore the cell to its non cancerous state.

Cold Spring Harbor Laboratory has had success with other diseases and other types of cancer, which is where the optimism comes from, explained Paul Paternoster, President of Selectrode Industries, Inc. and the founder of the Michelle Paternoster Foundation for Cancer Research.

As a part of her doctoral research which she’s been conducting for four years, Sroka is also working with Switzerland-based pharmaceutical company Novartis AG to test the effect of using approved and experimental drugs that can coax cells back into their muscular, non-cancerous condition.

The work Sroka and Vakoc have been doing and the approach they are taking could have applications in other cancers.

“The technology that we’ve developed to look at myodifferentiation in rhabdomyosarcoma can be used to study other cancers (in fact, we are currently applying it to ask similar questions in other cancer contexts),” said Sroka. “In addition, our findings in RMS might also shed light on normal muscle development, regeneration and the biology of other diseases that impact myodifferentiation, e.g. muscular dystrophy.”

Martyna Sroka’s journey

Described by Vakoc as a key part of the sarcoma research effort in his lab, Martyna Sroka, who was born and raised in Gdańsk, Poland, came to Long Island after a series of eye-opening medical experiences.

In Poland, when she was around 16, she shadowed a pediatric oncology doctor who was visiting patients. After she heard the patient’s history, she and the doctor left the room and convened in the hallway.

Martyna Sroka. Photo by Sofya Polyanskaya

“He turned to me and said, ‘Yeah, this child has about a month or two tops.’ We moved on to the next case. I couldn’t wrap my head around it. That’s as far as we could go. There’s nothing we could do to help the child and the family,” said Sroka.

Even after she started medical school, she struggled with the limited ammunition modern medicine provided in the fight against childhood cancer.

She quit in her first year, disappointed that “for a lot of patients diagnosed with certain rare types of tumors, the diagnosis is as far as the work goes. I found that so frustrating. I decided maybe my efforts will be better placed doing the science that goes into the development of novel therapies.”

Sroka applied to several PhD programs in the United Kingdom and only one in the United States, at Cold Spring Harbor Laboratory, where she hoped to team up with Vakoc.

Sroka appreciated Vakoc’s approach to the research and his interest in hearing about her interests.

“I knew that we could carve out an exciting scientific research project that tries to tackle important questions in the field of pediatric oncology, [the] results of which could potentially benefit patients in the future,” she explained in an email.

The two of them looked at where they could make a difference and focused on rhabdomyosarcoma.

Sroka has “set up a platform by which advances” in rhabdomyosarcoma medicines will be possible, Vakoc said. “From the moment she joined the sarcoma project, she rose to the challenge” of conducting and helping to lead this research.

While Sroka is “happy” with what she has achieved so far, she finds it difficult at times to think about how the standard of care for patients hasn’t changed much in the last few decades.

“Working closely with foundations and having met a number of rhabdomyosarcoma patients, I do feel an intense sense of urgency,” she wrote.

Read Part 2 here.

 

BNL LECTURE: ZHANGBU XU

By Daniel Dunaief

Gregory Breit and John Wheeler were right in the 1930s and Werner Heisenberg and Hans Heinrich Euler in 1936 and John Toll in the 1950s were also right.

Breit, who was born in Russia and came to the United States in 1915, and Wheeler, who was the first American involved in the theoretical development of the atomic bomb, wrote a paper that offered theoretical ideas about how to produce mass from energy.

Breit and Wheeler suggested that colliding light particles could create pairs of electrons and their antimatter opposites, known as positrons. This idea was an extension of one of Albert Einstein’s most famous equations, E=mc2, converting pure energy into matter in its simplest form.

Zhangbu Xu in front of the time-of-flight detector, which is important for identifying the electrons and positrons the STAR Collaboration measured. Photo from BNL

Working at the Relativistic Heavy Ion Collider (RHIC) at Brookhaven National Laboratory, a team of scientists in the STAR Collaboration has provided experimental proof that the ideas of some of these earlier physicists were correct.

“To create the conditions which the theory predicted, even that process is quite exhausting, but actually quite exciting,” said Zhangbu Xu, a senior scientist at BNL in the physics department.

The researchers published their results recently in Physics Review Letters, which provides a connection to Breit and Wheeler, who published their original work in a predecessor periodical called Physics Review.

While Breit and Wheeler wrote that the probability of two gamma rays colliding was “hopeless,” they suggested that accelerated heavy ions could be an alternative, which is exactly what the researchers at RHIC did.

The STAR team, for Solenoidal Tracker at RHIC, also proved another theory proposed decades ago by physicists Heisenberg, who also described the Heisenberg Uncertainty Principle, and Hans Heinrich Euler in 1936 and John Toll, who would later become the second president at Stony Brook University, in the 1950s.

These physicists predicted that a powerful magnetic field could polarize a vacuum of empty space. This polarized vacuum should deflect the paths of photons depending on photon polarization.

Researchers had never seen this polarization-dependent deflection, called birefringence, in a vacuum on Earth until this set of experiments.

Creating mass from energy

Xu and others started with a gold ion. Without its electrons, the 79 protons in the gold ion have a positive charge, which, when projected at high speeds, triggers a magnetic field that spirals around the particle as it travels.

Once the ion reaches a high enough speed, the strength of the magnetic field equals the strength of the perpendicular electric field. This creates a photon that hovers around the ion.

