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Cold Spring Harbor Laboratory

Partha Mitra at the Shanghai Natural History Museum in China where he was giving a talk to children on how birds learn to sing.

By Daniel Dunaief

Throw a giant, twisted multi-colored ball of yarn on the floor, each strand of which contains several different colored parts. Now, imagine that the yarn, instead of being easy to grasp, has small, thin, short intertwined strings. It would be somewhere between difficult and impossible to tease apart each string.

Instead of holding the strings and looking at each one, you might want to construct a computer program that sorted through the pile.

That’s what Partha Mitra, a professor at Cold Spring Harbor Laboratory, is doing, although he has constructed an artificial intelligence program to look for different parts of neurons, such as axons, dendrites and soma, in high resolution images.

Partha Mitra at the Owl Cafe in Tokyo

Working with two dimensional images which form a three dimensional stock, he and a team of scientists have performed a process called semantic segmentation, in which they delineated all the different neuronal compartments in an image.

Scientists who design machine learning programs generally take two approaches: they either train the machine to learn from data or they tailor them based on prior knowledge. “There is a larger debate going on in the machine learning community,” Mitra said.

His effort attempts to take this puzzle to the next step, which hybridizes the earlier efforts, attempting to learn from the data with some prior knowledge structure built in. “We are moving away from the purely data driven” approach, he explained.

Mitra and his colleagues recently published a paper about their artificial intelligence-driven neuroanatomy work in the journal Nature Machine Intelligence.

For postmortem human brains, one challenge is that few whole-brain light microscopic data sets exist. For those that do exist, the amount of data is large enough to tax available resources.

Indeed, the total amount of storage to study one brain at light microscope resolution is one petabyte of data, which amounts to a million megapixel images.

“We need an automated method,” Mitra said. “We are on the threshold of where we are getting data a cellular resolution of the human brain. You need these techniques” for that discovery. Researchers are on the verge of getting more whole-brain data sets more routinely.

Mitra is interested in the meso-scale architecture, or the way groups of neurons are laid out in the brain. This is the scale at which species-typical structures are visible. Individual cells would show strong variation from one individual to another. At the mesoscale, however, researchers expect the same architecture in brains of different neurotypical individuals of the same species.

Trained as a physicist, Mitra likes the concreteness of the data and the fact that neuroanatomical structure is not as contingent on subtle experimental protocol differences.

He said behavioral and neural activity measurements can depend on how researchers set up their study and appreciates the way anatomy provides physical and architectural maps of brain cells.

The amount of data neuroanatomists have collected exceeds the ability of these specialists to interpret it, in part because of the reduction in cost of storing the information. In 1989, a human brain worth of light microscope data would have cost approximately the entire budget for the National Institutes of Health based on the expense of hard disk storage at the time. Today, Mitra can buy that much data storage every year with a small fraction of his NIH grant.

“There has been a very big change in our ability to store and digitize data,” he said. “What we don’t have is a million neuroanatomists looking at this. The data has exploded in a systematic way. We can’t [interpret and understand] it unaided by the computer.”

Mitra described the work as a “small technical piece of a larger enterprise,” as the group tries to address whether it’s possible to automate what a neuroanatomist does. Through this work, he hopes computers might discover common principals of the anatomy and construction of neurons in the brain.

While the algorithms and artificial intelligence will aid in the process, Mitra doesn’t expect the research to lead to a fully automated process. Rather, this work has the potential to accelerate the process of studying neuroanatomy.

Down the road, this kind of understanding could enable researchers and ultimately health care professionals to compare the architecture and circuitry of brains from people with various diseases or conditions with those of people who aren’t battling any neurological or cognitive issues.

“There’s real potential to looking at” the brains of people who have various challenges, Mitra said.

The paper in Nature Machine Intelligence reflected a couple of years of work that Mitra and others did in parallel with other research pursuits.

A resident of Midtown, Mitra, his wife Tatiana and their seven-year-old daughter have done considerable walking around the city during the pandemic.

The couple created a virtual exhibit for the New York Hall of Science in the Children’s Science Museum in which they described amazing brains. A figurative sculptor, Tatiana provided the artwork for the exhibition.

Mitra, who has been at Cold Spring Harbor Laboratory since 2003, said neuroanatomy has become increasingly popular over the last several years. He would like to enhance the ability of the artificial intelligence program in this field.

“I would like to eliminate the human proofreading,” he said. “We are still actively working on the methodology.”

Using topological methods, Mitra has also traced single neurons. He has published that work through a preprint in bioRxiv.

The Monti and Saladino families, above, continue the work of The Don Monti Memorial Research Foundation. Photo from Jim Kennedy

Even amid the COVID-19 pandemic, The Don Monti Memorial Research Foundation continues to raise money to support cancer care and research on Long Island.

Caroline Monti Saladino speaks at last year’s Cancer Survivors Day. Photo from Mel Saladino

The foundation, named for Don Monti, who died at 16 in 1972 from acute myeloblastic leukemia, has changed some of the events this year, but not the mission.