The speeds necessary for this experiment is even closer to the speed of light, at 99.995%, than ivory soap is to being pure, at 99.44%.

When the ions move past each other without colliding, the photon fields interact. The researchers studied the angular distribution patterns of each electron and its partner positron.

“We also measured all the energy, mass distribution, and quantum numbers of the system,” Daniel Brandenburg, a Goldhaber Fellow at BNL who analyzed the STAR data, said in a statement.

Even in 1934, Xu said, the researchers realized the cross section for the photons to interact was so small that it was almost impossible to create conditions necessary for such an experiment.

“Only in the last 10 years, with the new angular distribution of e-plus [positrons] and e-minus [electrons] can we say, ‘Hey, this is from the photon/ photon creation,’” Xu said.

Bending light in a vacuum

Heisenberg and Euler in 1936 and Toll in the 1950’s theorized that a powerful magnetic field could polarize a vacuum, which should deflect the paths of photons. Toll calculated in theory how the light scatters off strong magnetic fields and how that connects to the creation of the electron and positron pair, Xu explained. “That is exactly what we did almost 70 years later,” he said.

This is the first experiment on Earth that demonstrates experimentally that polarization affects the interactions of light with the magnetic field in a vacuum.

Xu explained that one of the reasons this principle hasn’t been observed often is that the effect is small without a “huge magnetic field. That’s why it was predicted many decades ago, but we didn’t observe it.”

Scientists who were a part of this work appreciated the connection to theories their famous and successful predecessors had proposed decades earlier.

“Both of these findings build on predictions made by some of the great physicists in the early 20th century,” Frank Geurts, a professor at Rice University, said in a statement. 

The work on bending light through a vacuum is a relatively new part of the research effort.

Three years ago, the scientists realized they could study this, which was a surprising moment, Xu said.

“Many of our collaborators (myself included) did not know what vacuum birefringence was a few years ago,” he said. “This is why scientific discovery is exciting. You don’t know what nature has prepared for you. Sometimes you stumble on something exciting. Sometimes, there is a null set (empty hand) in your endeavor.

Xu lives in East Setauket. His son Kevin is earning his bachelor’s degree at the University of Pennsylvania, where he is studying science and engineering. His daughter Isabel is a junior at Ward Melville High School.

As for the recent work, Xu, who earned his PhD and completed two years of postdoctoral research at Yale before coming to BNL, said he is pleased with the results.

“I’ve been working on this project for 20 years,” he said. “I have witnessed and participated in quite a few exciting discoveries RHIC has produced. These are very high on my list.”

Tobias Janowitz. Photo from CSHL

By Daniel Dunaief

The body’s savior in its battle against disease, immune cells respond to a collection of signals which tell them to dial up or down their patrolling efforts.

Scientists and doctors are constantly trying to determine what combination of beneficial or detrimental signals can lead to different outcomes.

Recently, Assistant Professor Tobias Janowitz and Professor Douglas Fearon of Cold Spring Harbor Laboratory, working with Duncan Jodrell at the University of Cambridge Cancer Research Institute, used an inhibitor developed and tested for the treatment of the human immunodeficiency virus (HIV), the virus that causes AIDS, in patients with colorectal and pancreatic cancer for a week.

Douglas Fearon. Photo from CSHL

The study was done on 24 patients and is a phase 0 effort, in which scientists and doctors test the pharmacokinetics and pharmacodynamics of the treatment.

In the study, which was published in the prestigious journal Proceedings of the National Academy of Sciences of the United States of America, the researchers showed that the treatment got into the blood, that the patients tolerated it, and that it enabled immune treatments to reach the tumors.

While this is an encouraging step, Janowitz cautioned that any such studies are far from a potentially viable treatment for either type of cancer. Indeed, the Food and Drug Administration requires a lengthy and rigorous scientific process for any possible therapy, in part because numerous promising efforts haven’t led to viable therapies for a host of reasons.

Still, this study offers a promising beginning for a potential approach to treating various forms of cancer.

Janowitz said patients “tolerated the treatment by and large very well,” and that “no new toxicities were observed compared to the ones that were known.” Some people developed slight disturbances in their sleep, which were immediately resolved after they discontinued using the treatment.

The history of the possible treatment for HIV showed similar side effects years ago. “We anticipated it would have a favorable toxicity profile,” said Janowitz.

The link between this early candidate for HIV treatment and cancer came from an analysis of the receptor that is expressed on immune cells, called CXCR4.

This receptor is targeted by the drug plerixafor. Most of the work linking the inhibited receptor to potential cancer treatment came from Fearon’s lab, Janowitz explained.

Fearon found that blocking the receptor enabled immune cells to migrate to cancer in a mouse study. Along with Janowitz and CSHL Cancer Director David Tuveson, he published a paper on the preclinical study in a mouse model in PNAS in 2013.

This inhibitor also has been used to release stem cells from bone marrow that can be used in a hematological context for treatment and transplantation. During their cancer study, the scientists found these stem cells circulating in the blood. It’s unclear from this first study how the combination of cancer therapy and releasing stem cells from bone marrow affects patients.

“We are not able to say that that has a relevancy to the cancer patient,” Janowitz said.

While some drug treatments work for a period of time until a cancer returns, immunotherapy may have a longer term benefit than chemotherapeutics, as some studies suggest.

“By giving this drug, our hope is that we enable an influx of immune cells into the tumor and have an across the board integrated immune response,” Janowitz said.

Down the road, Janowitz said the group hopes that this treatment will be a part of a combination of treatments that treat cancer.

By enabling immune cells to access cancer where the mutation rate is lower, these treatments could provide a sustained treatment.

The researchers chose pancreatic and colorectal cancer because those cancers don’t respond to current immunotherapy. “It’s really important to uncover why that is,” said Janowitz. The scientists had evidence from pre-clinical models that the pathway and the biochemistry that this drug activates can be effective.

In his lab, Janowitz performed some of the mechanistic work to understand why this drug might function. A medical doctor who is awaiting his license to practice in New York, Janowitz was also involved in the trial management group and in analyzing the multiplicity of data that came together.

The researchers in this study came from fields including bioinformatics, clinical medicine, pharmacology, and immunology. Fearon explained in an email that Jodrell wrote the grant to Stand Up to Cancer, or SU2C, in 2014 to obtain funding for the trial. Jodrell oversaw the clinical trial and Fearon directed the evaluation of the immunology findings.

Janowitz had a “major role in putting together the clinical data for the write-up,” and Daniele Biasci, a computational biologist at Cambridge, developed the analysis of the transcriptional data of the tumor biopsies, said Fearon.

As for the next stages in this work, physicians at Johns Hopkins Medicine International and Dana Farber Cancer Institute will soon start a phase 2 trial that is already registered and that combines this inhibitor with anti-PD-1.

Fearon said his continued pre-clinical research has shown that this immune suppressive pathway may be relevant to multiple human carcinomas, and has identified new potential targets for more effective immunotherapy.

Janowitz, meanwhile, will explore the systemic immune competence of the body as he continues to take a top down, broad-based approach to cancer.

He would like to know the degree to which the body can mount an effective immune response, while also exploring the factors that diminish that ability.

Separately, with three young children at home, Janowitz and his wife Clary, who is a radiation oncologist, have been balancing between their busy careers and the demands of parenting during the pandemic. Their extended families are both in Europe.

“We can’t visit them and they can’t visit us,” he said adding that he appreciated the way CSHL has offered day care to young children on campus.

As for this study, Janowitz said he’s encouraged by the early results.

Bruce Stillman. Photo from CSHL

By Daniel Dunaief

Bruce Stillman, the CEO of Cold Spring Harbor Laboratory, last week won the Dr. H.P. Heineken Prize for Biochemistry and Biophysics, which is considered the most distinguished scientific prize from the Netherlands.

The prize, which has been awarded to 13 researchers who have gone on to win Nobel Prizes, includes a $200,000 award and a crystal trophy.

Stillman earned the award, which began in 1964 and is given every two years in categories including Medicine, Environmental Sciences and History, for his decades of work on mechanisms involved in the replication, or copying, of eukaryotic DNA.

The understated Stillman, who was born and raised in Australia, expects he’ll put the prize money into a foundation, although he hasn’t thought much about it given the other concerns that dominate his time, including not only running his own lab amid the COVID-19 pandemic but also overseeing a facility where he has been the Director since 1994 and its CEO since 2003.

Stillman said the lab has had “extensive discussions” among the faculty about whether to pursue additional research fields on an ongoing basis to combat the current virus as well as any future public health threats.

While CSHL is not an infectious disease center, the facility does have a historical precedent for contributing to public health efforts during a crisis. Indeed, during World War II, the laboratory helped create a mutated strain of fungus that increased its yield of the drug penicillin.

At this point, CSHL does not have a high containment facility like Stony Brook University where it can handle highly infectious agents.

“We may have to have one here,” Stillman said. “The reality is there are tons of infectious diseases” and the lab might need to repurpose its scientific skills towards coming up with answers to difficult questions.

Even without such a Biosafety Level 3 designation, CSHL researchers have tackled ways to understand and conquer COVID-19. Associate Professor Mikala Egeblad has been exploring whether neutrophil extracellular traps, which are ways bodies fight off bacterial infections, are playing a role in blood clotting and severe respiratory distress.

These NETS may be “promoting severe symptoms in COVID,” Stillman said. Egeblad is working on a case study with several other collaborators who have focused on these traps. Egeblad is also studying the effectiveness of NETS as a biomarker for the most severe patients, Stillman said.

CSHL is also investigating a small molecule compound to see if it inhibits viral infection. Researchers including Assistant Professor Tobias Janowitz are about to participate in a combined Northwell Health-CSHL double blind study to determine the effectiveness of famotidine, which is the active ingredient in the ulcer-treating medication Pepcid.

The coronavirus treatment, which will include patients who don’t require hospitalization, would require a higher dose than for heartburn.

As a part of this study, the scientists will use a patient tracking system that has been used for cancer to determine the effectiveness of the treatment through patient reporting, without requiring laboratory tests.

Stillman is pleased with how CSHL has “repurposed ourselves quickly, as have many institutions around the world.” He highlighted the constructive interactions among scientists.

The public health crisis has “generated a different kind of behavior in science, where there’s a lot of interaction and cooperation,” Stillman said. The preprint journal BioRxiv, which CSHL operates, has had nearly 5,000 papers about COVID-19 since January. The preprints have “not only helped disseminate information rapidly [to the scientific community], but they are also “being used to determine policy by government leaders.”

Stillman urged scientists to apply the same analytical technique in reading preprinted research that they do with peer-reviewed studies, some of which have required corrections.