Instead of the annual ball at the Woodbury-based Crest Hollow Country Club, which the Montis own, the foundation started its Capital Giving Campaign and hopes to raise $1 million this year. All of the proceeds support the mission, since the foundation’s senior staff, including Caroline Monti Saladino, president, work for free.

“Today with COVID, nothing has changed with the journey,” she said.

The foundation has mailed out a capital campaign brochure that includes letters from Michael Dowling, president and CEO of Northwell Health; Richard Barakat, director of Northwell Health Cancer Institute; and Bruce Stillman, president of Cold Spring Harbor Laboratory.

“Your investment in cancer clinical care, research, wellness and survivorship enhances our ability to provide comprehensive, multidisciplinary care for our patients and enables us to provide support services for their families and loved ones,” Barakat wrote in his letter.

Monti Saladino, who has helped cancer patients for close to five decades, said the needs of cancer patients haven’t changed.

The Monti foundation has become a multigenerational family cause, which Tita and Joseph started months after their son died. The foundation has raised more than $47 million to support research, education and patient care in oncology and hematology. It has donated money to Northwell Health, Huntington Hospital, Long Island Jewish and Cold Spring Harbor Laboratory for everything from patient care and treatment to genetic counseling to basic research.

The foundation recently donated $50,000 to Huntington Hospital to help fund its developing cancer center.

Numerous members of the Monti and Saladino families have dedicated time and effort to improving the lives of people with cancer and to offering support to the families of patients. Monti Saladino said her children are involved, as are some of her 12 grandchildren, who have continued the family tradition by raising money to support the foundation.

The foundation has an office at CSHL, where Stillman said he often sees “family members working there, helping to raise support — it’s an amazing dedication.”

In addition to the visible connection through laboratories at CSHL, the foundation has supported four Don Monti cancer centers in Nassau and Suffolk, at North Shore University Hospital, also Huntington, Glen Cove and Plainview hospitals.

The members of the Monti and Saladino families have also played instrumental roles by visiting patients, hosting Don Monti Cancer Survivors Day events and forging new relationships with recipients of their support.

When Northwell and CSHL were looking for a link between the basic research at the Lab where new ideas and methods are developed, and the clinic where medical teams worked to provide personalized care, the Monti foundation helped facilitate a partnership.

“We were very familiar with what was going on” at Northwell partly “through the Monti foundation,” Stillman said. “They were helpful. It was good that people on both sides knew each other.”

Cold Spring Harbor Lab Connection

CSHL has received between $300,000 to $500,000 each year for over a decade from the foundation, which supports innovative research and supplements the funds the scientists receive from government agencies like the National Cancer Institute.

Receiving national grants is difficult and competitive, which increases the value of philanthropic funding that is the “driver of innovation and one of the reasons the United States is so prominent in research,” Stillman said.

He appreciates how the foundation offers a direct connection between the scientists working to cure a disease and the patients and their families who are, and have been, battling cancer.

Principal investigators, postdoctoral researchers and graduate students attend Cancer Survivors Day, during which they see people who might benefit from their research efforts.

“When you see patients, it does change the way you think about how you do the research,” Stillman said.

The funds from the foundation have supported numerous research initiatives at CSHL, including the work of Nicholas Tonks and Christopher Vakoc.

Working with chemists, Tonks developed molecules that inhibit enzymes called protein tyrosine phosphatases, which could be used to treat breast cancer.

Vakoc, meanwhile, has found subtypes of cancer that require critical proteins to grow. He is working on a program to identify how to target what Stillman described as the “Achilles heel” of some cancers.

“Our reputation through the years as a patient-oriented organization and a research-oriented organization has really sustained us. A lot of the people we have healed through our organization are very generous.”

— Caroline Monti Saladino

Northwell Health Connection

The Monti foundation works closely with Dr. Ruthee-Lu Bayer, who is the chief of stem cell transplantation at Northwell Health.

“She and her team are amazing,” Monti Saladino said.

She recalled that Bayer was doing clerical work she didn’t have time to do in the midst of her life-saving and life-extending efforts.

The foundation’s president suggested that the hospital should hire an administrator so Bayer’s team could see more patients. Monti Saladino spoke to the hospital administrator and said she would contribute $100,000 a year for five years, if the hospital contributed the remaining cost. The hospital agreed, providing some relief for Bayer’s efforts.

Monti Saladino said contributors appreciate the history of the Monti foundation and its ongoing focus.

“Our reputation through the years as a patient-oriented organization and a research-oriented organization has really sustained us,” she said. “A lot of the people we have healed through our organization are very generous.”

Stuart Hayim, who is a dealer of Ferraris and Maseratis on Long Island, recovered from lymphoma in 1979 while receiving medical treatment and personalized attention from Tita Monti, at the Don Monti Division of Oncology at North Shore University Hospital in Manhasset. Since then, he has won boat races and raised money each year for the foundation.

Monti Saladino said the foundation helps patients wherever and however it can.

When her young brother Don was diagnosed with leukemia in 1972, oncology and chemotherapy were “primitive,” she said. In terms of patient care, the medical experience “didn’t make people very comfortable.”