As for the government’s response, Stillman believes a retrospective analysis will provide opportunities to learn from mistakes. “I don’t think the [Centers for Disease Control and Prevention] has done a very good job,” he said. He suggested that the well-documented problems with the roll out of testing as community transmission was increasing, was a “disaster.”

The CSHL CEO also said the balkanized medical system, in which every state has a different system and even some local communities have their own processes, creates inefficiencies in responding to a fluid and dangerous public health crisis.

Coordinating those efforts “could have been done very, very rapidly to develop a modern, clear [polymerase chain reaction] test of this virus and yet states and federal agencies had regulations about how these tests can be approved and controlled and regulated that are far too bureaucratic and did not set a national standard quickly,” he said.

He hopes agencies like the CDC, FDA and the Biomedical Advanced Research and Development Authority have better coordination. The country needs a national response, like it had after the Homeland Security effort following 9/11.

Optimistically, Stillman expects a therapeutic antibody will be available by the end of the summer to treat COVID-19. The treatment, which will use monoclonal antibodies, will likely be injectable and will be able to prevent infection for a month or two. These treatments could also help limit the severity of symptoms for people who have been infected.

Regeneron has taken the same approach with Ebola effectively. Stillman doesn’t think such treatments can be used with everybody in the world, which increases the need to develop a vaccine. Creating a safe vaccine, which could be available as early as next year, is a “massive, under-recognized undertaking.”

Between now and next year, a second wave of the virus is certainly possible and may be likely, given that other coronaviruses have been seasonal. 

“This happened with the influenza pandemic a century ago, so we have to be careful about this,” Stillman said. He believes that the medical community has learned how to treat severe patients, which should help mitigate the effects of a second wave in the United States. 

That may not be the case in developing countries, which is a “concern,” he said.

Members of the quantum materials team, from left, Gregory Doerk, Jerzy Sadowski, Kevin Yager, Young Jae Shin and Aaron Stein. Photo from BNL

By Daniel Dunaief

Henry Ford revolutionized the way people manufactured cars through automation, speeding up the process, reducing waste and cutting costs.

Similarly, at Brookhaven National Laboratory, researchers like the newly hired Young Jae Shin, who is a staff scientist at the Center for Functional Nanomaterials, hopes to improve the process of automating the handling of thin flakes of material used in a next generation technology called quantum information science, or QIS.

Working with scientists at Harvard University and the Massachusetts Institute of Technology, Shin is looking for ways to handle these flakes, which are one atom thick, of two-dimensional layers from different materials. Stacked together, these flakes can help create structures with specific electronic, magnetic or optical properties that can be used as sensors, in communication, or encryption.

Young Jae Shin at Harvard University, where he was a post doctoral researcher. Photo from Y. Shin

“Researchers are building these kinds of customized structures manually now,” explained Kevin Yager, leader of the CFN Electronic Nanomaterials Group, in an email. “QPress [Quantum Material Press] will allow us to automate this.” At this point, QPress is just starting, but, if it works, it will “absolutely allow us to accelerate the study of these materials, allowing researchers to find optimal materials quickly,” Yager continued.

Theoretically, quantum computers overcome the limitations of other systems, Shin explained.

The flakes come from the exfoliation of thin structures taken from a bulk material. This is akin to a collection of leaves that fall around trees. According to Yager, the structures scientists hope to make would be akin to a collection of leaves from different trees, put together to make a new structure or material with specific properties. “The idea is for the robot to sift through the flakes, and identify the ‘best’ ones and to stack these together into the right structure. The ‘stacking’ will involve combining flakes of different materials,” he said.

The less desirable flakes typically are the wrong size, have tears, ripples or other defects and have contaminants. Groups of scientists are predicting the kinds of layered designs that will have desired properties.

Shin suggested that the CFN supports the needs of the end user community, as CFN is a “user-based facility.”

Physicists at Harvard and MIT plan to use the QPress to study unusual forms of superconductivity. By tapping into materials that conduct electricity without losing energy at lower temperatures, researchers may make progress in quantum computing, which could exceed the ability of the current state-of-the-art supercomputers.

Stacking the flakes can create new materials whose properties not only depend on the individual layers, but also on the angle between the stacks. Scientists can change one of these new structures from having metallic to having insulating properties, just by altering the relative angle of the atoms. The challenge, however, is that putting these fine layers together by hand takes time and generates errors which, BNL hopes, an automated approach can help reduce.

“Ultimately, we would like to develop a robot that delivers a stacked structure based on the 2-D flake sequences and crystal orientations that scientists select through a web interface” to a machine, Charles Black, the head of the Center for Functional Nanomaterials at BNL, explained in a recent BNL feature. “If successful, the QPress would enable scientists to spend their time and energy studying materials, rather than making them.”

Barring unforeseen delays, scientists anticipate that they will be able to build a machine that creates these flakes, catalogs them, stacks them and characterizes their properties within three years. These functions will be available online in stages, to allow the use of the QPress prior to its completion.

Each stage in the QPress process uses computer software to reduce the effort involved in generating and interpreting usable structures.

Minh Hoai Nguyen, an assistant professor in the Department of Computer Science at Stony Brook University and doctoral student Boyu Wang from the Computer Vision Lab at SBU are creating a flake cataloger, which will use image analysis software to scan and record the location of flakes and their properties.

“The flakes that scientists are interested in are thin and thus faint, so manual and visual inspection is a laborious and error-prone process,” Nguyen said in the BNL feature.

At BNL, Shin is one of three scientists the Upton-based facility is hiring as a part of this effort. They are also seeking robot or imaging process experts. Shin has “been in the CFN just a short while, but is already having an impact- — for instance, allowing us to handle classes of two-dimensional materials that we were not working with before,” Yager said.

The field of quantum information science is extremely competitive, with researchers from all over the world seeking ways to benefit from the properties of materials on such a small scale. The United States has been investing in this field to develop leadership science in this area.

The University of Tokyo has developed an automation system, but Shin explained that it is still not perfect.

Yager said that numerous unknown applications are “waiting to be discovered. Researchers are working hard on real quantum computers. Prototypes already exist but creating viable large-scale quantum computers is a major challenge.”

A resident of on-site housing at BNL, Shin was born in the United States and grew up in Korea. He is married to Hyo Jung Kim, who is studying violin at Boston University. 

As for the work Shin and others are doing, Yager suggested that the effort has generated considerable interest at the CFN.

“There is huge excitement at BNL about quantum research broadly and QPress in particular,” said Yager. Shin is “a big part of this — bringing new technical knowledge and new enthusiasm to this ambitious project.”

From left, Megan Crow, Associate Professor Jesse Gillis and postdoctoral researcher Sara Ballouz Photo by Gina Motisi/CSHL

By Daniel Dunaief

Diversity has become a buzz word in the workplace, as companies look to bring different perspectives that might represent customers, constituents or business partners. The same holds true for the human brain, which contains a wide assortment of interneurons that have numerous shapes and functions.

Interneurons act like a negative signal or a brake, slowing or stopping the transmission. Like a negative sign in math, though, some interneurons put the brakes on other neurons, performing a double negative role of disinhibiting. These cells of the nervous system, which are in places including the brain, spinal chord and retina, allow for the orderly and coordinated flow of signals.

One of the challenges in the study of these important cells is that scientists can’t agree on the number of types of interneurons.

“In classifying interneurons, everyone argues about them,” said Megan Crow, a postdoctoral researcher in Jesse Gillis’ lab at Cold Spring Harbor Laboratory. “People come to this question with many different techniques, whether they are looking at the shape or the connectivity or the electrophysiological properties.”

Megan Crow. Photo by Constance Brukin

Crow recently received a two-year grant from the National Institutes of Health to try to measure and explain the diversity of interneurons that, down the road, could have implications for neurological diseases or disorders in which an excitatory stimulus lasts too long.

“Understanding interneuron diversity is one of the holy grails of neuroscience,” explained Gillis in an email. “It is central to the broader mission of understanding the neural circuits which underlie all behavior.”

Crow plans to use molecular classifications to understand these subtypes of neurons. Her “specific vision” involves exploiting “expected relationships between genes and across data modalities in a biologically thoughtful way,” said Gillis.

Crow’s earlier research suggests there are 11 subtypes in the mouse brain, but the exact number is a “work in progress,” she said.

Her work studying the interneurons of the neocortex has been “some of the most influential work in our field in the last two to three years,” said Shreejoy Tripathy, an assistant professor in the Department of Psychiatry at the University of Toronto. Tripathy hasn’t collaborated with Crow but has been aware of her work for several years.

The interactivity of a neuron is akin to personalities people demonstrate when they are in a social setting. The goal of a neuronal circuit is to take an input and turn it into an output. Interneurons are at the center of this circuit, and their “personalities” affect the way they influence information flow, Crow suggested.

“If you think of a neuron as a person, there are main personality characteristics,” she explained. Some neurons are the equivalent of extraverted, which suggests that they have a lot of adhesion proteins that will make connections with other cells.

“The way neurons speak to one another is important in determining” their classes or types, she said.

A major advance that enabled this analysis springs from new technology, including single-cell RNA sequencing, which allows scientists to make thousands of measurements from thousands of cells, all at the same time.

“What I specialize in and what gives us a big leg up is that we can compare all of the outputs from all of the labs,” Crow said. She is no longer conducting her own research to produce data and, instead, is putting together the enormous volume of information that comes out of labs around the world.

Megan Crow. Photo by Daniel Katt

Using data from other scientists does introduce an element of variability, but Crow believes she is more of a “lumper than a splitter,” although she would like to try to understand variation where it is statistically possible.

She believes in using data for which she has rigorous quality control, adding, “If we know some research has been validated externally more rigorously than others, we might tend to trust those classifications with more confidence.”

Additionally she plans to collaborate with Josh Huang, the Charles Robertson professor of neuroscience at Cold Spring Harbor Laboratory, who she described as an interneuron expert and suggested she would use his expertise as a “sniff test” on certain experiments.

At this point, Crow is in the process of collecting baseline data. Eventually, she recognizes that some interneurons might change in their role from one group to another, depending on the stimuli.,

Crow hasn’t always pursued a computational approach to research. 

In her graduate work at King’s College London, she produced data and analyzed her own experiments, studying the sensory experience of pain.

One of the challenges scientists are addressing is how pain becomes chronic, like an injury that never heals. The opioid crisis is a problem for numerous reasons, including that people are in chronic pain. Crow was interested in understanding the neurons involved in pain, and to figure out a way to treat it. “The sensory neurons in pain sparked my general interest in how neurons work and what makes them into what they are,” she said.