The Foundation’s Goal

Through the money the Don Monti foundation raised, the goal was to make the challenging experience of dealing with treating cancer more bearable for people and the families who go through it, she said.

The foundation built the first bone-marrow transplant unit in the 1990s, added a patient lounge and funded Cancer Survivors Day.

Monti Saladino said she “lives and breathes” her brother every day. Don died in June 1972, and her parents, Tita and Joseph Monti, had their first fundraiser that December.

Tita Monti, who died in 2006, said she didn’t want what happened to Don to happen to other people.

“We need to make a purpose out of his short 16 years of life, from the joy he gave us,” Monti Saladino recalled her mother saying.

Her brother’s story is a credit to his determination and to his mother’s perseverance, Monti Saladino said. Doctors had given him six weeks to live. His mother combined beetroot powder with natural and other healthy treatments that extended his life by 16 months.

Stillman said the legacy of the Monti family is evident throughout Long Island.

“It’s quite impressive, all of the number of people they’ve touched,” he said. “They’ve improved the treatment environment, the cancer environment, the clinicians and researchers.”

Monti Saladino said she and the family are far from perfect.

“We’ve got our issues,” she said. “They don’t affect this. This is a real focus that never changes.”

For more information, visit www.donmontifoundation.org.

Jeremy Borniger. Photo from CSHL

By Daniel Dunaief

Much as New Yorkers might want to minimize sleep, even during the pandemic when the need to be active and succeed is hampered by limited options, the body needs rest not only for concentration and focus, but also for the immune system.

Recently, Assistant Professor Jeremy Borniger, who joined Cold Spring Harbor Laboratory in January, collaborated with his former colleagues at Stanford University to publish research in the journal Science Advances that sheds light on the mechanism involved in this linkage.

Doctors and researchers had known for a long time that the release of glucocorticoids like cortisol, a stress hormone, can suppress the ability to fight off an infection. “That happens in people that are chronically stressed, even after surgery,” said Borniger in a recent interview.

A comprehensive understanding of the link between neuronal cells that are active during stress and a compromised immune system could help develop new ways to combat infections. The Stanford-led study provides evidence in a mouse model of the neuronal link between stress-induced insomnia and a weakened immune system.

Ideally, scientists would like to understand the neural pathways involved, which could help them design more targeted approaches for controlling the immune system using natural circuitry, according to Borniger.

Scientists could take similar approaches to the therapies involved with Parkinson’s, depression and obesity to increase or decrease the activity of the immune system in various disease states, instead of relying on a broader drug that hits other targets throughout the body.

In theory, by controlling these neurons, their gene products or their downstream partners, researchers could offer a way to fight off infections caused by stress.

While their studies didn’t look at how to gauge the effect of various types of sleep, such as napping or even higher or lower quality rest, their efforts suggest that sleep can help protect against stress-triggered infections.

The total amount and the structure of sleep play roles in this feedback loop. The variability among people makes any broad categorization about sleep needs difficult, as some people function well with six hours of sleep, while others need closer to eight or nine hours per day.

“Scientists are still working out how the brain keeps track of how much sleep it needs to rest and recover,” Borniger explained. “If we can figure this out, then, in principle, we could mess with the amount of sleep one needs without jeopardizing health.”

Researchers don’t know much about the circuitry controlling sleep amount. Borniger recognizes that the conclusions from this study are consistent with what doctors and parents have known for years, which is that sleep is important to overall health. The research also identifies a brain circuit that may be responsible for the way sleep buffers stress and immune responses.

People who have trouble sleeping because of elevated stress from an upcoming deadline often have a flare up of diseases they might have had under control previously, such as herpes viruses or psoriasis. These diseases opportunistically reemerge when the immune system is weakened.

The major finding in this study is not that the connection exists, but that the researchers, including principal investigator Luis de Lecea and first author Shi-Bin Li at Stanford, found the neural components.

While the studies of these linkages in the hypothalamus of mice were consistent across individuals, the same can’t be said for anecdotal and epidemiological evidence in humans, in part because the mice in the study were genetically identical.

For humans, age, sex, prior experiences, diet, family history and other factors make the linkage harder to track.

Even though researchers can’t control for as many variables with humans as they can with mice, however, several other studies have shown that stress promotes insomnia and poor immune function.

Borniger emphasized that he is the second author on the paper, behind Li and was involved in tracking the immune system component of the work.

Borniger and de Lecea are continuing to collaborate to see if drugs that target the insomnia neurons block the effect of stress on the immune system.

Now that he has moved into the refurbished Demerec Laboratory at CSHL, Borniger plans to work on projects to investigate how to use the nervous system to control anti-tumor immunity in models of breast and colorectal cancer, among others.

By understanding this process, Borniger can contribute to ways to manipulate these cells and the immune system to combat cancer and other inflammatory diseases.

Ideally, he’d like to be a part of collaborations that explore the combination of manipulating nervous and immune systems to combat cancer.