Crow indicated that two things brought her to the pain field. For starters, she had a fantastic undergraduate mentor at McGill University, Professor of Psychology Jeff Mogil, who “brought the field to life for me by explaining its socio-economic importance, its evolutionary ancient origins, and showed me how mouse behavioral genetic approaches could make inroads into a largely intractable problem.”

Crow also said she had a feeling that there might be room to make an impact on the field by focusing on molecular genetic techniques rather than the more traditional electrophysiological and pharmacological approaches.

As for computational biology, she said she focuses on interpreting data, rather than in other areas of the field, which include building models and simulations or developing algorithms and software.

In the bigger picture, Crow said she’s still very interested in disease and would like to understand the role that interneurons and other cells play. “If we can get the tools to be able to target” some of the cells involved in diseases, “we might find away to treat those conditions.”

The kind of research she is conducting could start to provide an understanding of how cells interact and what can go wrong in their neurodevelopment.

Gillis praises his postdoctoral researcher for the impact of her research.

“Just about any time [Crow] has presented her work — and she has done it a lot — she has ended up convincing members of the audience so strongly that they either want to collaborate, adapt her ideas, or recruit her,” Gillis wrote in an email. 

Crow grew up in Toronto, Canada. She said she loved school, including science and math, but she also enjoyed reading and performing in school plays. She directed a play and was in “The Merchant of Venice.” In high school, she also used to teach skiing.

A resident of Park Slope in Brooklyn, Crow commutes about an hour each way on the train, during which she can do some work and catch up on her reading.

She appreciates the opportunity to work with other researchers at Cold Spring Harbor, which has been “an incredible learning experience.”

Lori Chan, standing, in the lab with doctoral student Jiabei He. Photo from SBU

By Daniel Dunaief

It’s like a factory that makes bombs. Catching and removing the bombs is helpful, but it doesn’t end the battle because, even after many or almost all of the bombs are rounded up, the factory can continue to produce damaging products.

That’s the way triple-negative breast cancer operates. Chemotherapy can reduce active cancer cells, but it doesn’t stop the cancer stem cell from going back into the cancer-producing business, bringing the dreaded disease back to someone who was in remission.

Scientists who stop these cancer stem cells would be doing the equivalent of shutting down the factory, reducing the possible return of a virulent type of cancer.

Lori Chan, an assistant professor in the Department of Pharmacological Sciences in the Renaissance School of Medicine at Stony Brook University, recently published research in Cell Death & Disease that demonstrated the role of a specific gene in the cancer stem cell pathway. Called USP2, this gene is overexpressed in 30 percent of all triple-negative breast cancers.

Inhibiting this gene reduced the production of the tumor in a mouse model of the disease.

Chan’s results “suggest a very important role [of this gene] in cancer stem cells,” Yusuf Hannun, the director of the Stony Brook University Cancer Center, explained in an email.

Lori Chan with her dog KoKo. Photo by Joshua Lee

Chan used a genetic and a pharmacological approach to inhibit USP2 and found that both ways shrink the cancer stem cell population. She used RNA interference to silence the gene and the protein expression, and she also used a USP2-specific small molecular inhibitor to block the activity of the USP2 protein.

With the knowledge that the cancer stem cell factory population needs this USP2 gene, Chan inhibited the gene while providing doxurubicin, which is a chemotherapy treatment. The combination of treatments suppressed the tumor growth by 50 percent.

She suggested that the USP2 gene can serve as a biomarker for the lymph metastasis of triple-negative breast cancer. She doesn’t know if it could be used as a biomarker in predicting a response to chemotherapy. Patients with a high expression of this gene may not respond as well to standard treatment.

“If a doctor knows that a patient probably wouldn’t respond well to chemotherapy, the doctor may want to reconsider whether you want to put your patient in a cycle for chemotherapy, which always causes side effects,” Chan said.

While this finding is an encouraging sign and may allow doctors to use this gene to determine the best treatment, the potential clinical benefit of this discovery could still be a long way off, as any potential clinical approach would require careful testing to understand the consequences of a new therapy.

“This is the beginning of a long process to get to clinical trials and clinical use,” Hannun wrote. Indeed, researchers would need to understand whether any treatment caused side effects to the heart, liver and other organs, Chan added. 

In the future, doctors at a clinical cancer center might perform a genomic diagnostic, to know exactly what type of cancer an individual has. Reducing the cancer stem cell population can be critically important in leading to a favorable clinical outcome.

A few hundred cancer cells can give rise to millions of cancer cells. “I want to let chemotherapy do its job in killing cancer cells and let [cancer stem cell] targeted agents, such as USP2 inhibitors, prevent the tumor recurrence,” Chan said. 

She urges members of the community to screen for cancer routinely. A patient diagnosed in stage 1 has a five-year survival rate of well over 90 percent, while that rate plummets to 15 to 20 percent for patients diagnosed with stage 4 cancer.

The next step in Chan’s research is to look for ways to refine the inhibitor to make it more of a drug and less of a compound. She is also interested in exploring whether USP2 can be involved in other cancers, such as lung and prostate, and would be happy to collaborate with other scientists who focus on these types of cancers.

For Chan, the moment of recognition of the value of studying this gene in this form of breast cancer came when she compared the currently used drug with and without the inhibitor compound. With the inhibitor, the drug becomes much more effective.