Borniger came to Cold Spring Harbor Laboratory because he was eager to collaborate with fellow scientists on site, including those who look at the immune system and metabolism. He appreciates how researchers at the famed research center look at how bodies and the brain respond to a growing tumor and would like to explore how tumors “influence nerves and then, reciprocally, how nerves influence tumor progression.”

The first few steps towards working at CSHL started in 2018, when Tobias Janowitz, Assistant Professor at CSHL, saw a paper Borniger published on breast cancer and asked him to give a 15-minute talk as a part of a young scholars symposium.

Borniger grew up in Washington, DC, attended college at Indiana University, went to graduate school at Ohio State and conducted his post-doctoral work at Stanford. Coming to CSHL brings him back to the East Coast.

Borniger and his fiancée Natalie Navarez, Associate Director of Faculty Diversity at Columbia University, met when they were in the same lab at Stanford. The couple had planned to get married this year. During the pandemic, they have put those plans on hold and may get married at City Hall.

Borniger and Navarez, who live on campus at Hooper House at CSHL, look forward to exploring opportunities to run, hike and swim on Long Island.

The new CSHL researcher appreciates the new opportunities on Long Island.

“This sort of collaborative atmosphere is what I would have in my Utopian dream,” Borniger said.

Taken around 1890, the photo above includes Lucas Cheadle’s great, great grandparents Martin Van Buren Cheadle and his wife Mary Vera with their children, from left, Overton, Ellis, Lurena and Thomas (who is Cheadle’s great grandfather).

By Daniel Dunaief

In joining Cold Spring Harbor Laboratory, Lucas Cheadle has continued his professional and personal journey far from his birthplace in Ada, Oklahoma.

Then again, his travels, which included graduate work in New Haven at Yale University and, most recently, post doctoral research in Boston at Harvard Medical School, wasn’t nearly as arduous or life threatening as the forced trip his ancestors had to take.

In 1837, Cheadle’s great, great, great grandparents had to travel from Pontotoc, Mississippi to southern Indian Territory, which is now near Tishomingo, Oklahoma as a part of the Trail of Tears. Native American tribes, including members of Cheadle’s family who are Chickasaw, cleared out of their lands to make way for Caucasian settlers.

Lucas Cheadle

Proud of his biracial heritage, which includes Chickasaw, Choctaw, and Cherokee lineages, Cheadle hopes to make his mark professionally in his studies of the development of the brain (see article on page B). At the same time, he hopes to explore ways to encourage other members of the Chickasaw tribe to enter the fields of science, technology, engineering and mathematics.

One of three sons of a mixed Chickasaw father named Robert Cheadle and a Caucasian mother named Cheryl, Cheadle would eventually like to provide the kind of internship opportunities through his own lab that he had during his high school years.

Indeed, during the summer of his junior year, Cheadle did a health care internship, in which he shadowed different types of physicians. He watched active surgeries and observed a psychiatrist during patient visits. After that summer, Cheadle thought he might become a psychiatrist as well because he knew he was interested in the study of the brain.

Down the road, Cheadle envisions having one or two people learn as interns in the lab during the summer. Longer term, Cheadle hopes other investigators might also pitch in to provide additional scientific opportunities for more Native American high school students.

Growing up in Oklahoma, Cheadle never felt he stood out as a member of the Chickasaw tribe or as a biracial student.

His father, Robert, was active with the tribe, serving as a tribal judge and then as a legislative attorney for the Chickasaw. His grandfather, Overton Martin Cheadle, was a legislator.

Through their commitment to the Chickasaw, Cheadle felt a similar responsibility to give back to the tribe. “It was an incredibly important part of their professional lives and it was a passion” to help others, he said. “I’m driven by that spirit.”

His father took people in who had nowhere to go. In a few cases, people he put up robbed the family. Even after they robbed him, Cheadle’s father took them back. When Robert Cheadle died earlier this year, one of the people whom Cheadle supported helped out with his funeral arrangements.

Driven to accomplish his mission as a scientist, Lucas Cheadle feels he can reach out to help high school students and others interested in science during his research journey.

“The better I can do, the more I can help,” Cheadle said. He hopes to “open doors for other people.”

With some of these efforts to encourage STEM participation among Native Americans, Cheadle hopes to collaborate with John Herrington, a Chickasaw astronaut who took a Native American flute into space during one of his missions. “It would be wonderful to discuss this” with Herrington, “if he has time for me,” said Cheadle.

In modern times, the Chickasaw tribe has made “good strides” in being successful. One challenge to that success, however, is that it has included assimilation.“The main goal is to hold onto the heritage as much as we can,” said Cheadle.

As for now, he plans to honor his heritage in his lab by “working hard to create a safe, respectful environment where people’s unique backgrounds and characteristics are supported and embraced. I try to create a space where diversity can thrive.”

Lucas Cheadle. Photo from CSHL

By Daniel Dunaief

One of the newest additions to Cold Spring Harbor Laboratory’s neuroscience program, Lucas Cheadle, who is an assistant professor, is exploring the early environmental factors at a molecular level that shape the neurological development of the mouse visual system.