A resident of Stony Brook, Chan lives with her husband, Joshua Lee, who is working in the same lab. The couple, who have a 1½-year-old rescue dog from Korea named KoKo, met when they were in graduate school.

Concerned about snow, which she hadn’t experienced when she was growing up in Taiwan, Chan started her tenure at Stony Brook five years ago on April 1, on the same day a snowstorm blanketed the area. “It was a very challenging first day,” she recalled. She now appreciates snow and enjoys the seasonal variety on Long Island.

Chan decided to pursue a career in cancer research after she volunteered at a children’s cancer hospital in Taiwan. She saw how desperate the parents and the siblings of the patient were. In her role as a volunteer, she played with the patients and with their siblings, some of whom she felt didn’t receive as much attention from parents who were worried about their sick siblings.

“This kind of disease doesn’t just take away one person’s life,” Chan said. “It destroys the whole family.” When she went to graduate school, she wanted to know everything she could about how cancer works.

Some day Chan hopes she can be a part of a process that helps doctors find an array of inhibitors that are effective in treating patients whose cancers involve the overexpression of different genes. “It would be a privilege to participate in this process,” she said.

Michael Jensen on a container ship in the Pacific Ocean, where he was measuring marine clouds. Photo from M. Jensen

By Daniel Dunaief

They often seem to arrive at the worst possible time, when someone has planned a picnic, a wedding or an important baseball game. In addition to turning the sky darker, convective clouds can bring heavy rains and lightning.

For scientists like Michael Jensen, a meteorologist at Brookhaven National Laboratory, these convective clouds present numerous mysteries, including one he hopes to help solve.

Aerosols, which come from natural sources like trees or from man-made contributors, like cars or energy plants, play an important role in cloud formation. The feedbacks that occur in a cloud system make it difficult to understand how changes in aerosol concentrations, sizes or composition impact the properties of the cloud.

“One of the big controversies in our field is how aerosols impact convection,” Jensen explained in an email. “A lot of people believe that when a storm ingests aerosols, it makes it stronger, because there are changes to precipitation and particles in the clouds.”

This process is called convective invigoration, which could make it rain more.

Another group of scientists, however, believes that the aerosols have a relatively small effect that is masked by other storm processes, such as vertical winds. 

Strong vertical motions that carry air, water and heat through the atmosphere are a signature of convective storms.

Jensen will lead an effort called Tracking Aerosol Convection Interactions Experiment, or TRACER, starting in April of 2021 in Houston that will measure the effect of these aerosols through a region where he expects to see hundreds of convective storm clouds in a year. 

From left, Donna Holdridge, from Argonne National Laboratory; Michael Jensen, kneeling; and Petteri Survo, from Vaisal Oyj in Helsinki, Finland during a campaign in Oklahoma to study convective storms. The team is testing new radiosondes, which are instruments sent on weather balloons. Photo from M. Jensen

The TRACER team, which includes domestic and international collaborators, will measure the clouds, precipitation, aerosol, lighting and atmospheric thermodynamics in considerable detail. The goal of the campaign is to develop a better understanding of the processes that drive convective cloud life cycle and convective-aerosol interactions.

Andrew Vogelmann, a technical co-manager of the Cloud Properties and Processes Group at BNL with Jensen, indicated in an email that the TRACER experiment is “generating a buzz within the community.” 

While other studies have looked at the impact of cities and other aerosol sources on rainfall, the TRACER experiment is different in the details it collects. In addition to collecting data on the total rainfall, researchers will track the storms in real time and will focus on strong updrafts in convection, which should provide specific information about the physics.

Jensen is exploring potential sites to collect data on the amount of water in a cloud, the size of the drops, the phase of the water and the shapes of the particles. He will use radar to provide information on the air velocities within the storm.

He hopes to monitor the differences in cloud characteristics under a variety of aerosol conditions, including those created by industrial, manufacturing and transportation activities.

Even a perfect storm, which starts in an area with few aerosols and travels directly through a region with many, couldn’t and wouldn’t create perfect data.

“In the real atmosphere, there are always complicating factors that make it difficult to isolate specific processes,” Jensen said. To determine the effect of aerosols, he is combining the observations with modeling studies.

Existing models struggle with the timing and strength of convective clouds.

Jensen performed a study in 2011 in Oklahoma that was focused on understanding convective processes, but that didn’t hone in on the aerosol-cloud interactions.

Vogelmann explained that Jensen is “well-respected within the community and is best known for his leadership” of this project, which was a “tremendous success.”

Since that study, measurement capabilities have improved, as has modeling, due to enhanced computing power. During the summer, Long Island has convective clouds that are similar to those Jensen expects to observe in Houston. Weather patterns from the Atlantic Ocean for Long Island and from the Gulf of Mexico for Houston enhance convective development.

“We experience sea breeze circulation,” Jensen said. Aerosols are also coming in from New York City, so many of the same physical processes in Houston occur on Long Island and in the New York area.

As the principal investigator, Jensen will travel to Houston for site selection. The instruments will collect data every day. During the summer, they will have an intensive operational period, where Jensen and other members of the TRACER team will forecast the convective conditions and choose the best days to add cloud tracking and extra observations.

Jensen expects the aerosol impact to be the greatest during the intermediate strength storms. 

The BNL meteorologist described his career as jumping back and forth between deep convective clouds and marine boundary layer clouds.