While nature and nurture combine to produce the individuals each life form becomes, Cheadle is focused on the ways nurture, specifically, shapes the pathways in the brain that affect the development of sight.

Microglia are an unlikely player in this environmentally-triggered development, as doctors and researchers previously saw these cells primarily as participants in neurinflammation.

That is not the case anymore, with Cheadle and other scientists demonstrating over the past decade or so that microglia play important parts in the healthy brain. Cheadle, specifically, has demonstrated that these cells play a role in experience-dependent circuit development.

Indeed, the process of circuit refinement in the developing brain, which Cheadle describe as being among the “most complex structures in the known universe,” is akin to a room full of half-full boxes, which represent synaptic connections between neurons.

The brain begins with numerous little boxes that make the room difficult to navigate. As the brain consolidates the important items into a smaller number of larger boxes and removes the smaller boxes, the room becomes more manageable.

This is consistent with what Cheadle has seen during refinement. A smaller number of synapses become stronger and are maintained, while others are removed. This promotes the efficiency and precision of neural processing, he explained.

When the contents of some of those boxes disappear, however, the result can lead to neurodegenerative diseases like Alzheimer’s, in which a person struggles to find memories that may have been unwittingly cleared out.

Cheadle, who most recently was a post doctoral researcher at Harvard Medical School, is exploring the way microglia shape the connections between the eyes and the brain between when a mouse is born and when it reaches one month of age.

His work has shown that microglial cells are required for the sensory-dependent phase of visual circuit development. Disrupting signals between microglia and neurons affects synapse elimination, akin to removing the smaller boxes, which is important for circuit function.

Indeed, prior to work Cheadle and others have done in recent years with these cells in the brain, researchers thought microglia in the brain were quiescent, or inactive, after birth, except for their role in brain injury, disease pathology and neuroinflammation.

Until the first week of life, microglia engulf and then digest synaptic connections between some neurons, in a process called phagocytosis. During the sensory-dependent phase of refinement in the third week after birth, which Cheadle demonstrated in a paper published this month in the journal Neuron, microglia stop phagocytosis and rely on cytokines to break down synapses.

The cytokine pathway Cheadle discovered, called TWEAK, which is a ligand expressed by microglia, and Fn14, a receptor expressed by neurons, becomes active between eye opening, which is around two weeks, and peaks at about four weeks old.

When mice don’t have exposure to important visual stimuli during this critical period, the circuit has too many synaptic connections, which reduces the effectiveness of the developing visual system.

While Cheadle is working on visual development, specifically, he is interested in the broader implications of this work in the context of the environmental signals that affect the development of the brain.

In that broader context, the processes involved in autism and schizophrenia could reflect a period in which individuals have an overabundance of synapses that weren’t sufficiently pruned and refined.

Despite the fact that researchers hypothesized that synaptic pruning may lead to these disorders decades ago, they still have a limited awareness of whether and how this might happen. Studying the way microglia contribute to healthy circuit development could provide important clues about these processes.

Some epidemiological evidence points to the linkage between immune activity and neurodevelopmental disorders. In 1918 and 1919, during the Spanish Flu pandemic, children born during that period had a higher incidence of an autism or schizophrenia later in life.

Other evidence shows an interaction between immune activation and neurodevelopmental dysfunction, including the genetic loci associated with such disorders and increased inflammatory markers in the blood and brains of people with such disorders. “There’s really no question that there is a link,” Cheadle explained. “The nature of the link is still poorly understood.”

While earlier epidemiological data raises questions about the current pandemic, it doesn’t provide a definitive answer because “we still don’t quite understand what the nuanced molecular factors are that link the immune activation to the increase in disease prevalence,” Cheadle suggested.

“There’s a real chance that having COVID during pregnancy may impact the development of the offsprings’ nervous systems as has been seen in other infections,” Cheadle wrote. “While it is not the current priority of COVID research, it certainly warrants studying.”

Cheadle hopes to understand the “underlying principals of disorders” he said.

A resident of Huntington, Cheadle lives five minutes from the lab. He plans to rent for now because he didn’t want to start a new lab and move into a new house at the same time.

Cheadle has hired a technician and is in the process of hiring another. A post doctoral scientist will join his lab in November.

Early on in his life, Cheadle said he was fascinated with the interface between the world and biology. He wanted to understand how human brains interpret the information that comes from our senses. Everything culminated, professionally, in his interest in neurobiological mechanisms.

Currently, Cheadle is also interested in the looming behavior of mice. In the field, when mice see a bird that is flying slowly overhead, they are more likely to make a mad dash for safety, running into weeds or for cover from a tree. When the bird, however, is flying too rapidly, the mice freeze.

“I’m intrigued to find out whether the dichotomy of fight or flight could be shifted by the function of microglia,” he said. “I like to understand something at a functional level and dissect it to a molecular level.”

DNALC Assistant Director Amanda McBrien teaches a live session. Photo by Chun-hua Yang, DNALC

By Daniel Dunaief

Two letters defined the DNA Learning Center at Cold Spring Harbor Laboratory over the last several months: re, as in rethink, reimagine, reinvent, recreate, and redevelop. They also start the word reagent, which are chemicals involved in experiments.

The 32-year-old Learning Center, which teaches students from fifth grade through undergraduates, as well as teachers from elementary school to college faculty, shared lessons and information from a distance.

At the Learning Center, students typically benefit from equipment they may not have in their schools. That has also extended to summer camps. “Our camps are built on this experiential learning,” said Amanda McBrien, an Assistant Director at the Learning Center.

DNALC Educator Dr. Cristina Fernandez-Marco, teaches a Genome Science Virtual Class. Photo by Sue Lauter, DNALC

While that part of the teaching experience is missing, the center adapted to the remote model, shifting to a video based lessons and demonstrations. Indeed, campers this year could choose between a live-streamed and an on-demand versions.

Dave Micklos, the founder of the Learning Center, was pleased with his staff’s all-out response to the crisis.

“The volume of new videos that we posted on YouTube was more than any other science center or natural history museum that we looked up,” Micklos said. “It takes a lot of effort to post content if you’re doing it in a rigorous way.” During the first few months of the lockdown, the Learning Center was posting about three or four new videos each day, with most of them produced from staff members’ homes.

As for the camps, the Learning Center sent reagents, which are safe and easy to use, to the homes of students, who performed labs alongside instructors. In some camps, students isolated DNA from their own cells, plant or animal cells and returned the genetic samples to the lab. They can watch the processing use the DNA data for explorations of biodiversity, ancestry and detecting genetically modified organisms.

The Learning Center has been running six different labs this summer.

The virtual camps allowed the Learning Center to find a “silver lining from a bad situation” in which students couldn’t come to the site, McBrien said. The Learning Center developed hands-on programs that they sent throughout the country.

McBrien said the instructors watched each other’s live videos, often providing support and positive feedback. Some people even watched from much greater distances. “We had a few regulars who were hysterical,” McBrien said. “One guy from Germany, his name is Frank, he was in all the chats. He loved everything we did” and encouraged the teachers to add more scientific lessons for adults.

McBrien praised the team who helped “redevelop a few protocols” so high-level camps could enable students to interact with instructors from home.

A DNA Barcoding Virtual Camp featuring DNA Learning Center Educator Dr. Sharon Pepenella, with her virtual class. Over Pepenella’s shoulder is a picture of Nobel Prize winners Francis Crick and James Watson. Photo by Sue Lauter, DNALC.

Using the right camera angles and the equipment at the lab, the instructors could demonstrate techniques and explain concepts in the same way they would in a live classroom setting. To keep the interest of the campers, instructors added polls, quizzes and contests. Some classes included leader boards, in which students could see who answered the most questions correctly.

This summer, Micklos and Bruce Nash, who is an Assistant Director at the Learning Center, are running a citizen science project, in which teams from around the country are trying to identify ants genetically throughout the United States.

Using a small kit, one reagent and no additional equipment, contributing members of the public, whom the Learning Center dubs “Citizen Scientists,” are isolating DNA from about 500 of the 800 to 900 species of ants.

In one of the higher level classes called metabarcoding or environmental DNA research, teachers collected microbes in a sample swabbed from their nose, their knees, tap water, and water collected from lakes.

The Learning Center supports this effort for high school research through Barcode Long Island, which is a partnership with the Hudson River Park to study fish in the Hudson. High school interns and the public help with sampling and molecular biology.

“Much like barcoding, we aim to democratize metabarcoding,” Nash explained in an email. A metabarcoding workshop that ended recently had participants in Nigeria, Canada, Antigua and distant parts of the United States, with applicants from Asia.

After teaching college faculty on bar coding, Micklos surveyed the teachers to gauge their preference for future courses, assuming in-person meetings will be possible before too long.

When asked if they would like in-person instruction only, a hybrid model, or classes that are exclusively virtual, none of the teachers preferred to have the course exclusively in person. “People are beginning to realize it is more time efficient to do things virtually,” Micklos said.

Nash added that the preference for remote learning predated the pandemic.

Micklos appreciates the Learning Center’s educational contribution. “To pull these things off with basically people talking to each other via computer, to me, is pretty amazing,” he said.

Around four out of 10 students who enter college who have an interest in pursuing careers in science continue on their scientific path. That number, however, increases to six out of 10, when the students have a compelling lab class during their freshman year, Micklos said.

Lab efforts such as at the Learning Center may help steady those numbers, particularly during the disruption caused by the pandemic.

The longer-term goal at the Learning Center, Micklos said, is to democratize molecular biology with educational programs that can be done in the Congo, the Amazon or in other areas.

As for the fall, the leadership at the center plans to remain nimble.

The Learning Center is planning Virtual Lab field trips and will also continue to offer “Endless Summer” camp programs for kids and parents looking for science enrichment.

The Center also hopes to send instructors for in-person demonstrations at schools, where they can host small groups of student on site.