Jensen is a resident of Centerport and lives with his wife Jacqui a few blocks from where he grew up. Jacqui is a banker for American Community Bank in Commack. The couple has a 22-year-old son Mack, who is a substitute teacher at the Harborfields school district.

Jensen describes his family as “big music people,” adding that he plays euphonium in a few community band groups, including the North Shore Community Band of Longwood and the Riverhead Community Band.

As an undergraduate at SUNY Stony Brook, Jensen was broadly interested in science, including engineering. In flipping through a course catalog, he found a class on atmospheric science and thought he’d try it.

Taught by Robert Cess, who is now a professor emeritus at SBU, the class “hooked” him.

Jensen has been at BNL for almost 15 years. Over that time, he said the team has “more influence in the field,” as the cloud processing group has gone from six to 18 members. The researchers have “expanded our impact in the study of different cloud regimes and developed a wide network of collaborations and connections throughout the globe.”

As for his work in the TRACER study, Jensen hopes to “solve this ongoing debate, or at least provide new insights into the relative role of aerosols and dynamics.”

From left, Anne Churchland and Tatiana Engel. Photo from CSHL

By Daniel Dunaief

Movies have often used an image of a devil on one shoulder, offering advice, and an angel on another, suggesting a completely different course of action. People, however, weigh numerous factors when making even the simplest of decisions.

The process the brain uses to make decisions involves excitatory and inhibitory neurons, which are spread throughout the brain. Technology has made it possible to study thousands of these important cells on an active mouse, showing areas that are active at the same time.

Anne Churchland, an associate professor at Cold Spring Harbor Laboratory, and Tatiana Engel, an assistant professor at the same facility, are collaborating on a three-year grant from the National Institutes of Health that will study the way neurons interact to understand the patterns that lead to decisions. 

Engel said she, Churchland and another collaborator on the project, Stanford University Professor Krishna Shenoy, applied for the funding in response to a call from the NIH to develop computational methods and models for analyzing large-scale neural activity recordings from the brain.

Churchland and Shenoy will provide experimental data for the computational models Engel’s lab will develop. The data is “huge and complex,” Engel said, and researchers need new methods to understand it. “The simple techniques don’t translate to large-scale recordings,” Engel said.

Churchland and Engel jointly hired James Roach, a postdoctoral researcher who recently earned his doctorate from the University of Michigan and works in both of their labs. 

Churchland’s lab will provide data from the mouse model, while Engel’s lab brings computational expertise.

“Little is known about how these neurons are connected to behavior,” Engel said. Their research will hope to explain the role of inhibitory cells, which may have a more finely tuned function beyond keeping cells from remaining in an excited state.

The prevailing view in the field is that inhibitory neurons provide a balancing input to the network to prevent it from generating too much excitation or creating a seizure. Inhibitors are like the regulators that tap the brakes on a network that’s becoming too active.

Excitatory neurons, by contrast, are the ones that have an important job, representing the decisions individuals make.

Churchland is going to measure neural activity using a 2-photon microscope that allows her to measure the activity of about 600 neurons simultaneously. 

“This provides an incredible opportunity to analyze the data, using tools borrowed from machine learning and dynamical systems,” she explained in an email.

What Churchland’s data has helped show, however, is that the inhibitory neurons are doing more than providing a global braking signal. “They have some dedicated role in the circuit and we don’t know what that role is yet,” Engel said.

The team will build neural circuit models to help understand how the system is wired and what role each type of cell plays in various behaviors.

“We are developing computational frameworks where we can go and analyze activities of large groups of cells and, from the data, determine how individual cells contribute to the activity of the population,” Engel said.

Brains have considerable plasticity, which means that when one area of the brain isn’t functioning for whatever reason — through an injury or a temporary blockage ‒ other areas can compensate. “The whole problem is immensely complicated to figure out what a brain area is doing normally,” she explained. The picture can “completely change when there’s brain damage.”

Research is moving in the direction of understanding and manipulating large neural circuits at once, rather than a single area at a time. 

“Models can extract general principles, which still hold true even in more complex” systems Engel said. The principles include understanding how excitatory and inhibitory cells are balanced. “Models can help you figure out what works and doesn’t work.”

Roach, the current postdoctoral researcher working with Engel and Churchland, will start with modeling and then will develop experiments to test the role of inhibitory cells. He has already worked on computer programs that interpret neurological circuits and laboratory results. He is also receiving laboratory training.

At this point, Engel and Churchland are working on basic science. Engel explained that this type of research is the foundation for translation work that will lead to an improved diagnosis and treatment of neurological disorders. Basic science can, and often does, provide insights and information that help those working to understand or treat disease, she suggested.

Churchland was pleased with her collaboration with Engel.

Engel is “best known for modeling work she did studying neural mechanisms of attention,” Churchland explained in an email. “She is a great addition to Cold Spring Harbor! We work together in the same building and are trying to unravel the mysteries of how large groups of neurons in the brain work together to make decisions.”

A resident of the facilities at Cold Spring Harbor Laboratory, Engel grew up in Vologda, which is over 300 miles north of Moscow. Starting in seventh grade, she attended physics and math schools, first in her home town and then at a boarding school at the Moscow State University.

She learned to appreciate the value of science from the journals her parents subscribed to, including one for children called Kvant magazine. She solved physics problems in that magazine. “I enjoyed the articles and problems in Kvant,” she explained in an email.

As for her work, Engel suggested that there were many discoveries ahead. “It is an exciting and transformative time in neuroscience,” she said.