“We are supporting as many people as possible through our grant-funded programs and our (virtual) versions of camps and field trips,” Nash said. “These will be adapted to support schools and others to progressively improve them through the fall, with the hope of reaching all those we would normally reach.”

John Inglis. Photo courtesy of CSHL

By Daniel Dunaief

In the post COVID-19 world, the pace of science and, in particular, scientific publishing has changed, giving researchers a sense of urgency to share information that might lead to preventions, treatments and cures.

Cold Spring Harbor Laboratory has produced two preprint research services, bioRxiv and MedRxiv, that complement the longer peer-reviewed path to publication.

After numerous scientists restructured their labs to contribute to the growing body of knowledge and information about COVID-19, these researchers turned to preprint services to share the results of their work and the evolution of their thoughts on how to defeat the virus.

“It’s absolutely unprecedented for scientists to drop what they are doing and switch their focus to something completely new to aid society and mankind in general,” said John Inglis, the co-founder of bioRxiv and one of the members of joint management group for medRxiv.

MedRxiv, which started in June of 2019, helped provide the scientific community with an outlet for their health science research, with the caveat that the results haven’t received a thorough peer review, as they might in the New England Journal of Medicine, Cell, or other periodicals.

The number of preprint research papers has climbed dramatically this year, as scientists race to get their results from the bench to the server. The number of papers in bioRxiv increased to 88,268 in June from 71,458 in January. The increase at the newer medRxiv is much more dramatic, climbing from 953 in January to 7,541 in June.

The number of pandemic related papers on medRxiv and bioRxiv in total is 6,458, with 5,133 on medRxiv and 1,325 on bioRxiv.

Pandemic-related papers account for close to 70 percent of the new research published on medRxiv since January 1st, while the percentage of virus-related papers on bioRxiv is 6.2%, in large part because bioRxiv includes numerous other subject areas, including ecology, bioinformatics, plant biology and zoology.

The world has taken notice of all these papers, with page views peaking in April for medRxiv to almost 11 million for the month.

While the papers aren’t peer reviewed, the managers of these sites urge readers to remain cautious in their interpretation and use of these findings, while the scientific community continues to duplicate any encouraging or compelling results.

“We remind people all the time that these are preprints,” Inglis said, as the site has numerous reminders about the early nature of the findings. “They are preliminary reports and should not guide clinical practice or be reported as established information. That’s a battle we’re still fighting.”

The peer review process has also picked up some speed, as journals, inundated with potential game-changing material, have been accelerating the process of reading and reviewing papers. The median time between posting an article on bioRxiv and publication in a journal before the pandemic was nine months. Some papers in medRxiv have been published in journal in as few as 35 days.

For medRxiv, the screening process requires an ethics statement, a funding statement, and any potential conflicts of interest. These requirements are “all far more familiar in medical publishing than in scientific publishing,” said Inglis.

At bioRxiv, which recently introduced a competing interest statement as well for authors, freelancers and a group of Principal Investigators look at everything before it posts, to make sure it’s science and that it’s not dangerous. The screeners turn the manuscripts back to the team if they have any concerns.

“We felt, early in the pandemic, that it was necessary to make sure we have people with expertise in outbreak science,” Inglis explained. “We brought on volunteers.”

According to Inglis, the percentage of manuscripts that scientists submit, but that bioRxiv doesn’t publish, is between 5 and 10 percent, while that figure is closer to 20 to 25 percent for medRxiv.

Inglis said numerous scientists have done some modeling based on public data, but that the preprints don’t accept those papers unless they contain additional research.

The preprint management team was “worried about the indiscriminate use of these models to guide public policy,” he said.

Additionally, the team excluded manuscripts that might be dangerous to human health or human-health related behavior. They didn’t want people to rush out and take something that, theoretically, might help, but that hasn’t received sufficient testing. A treatment might block a receptor, but also have significant side effects.

Inglis said the team of people who work at the preprints, which includes five full-time preprint-platform dedicated staff members and seven other CSHL staff with other responsibilities, including the founders, tech developers and production staff, worked seven days a week, with long working days to meet the increased need and demand.

People working on this effort “are not doing it because they are getting rich or handsomely acknowledged.” An arduous job with thousands of papers, the staff are working out of a “sense of purpose and mission,” Inglis explained.

The Chan Zuckerberg Initiative and CSHL provide financial support for these preprints. The research community has shared their appreciation for these preprints and CSHL generously acknowledges the work of the staff.

Inglis and Richard Sever co-founded bioRxiv. MedRxiv is managed by Sever and Inglis in collaboration with Professors Harlan Krumholz and Joe Ross from Yale and Dr. Theo Bloom and Claire Rawlinson from BMJ, which was originally called the British Medical Journal.

Inglis said numerous papers have become game-changers in the battle against the virus, including a study from two weeks ago in the United Kingdom on dexamethasone, a steroid that was proven effective in severe cases of COVID-19. Indeed, just recently, a Bethesda hospital became the first in the nation to use the steroid to combat the virus.

The team working in preprints at CSHL appreciates the opportunity to contribute to the public health crisis.

Inglis is pleased with how the community trusted the preprints with their work, while numerous members of the community helped screen manuscripts and provide advice about how to react to the needs of the pandemic.

Saket Navlakha. Photo from CSHL

By Daniel Dunaief

When people walk into their own home, they immediately ignore sensory cues around them. They may not notice the picture of their children on the wall, the lush leaves of the ficus plant, or the constant smell of soup that greets them when they return from work.

Similarly, animals and even flies become accustomed to cues in their environment, habituating to them so they can focus on more important signals, like the smell of nearby food or the appearance of a fly swatter.

Cold Spring Harbor Laboratory Associate Professor Saket Navlakha and his post doctoral researcher Yang Shen recently studied the way flies subtract smells from the environment, giving them the opportunity to focus instead on odors that might be more important to their lives.

In a paper last month in the Proceedings of the National Academy of Sciences, Navlakha and Shen converted the way flies use a signal filtering process to create a computer algorithm.

Navlakha explained that the tandem were using computer science to understand better a basic biological phenomenon of habituation and how it happens. “We’ve been studying background subtraction,” he said in a recent interview.

One of the applications for their work is in electronic noses. Hotels and even military departments may in the not too distant future use these systems to process odors to determine what’s in the environment.

These electronic noses detect faint signals within noisy backgrounds. Habituation enables them to remove from consideration those scents that would otherwise distract from the goal of scanning the environment for new information.

Navlakha suggested that humans, who are often a visually dominant species, are not always the best species at using a sense of smell to perceive the environment.

Saket Navlaka with his wife Sejal Morjaria, during a run in Port Washington in mid-May. Photo by Lawrence Lau

“Many other species rely on their noses as much as we rely on vision,” he said. “We don’t always have an intuitive sense of what is possible in the olfactory space. Sometimes, that limits our imagination.”

While Navlakha is not crafting sensors that can detect compounds, he is working on the computer science analogs to odor recognition and discrimination. He is exploring the kind of data analysis that would have applications in a range of fields. 

In one example, he said a sensor in an airport might be surrounded by a symphony of smells, including new pungent or even subtle toppings on pizza or even a new cologne from someone working in a watch repair store. 

The sensor might need to sift through all that data to find someone who is transferring a toxic chemical through an airport, the scent of which might be faint and almost insignificant compared with the other odors spreading through the terminal.

In a more everyday example, a sensor in the refrigerator might detect the subtle changes in odors emitted by foods that are starting to become inedible, such as an onion or cream cheese.

“You want to detect” when food is starting to turn so you can “eat it and use it” before it becomes inedible, Navlakha said. “These are the kind of problems we are exploring on the data analysis side.”

Navlakha specifically looked at the activity of Kenyon cells, which are special odor neurons. When a fly receives a new scent, about five percent of these cells turn on, developing a unique activity tag.

Once the fly becomes habituated to a smell that isn’t relevant for its survival — either to indicate the presence of food or to announce the arrival of a predator — Navlakha believes the number of Kenyon cells that make up the tag for the odor declines. While this is his theory, he said more work needs to be done to confirm these predictions.

A new odor repeats the process, bringing the fly’s attention to a new smell. The fly brain in principal can reverse the subtraction process for habituated odors if the odor becomes more rare or important for the fly’s survival. Researchers need to conduct more work to confirm this as well.

Navlakha hopes to frame the fluid process of recognizing, habituating and bolstering the signal for odors to understand how the brain is functioning.

He said the fly brain responds to smells based on two mechanisms. In the first, the fly has an innate, evolutionary behavior. In the second, the fly learns through experience. Navlakha studied the learned behaviors.

The next steps involve pushing more on the experimental front, determining the limits of odor discrimination and looking at the role of habituation.

He hopes to extend an experiment that others have done with people. Experimenters took three odors that were all relatively similar that come from three flowers. Most people could not discriminate between two out of the three odors. In an experimental group, they allowed people to habituate to one of three smells and then they had to discriminate between the other two. By subtracting out the common part of all three smells, they were more successful at decoding the difference between the others.

“We want to see if we can do this in fruit flies” while recording from a region of the fly brain called the mushroom body.

Navlakha also bought an electronic nose. Using this artificial system, he wants to test odor discrimination algorithms.

“One thing this would allow us to do is to test and validate these algorithms to see how well they perform,” he explained. “There are all kinds of tests to see what kind of power these sensors have.”

In the PNAS paper, Navlakha mostly used the literature for their biological inspiration. They discussed numerous parts of the paper with biological collaborators and including biological experiments. They did not introduce any new biological data.

He came across this literature about 18 months ago.

“We thought it was interesting because we could understand the whole series of transformations when a fly smells,” he said. He worked on how to understand the process from input to output.

During the COVID-19 lockdown, he has been spending considerably more time doing theoretical work and modeling. He and his wife Sejal Morjaria have also gotten out of the house to do some running.

As for his work, Navlakha is hoping to build on what he’s done so far and expects he will, if you’ll pardon the pun, follow his nose as the research progresses.

 

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.

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

By Daniel Dunaief

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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